Tissues:

Cell and Organ Physiology

MedBio MSI 2016
Winter MEDC-30403
Lecture Notes
BSLC 115 8:00-10:50 a.m.

Module 1
Cell Physiology
Hanck, McGehee, & Xie

Module 2
Cardiovascular Physiology
Beiser, Poston, & Sattar

Module 3
Pulmonary Physiology
Hall, Naureckas, & Sattar

TISSUES: C e l l a n d O r g a n P h y s i o l o g y 2 0 1 6
(MEDC 30403)

TIMES
Lecture 1: 08:00 - 08:50
Lecture 2: 09:00 -09:50
Lecture 3: 10:00 -10:50
ROOMS
General Lectures & Review Sessions
Histology labs
Computer Simulation Labs
Applied Physiology /Case Studies
Pulmonary Function Lab

Room: BSLC 115

Rooms: 402/406/412/416
Room: 018
CPP Rooms: 346/350/354
DCAM 5E

MODULE 1
CELL PHYSIOLOGY
JANUARY
Mon 04

08:00-08:50
09:00-09:50
10:00-10:50

Introduction to Membrane Potential

Passive and Active Membrane Electrical Properties
Electrical and Chemical Synaptic Transmission

McGehee
McGehee
McGehee

Tue 05

08:00-08:50
09:00-09:50
10:00-10:50
11:00-12:00

Neuromuscular Junction
Central Nervous System Synaptic Transmission
Receptor Signal Transduction and Second Messengers
Nerve and Muscle Histology Minilab/Review

McGehee
McGehee
McGehee
Greenwald

Wed 06

08:00-08:50
09:00-09:50
10:00-10:50

Skeletal Muscle I
Skeletal Muscle II
Cardiac Muscle

Hanck
Hanck
Hanck

Thu 07

08:00-08:50
09:00-09:50
10:00-10:50

Smooth Muscle
Episodic Disorders (video/slides see chalk site)
Loss of Function Disorders (video/slides see chalk site)

Hanck
Xie
Xie

Fri 08

08:00-09:50

REVIEW SESSION

Greenwald/
Underriner

WEEKEND
Mon 11

08:00

EXAM 1 Neuromuscular Physiology

MODULE 2
CARDIOVASCULAR PHYSIOLOGY
Tue 12

08:00-08:50
09:00-09:50
10:00-10:50

Histology of Cardiovascular and Lymphatic Systems

Overview of the Circulation/The Cardiac Pump
Cardiac Electrophysiology I

Sattar
Poston
Beiser

Wed 13

08:00-08:50
09:00-09:50
10:00-10:50

Cardiac Electrophysiology II
Cardiac Electrophysiology III
Cardiovascular Histology Minilab/Review

Beiser
Beiser
Greenwald

Thu 14

08:00-08:50
09:00-09:50

The Peripheral Circulation including Hemodynamics

Microcirculation & Intrinsic Regulation of Blood Flow

Beiser
Beiser

Fri 15

08:00-08:50
09:00-09:50
10:00-10:50

Control of Cardiac Output: Ventricular-Vascular Coupling

Autonomic Regulation of the Heart & Circulation
Pulmonary Circulation

Poston
Beiser
Poston

WEEKEND
Mon 18

MLK Day - No Class

Tue 19

08:00-10:50

Computer Simulation Lab Group 1 and 2 (Room 018)

Poston/Beiser

Wed 20

08:00-08:50
09:00-09:50
10:00-10:50

Coronary Circulation
Special Circulations
Cardiovascular Integration and Adaptation

Poston
Poston
Poston

Thu 21

08:00-09:50

Applied Physiology: Case Studies

(Rooms: 346/350/354)

Poston/Beiser

REVIEW SESSION

Greenwald/
Grubbs

Fri 22

08:00-09:50

WEEKEND
Mon 25

08:00

EXAM 2 Cardiovascular Physiology

MODULE 3
PULMONARY PHYSIOLOGY
Tue 26

08:00-08:50
09:00-09:50
10:00-11:50

Histology of Respiratory System

Respiratory System Statics I
Pulmonary Histology Minilab/Review

Sattar
Naureckas
Greenwald

Wed 27

08:00-08:50
09:00-09:50
10:00-10:50

Respiratory System Statics II

Respiratory Dynamics I
Respiratory Dynamics II

Naureckas
Naureckas
Naureckas

Thu 28

08:00-08:50
09:00-11:00

Ventilation and Diffusion

Applied Physiology: Case Discussion

Naureckas
Naureckas

Fri 29

Symposium - No Class
WEEKEND

FEBRUARY
Mon 01

08:00-08:50
09:00-09:50
10:00- 10:50

O2 and CO2 Transport

Ventilation-Perfusion Relations I
Ventilation-Perfusion Relations II

Naureckas
Hall
Hall

Tue 02

08:00-08:50
09:00-09:50

Control of Ventilation
Physiology of Exercise

Naureckas
Naureckas

Wed 03

08:30-10:50

Pulmonary Function Lab DCAM 5E

Naureckas

Thu 04

08:00-09:50

REVIEW SESSION

Jordan/
Padavil

Fri 05

8:30

EXAM 3- PULMONARY Physiology

WEEKEND

MSI 2014-15 WINTER MEDC-30403

TISSUES: C e l l a n d O r g a n P h y s i o l o g y C o u r s e

(Neuromuscular, Cardiovascular and Pulmonary Modules)

Contact Information

Course Director

Dr. David G. Beiser

703-0307

dbeiser@medicine.bsd.uchicago.edu

Dr. David G. Beiser

702-0307

dbeiser@medicine.bsd.uchicago.edu

Dr. Dorothy Hanck

702-1758

dhanck@uchicago.edu

Dr. Jesse Hall

702-1454

jhall@medicine.bsd.uchicago.edu

Dr. Daniel McGehee

834-0790

dmcgehee@uchicago.edu

Dr. Ted Naureckas

702-1856

tnaureka@medicine.bsd.uchicago.edu

Dr. Jason Poston

702-7837

Jason.Poston@uchospitals.edu

Dr. Husain Sattar

702-7278

husain.sattar@uchospitals.edu

Dr. Tao Xie

txie@neurology.bsd.uchicago.edu

Faculty

702-6390

Physiology Teaching Assistants

Dominic Catalano

Module 4 & 5

djcatalano@uchicago.edu

Martin Greenwald

Module 1 & 2

greenwald@uchicago.edu

Allison Grubbs

Module 2 & 6

agrubbs@uchicago.edu

Aubrey Jordan

Module 3 & 6

aubreyjordan@uchicago.edu

Michael Underriner

Module 1

mjunderriner@uchicago.edu

Nisha Wadhwa

Module 4

nrwadhwa@uchicago.edu

Recommended Text Books

Title:
Author:
Edition:
Publisher:

Basic Histology Text & Atlas

Junqueira et al
12th Edition
McGraw-Hill

Title:
Author:
Edition:
Publisher:

Physiology
Costanzo
5th Edition
Saunders Elsevier

Title:
Author:
Edition:
Publisher:

Medical Physiology
Boron and Boulpaep
2nd
Saunders Elsevier

Title:
Author:
Edition:
Publisher:

Wheater's Functional Histology, A Text and Colour Atlas

Burkitt, et al
5th
Churchill-Livingstone

For the cardiovascular module we also recommend:

Title:
Author:
Edition:
Publisher:

Cardiovascular Physiology
Pappano and Wier
10th
Mosby-Elsevier

Lecture Notes
Module 1
Cell Physiology
Hanck, McGehee, & Xie

McGehee

Membrane Potential &

Ion Channels
Lecture 1

Ion channels are an important class of membrane spanning glycoproteins that exist
in all cells and govern the flow of ions across membranes. In nerve and muscle they
regulate the rapid changes in membrane potential associated with action potentials and
postsynaptic potentials. Ca2+-influx controlled by
these channels can alter many metabolic
processes within cells leading to activation of
various enzymes and proteins. Ca2+-influx acts
as a trigger for neurotransmitter release.
Channels are distinguished from each
other on the basis of their ionic selectivity and
factors that control their opening and closing, a
process called gating. Ion selectivity is achieved
through interactions between the ion and
various amino acid residues that line the walls
of the channel pore. Gating involves a Figure 1 - Plasma Membrane excludes ions.
conformational change of the channel in
response to changes in membrane voltage or to the binding of ligands.
To take an ion from a polar
environment like water and move it into
a lipid environment, takes a lot of energy.
It will not happen spontaneously. The
dielectric constant of water is ~80 and
lipid ~2.
Ions in solution are surrounded by
a cloud of water molecules which is
energetically favorable. Water provides
a polar environment. The atoms reorient
in relation to the ions in solution.

Figure 2

Ion channels are basically water filled channels that span the membrane. They
provide a polar environment inside the membrane that allows ions to cross under
energetically favorable conditions.
The Na channel shown allows Na+ to enter or leave the cell, but it excludes other
ions like K+ or Ca2+. That is the channels are selective for Na+. There are also channels that
are selective for K+ ions and Ca2+ ions. Ion channels cannot select exclusively on the basis
of ion size as Na+ has a size of 0.95 D, while K+ has a radius of 1.35 D. Thus how could
you ever make a channel that would allow K+ into cells but exclude Na+?

How does selectivity between ion channels come about? Please see B. Hille, Ionic
Channels of Excitable Membranes, Sinauer Associates for a more complete description.
Ionic hydration energies are large. Ions want to hold onto their waters tightly. The heat of

hydration is defined in thermodynamics as the

increase of enthalpy as one mole of free ion in a
vacuum is dissolved in a large volume of water.
Water stabilizes the ions by orienting
appropriately. Oxygens have a partial negative
charge while hydrogens have a partial positive
2+
+
+
Ca
Na charge. Thus water is a permanent and strong
K
dipole. Hydration energy then is the stabilization
gained by orienting water molecules appropriately
and polarizing their electron clouds in the intense
local field of the ion. Needless to say, if we
dehydrate the ions, interactions with other
chemical groups (mostly oxygens within the pore)
must replace that energy. Ions do not go through
Figure 3 - A sodium Channel
the lipid membrane because the hydrophobic lipid
core does not have polar groups that interact with the ion.
Atom
Li+
Na+
K+
Cs+

Radius ()
0.60
0.95
1.33
1.69

-H hydration (KCal/ mol)

-131
-105
-85
-71

The change in free energy for the ion to enter the ion channel is equal to the difference
in energy it takes to dehydrate the ion minus the energy the ion gets from interactions with
chemical groups in the channel. Ions are not thought to dehydrate completely when entering
the ion channels. Small ions hold onto their waters of hydration more tightly as they have a
more intense electric field. (For all cations with charge of +1, the electric field strength is simply
a function of the diameter of the cationic species).
Let's say that there is an anionic site within the channels that a cation interacts with.
From Coulomb's Law (remember freshman physics that you thought you would never have to
see again), the interaction energy (per mole) between a cation and anion depends inversely on
the sum of the anionic radius (rsite) and the cationic radius (rc).

z is the charge (+1, +2 etc.) of the ion or site.

N is Avogadro's number.
e is the elementary charge.

The equation can be simplified to:

K+

Na+

Sodium which requires 20 KCal

more energy to dehydrate than
potassium would not be favored by
this channel which does not supply
a large interaction energy.

Small differences in energy give large differences in selectivity. For instance 4.2 KCal/ mole
give 1000 to 1 difference in selectivity. This energy is quite small in relation to hydration energy.

As mentioned above selectivity occurs because of the interaction between ions and
the walls of the channels. Na, K, and Ca channels are thought to have selectivity filters
within the pore region where chemical groups are arranged in such a way as to provide
selectivity for certain groups.
Ion channels exist in either conducting or non conducting states. Na, K, and Ca
channels are voltage-dependent. At a typical neuronal resting potential they are closed. As
cells depolarize they open.

Na, Ca and many types of K channels enter a refractory state after they are
depolarized for a long period. This is called the inactivated state, where the channels are
closed again, even though the membrane voltage is still depolarized. The channels can be
modeled as follows.

Closed

Depolarization

Open

Inactivated

After a period of time at the resting potential channels return from the inactivated state and
can then open again. Channels do not reopen from the inactivated state.

That electricity was involved

with living cells was discovered in
the late eighteenth century. But it
wasn't until this century that
scientists came to appreciate the
electrical nature of cells. Our
understanding was based on
physics and chemistry developed in
the 19th century by scientists like
von Helmholtz, Nernst, Sydney
Ringer and others. In 1902, Julius
Bernstein made the rather
remarkable prediction that cells
would have resting potentials.
Bernstein suggested that cell
membranes were selectively
permeable to K ions and thus had a Figure 5 - Cells have resting potentials
resting potential. They lost their
resting potentials when permeabilities to
other ions developed.
In the early 20th century scientists like Planck and Einstein were formulating new
ideas. Bernsteins's ideas were not tested directly until the 1940's when microelectrodes
were developed by Ling and Gerard. These are fine glass tubes that are drawn down to
~0.5 micon tip size that can be used to impale living cells. When the electrodes are filled
with a salt solution, they report on the potential inside the cells.
How does a resting potential for a neuron or excitable cell come about? In most cells
the resting potential is a result of the K+ gradient that exists. At rest many cells have K
channels, but not Na or Ca channels that are open.
Sometimes Cl channels are important in setting the
resting potential.
Well use a simple bath to illustrate our
concepts. First let's look at the simplest case, a
neutral substance separated into two pools. The
partition keeps the two pools totally separate so
there is no way for diffusional or any other forces to
act.
Figure 6 - A simple bath

Let's change the system and give it a new property.

We'll put a hole in the membrane that can pass this substance.

Since there is a gradient this substance will diffuse out of the high concentration pool into
the low concentration pool. If we wait long enough
the molecule will come to equilibrium in both pools as
long as no other forces are acting on it. Now let's look
at a slightly more complicated case.

Now we have two solutes, but we will give the hole a

rather remarkable property, that it can pass only one
of the solutes. X goes through the hole but Y does
not. This is a real property of ion channels. What
happens if we wait until equilibrium is reached?

This is the equilibrium condition. Now let's

go one step further and make the solute ions.

We have a pore that is permeable only to K

ions and not the Cl ions. What happens now. Well if
you come back a long time later and look into the two
pools and look at the solute concentrations you see
the following:
There is a 59 mV potential difference between
the two pools, when you put electrodes in the pools

and measure the difference.

How does this come about?

Figure 10 - 59 mV potential difference between pools.

:
:

What does this mean - Let's go back to our original condition:

Only K+ is permeable in this system not Cl-. If we start with water on both sides of the
partition and the dump in salt at time = 0 there will be no potential difference between the
two pools at first. After a while a few K molecules would move from the 100 mM KCl side
to the 10 KCl side. This would create a potential between the pools with 100 mM KCl being
negative with respect to the 10 mM KCl pool (it has more anions than cations). As more
K ions move to the low concentration pool, the potential in the high concentration pool is
made more negative and starts to attract KCl ions back into high K pool. The equilibrium
potential is that which is required to keep all the K ions in the high pool. That is the
electrical attraction exactly balances out the diffusion potential. That is what the Nernst
Equation tells you. So for our problem we get the following: Thus after a while we would
measure -59 mV between the pools. If we had 1000 mM KCl in one pool and 10 mM KCl
in the second pool, we would measure -118 mV of potential difference between the pools.

We would measure -59 mV, with the 100 mM KCl pool being negative.
If we had 1000 mM and 10 mM we would measure -118 mV.

How much charge separation

does it take to get these
potentials. In a cell that is ~10
:icrons in diameter it takes
about 106 or 107 ions out of
1011 ions in the cell so it's a
small charge separation.
So we can get a cell
potential. And at -59 mV the
pools are at equilibrium, they
will stay like that forever and
not run down. What are real
cells like?

What is the resting potential in

this cell? Ignoring Ca2+ because
for the moment that adds a
needless complication, we can
use the Goldman-Hodgkin-Katz
Eqn.

With his equation you can

predict the resting potential under
a variety of conditions. The P's
are permeabilities. If the P's for Na and Cl are low then the equation reverts to the Nernst
equation that we discussed before.

For instance at rest the permeability for K is very high and so the resting potential
of the cell is near the K reversal potential. Typically resting potentials are set by K
channels. In some neurons resting potentials are set by Cl channels that are open. During
an action potential the permeability to Na rises dramatically so the peak of an action
potential approaches the reversal potential for Na.

In neurons a typical
resting potential is -55 to -70
mV. The resting potential is
usually set by non-gated
channels that are open all of
the time. The highest
permeability is to K+ ions but
there is sometimes a small Na+
ions as well. The resting potential is that potential where K+ efflux is balanced by Na+ influx.
The reason that there is movement of ions is that the cells are not at equilibrium for either
K+ ions (-75 to -80 mV is typical reversal potential) or for Na+ ions (+55 mV is typical
reversal potential). When the cell is at rest, the passive flux of Na+ and K+ into and out of
the cell are balanced by active transport driven in the opposite direction by ATP-dependent
Na-K pump.

At rest the steady Na+ influx through non-gated channels is balanced by the steady
K+ efflux, so that the membrane potential is constant. This steady state balance changes
when the cell is depolarized
enough to trigger an action
potential. A transient depolarizing
potential, such as an excitatory
synaptic input causes some
voltage-gated Na channels to
open and the resulting increase in
membrane permeability to Na+
allows Na+ influx to outstrip K+
efflux and depolarize the cell.
Positive charge builds up inside
the cell. As they depolarize more
Na channels open. This causes
more voltage-gated Na channels
to open, which produces a larger
Na+ influx etc. This regenerative
positive feedback cycle develops
explosively driving the membrane
potential to near the Na+
equilibrium potential (+55 mV).
Because of K+ efflux, the Na+
Figure 15 - Na, K and Cl fluxes at rest.
reversal potential is never quite
reached. Typical neuronal action potential reaches +15 mV to +45 mV.
Two processes repolarize the membrane terminating the action potential. Na
channels inactivate decreasing permeability to Na+. Second, voltage-gated K channels
open after a lag. K+ efflux increases which repolarizes the membrane.

The Goldman-Hodgkin-Katz equation predicts all these different behaviors.


In squid axon which has a large action potential at rest
PK:PNa: PCl 1/.04/.45
At the peak of the action potential:
PK:PNa: PCl 1/20/.45

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Passive Properties of Neurons

Lecture 2

McGehee

Passive Membrane Properties:

When currents flow into cell, the membrane voltage changes more slowly.
Im = Ii + Ic

Im is total membrane current

Ii is ionic current
Ic is capacitative current
Current flows through resistor and to charge capacitor (which is the plasma membrane).
V = Q/C

Lipid bilayers with ion channels have

both resistance and capacitance. A
typical cell membrane can be
modeled as a resistor in parallel with
a capacitor. For this circuit if we give
a constant current step we see the
following (Fig 1).
Time Constant :

Vt = V(1-e-t/RC)
=RC
is the time required to reach 0.63 V
Vt voltage at time point t
V voltage at steady state
R membrane resistance
C membrane capacitance

Figure1:Membranecapacitanceslowschangesin
membranepotential(Vm)

The size and shape of synaptic

potentials is dictated by the number of
ion channels open (R) and the
capacitance of the membrane (C).
Now we need to consider what
happens to that change in voltage as it
moves through the cell. With any
conductor, including copper wires
voltage signals decay over distance.
Depolarization to a threshold potential
is required to initiate an action
potential. Action potentials are
frequently initiated in the initial
segment, also called the axon hillock.

Figure2:Synapticinputsdecayoverdistance,which
determineswhetherthecellwillfireanactionpotential.B
showsthethresholdpotentialatdifferentlocationsina
neuron.Thelowthresholdattheaxonhillockisdueto
thehighdensityofvoltagegatedNachannels

For a capacitor to change voltage charge needs to be delivered.

V= Q/C

Where V is the voltage change

Q is the charge that need to be delivered
C is the capacitance

Thus as ion channels open and current flows membrane voltage changes only as capacitor
is charged. The typical membrane time constants are 10-50 msec.

Figure 3 - Importance of membrane time constant.

J=RC. When ion channels open at synapses the resistance falls and therefore J
becomes small and the current rises quickly. The large current induced by the ion channel
activation delivers the charge required to charge up the membrane capacitor quickly. When
channels close the membrane resistance goes back to resting levels, which is quite low,
and J approaches resting passive properties i.e. it becomes long (small number of ion
channels open, long J meaning it takes a long timee to charge membrane capacitor.
Neurons have irregular and often elongated shapes . They have different channels
in different regions. Currents propagate passively unless a threshold is reached and an
action potential is initiated. If one looks at the axon its basically a long tubelike structure
designed to carry an electrical
signal.
Each segment of the axon
or dendrite can be modeled as a
resistor in parallel with a
capacitor. If current is injected into
a neuron the voltage changes. If
you measure the voltage along
the axon you find that it
Figure 4 - Equivalent circuit for a dendrite.
diminishes exponentially (as long
as the voltage change is not large enough to produce aaan action potential).

it characterizes how far the voltage will spread. The length constant is defined as the
distance along the dendrite to the site where Vm has decayed to 1/e or 37% of its initial
value.

Larger processes have longer space constants.

Rm is the resistance of the membrane

Ra is the resistance of the cytoplasm.

Figure 5 - Decay of injected current as a function of distance.

As current is injected at location 0 it produces a voltage. The voltage decrements

with distance.
The better the insulation of the membrane the higher is Rm and the longer 8. Current
can spread further long the inner conductive core (cytoplasm) before leaking across the
membrane. In the absence of channel channel activity 8 is 0.1 - 1 mm.

Passive spread current is called

electrotonic conduction. The length
constant affects spatial summation, the
process by which synaptic potentials
generated in different regions of the
neuron are added together (at the trigger
zone aka the initial segment). For a cell
with a short length constant, synaptic
potentials that are initiated at the distal
end of dendrites will diminish
considerably as they are passively
conducted to the trigger zone. If so they
contribute relatively little to summation:
Channels shape subthreshold voltage
response (by changing membrane
resistance) and provide the mechanism
for action potential and propagation.
Both Na and Ca channels can initiate
action potentials. K currents help shape
Figure 6 - Space constant.
the action potentials (ie. terminate) and
determine membrane excitability but are not strictly necessary for action potentials.
Due to the short space constant the signal is dramatically attenuated at the bottom
synapse but not the one on top.
For the case where threshold is
reached at the trigger zone, an
action potential is initiated. What
happens then?
Lets look at the case where we
inject a current into the middle of
an axon to produce a voltage
change.
To get the maximum response
possible from the nervous system
as well as increasing
computational ability we want to
increase the speed of conduction.
One way to increase speed of
Figure 7 - Space constant affects signal conduction.
propagation is to make giant
nerve fibers. The passive spread of depolarization is the rate limiting step in the
propagation of an action potential.
An action potential generated in one segment of membrane supplies depolarizing
current to the adjacent membrane, causing it to depolarize toward threshold. The larger the
axoplasmic resistance Ra the smaller the current flow and thus the longer it takes to
change the charge on the membrane of the adjacent segment.

Remember that V=Q/C

If the current is small it takes a long time to deliver the

charge.
Also the larger the capacitance
the more charge must be
deposited to produce a change in
membrane potential. Therefore
the time for electrotonic spread is
given by both Cm and Ra. If the
product of Cm*Ra is reduced
passive spread speed will
increase. Therefore speed is
inversely related to Cm*Ra.
If we make giant nerve fibers Ra
decreases in proportion to the
square of the axon diameter while
the capacitance (Cm) increases
linearly with diameter. The net
effect is a decrease in Cm*Ra. This
adaptation is carried to the
extreme in the giantt axion of the
squid which is ~1 mm in diameter.
Because this axon carries the
signal for the squid escape
response to danger it needs to be
fast.

A second mechanism for

Figure 8 - Action potential propagation.
increasing conduction velocity by
reducing C m *R a is called
myelination, the wrapping of glial cell membranes around axons. This process is
functionally equivalent to increasing the thickness of the membrane by 100 fold.
Capacitance of a parallel plate capacitor is inversely proportional to the thickness of the
insulating material. As Cm decreases so does Cm*Ra. Myelination is much more effective
than increasing the diameter of axons. Conduction in myelinated axons is faster than in
non-myelinated axons of the same size, usually much faster.

Figure 9 - Conduction speed.

Figure 10 - Action potential propagation.

The length constant of the axon, 8, increases. As Cm goes down so does the
membrane time constant J (the amount of charge required for the membrane capacitance
goes down because the capacitance goes down remember V=Q/C . V stays constant
as C decreases so does Q. As the effective surface area decreases the metabolic cost of
an action potential decreases as well.
There are bare patches of membrane where myelination is interrupted. Myelination
interferes with the normal regenerative mechanism of an action potential. Action potentials
are typically triggered on the bare membrane of the axon hillock. Because the resistance
of the membrane is high, the currents spread for long distances (myelination increases
membrane resistance). The diminution of the current is not that much. Current reaches the
next patch of bare membrane, called the node of ranvier, where it initiates an action
potential. Myelin is interrupted every 1-2 mm for a node. The bare patches of membrane
are only 2 microns in length, but contain a very high density of Na channel and can

generate an inward Na current. The nodes thus boost the action potential which would die
out even with such a long space constant. In a typical neuron ~5 nodes are active during
the rising phase of an action potential.
The action
potential spreads
quite rapidly along
the internode due to
the low capacitance
o f t h e m ye lin
sheath. Action
potentials slow
down as they cross
t h e
h i g h
capacitance nodes.
Thus
a c t i o n Figure 11 - Nodes of Ranvier.
potentials appear to
jump between nodes. This process is called saltatory conduction.
Several diseases of the nervous system such as multiple sclerosis cause
demyelination. The lack of myelin slows down the conduction of the action potential and
can devastating effects on
behavior. In the demyelinated
regions action potential
propagation. Sometimes action
potential propagation is blocked.
Myelination is extremely
important for making a brain that
responds rapidly, but without
making it huge (as would be the
case if all neurons had giant
axons).

Figure 12 - Action potentials are regenerated at nodes.

Major points:
Passive properties of cells
Time constant
Space Constant
Myelination

Introduction To Synapses:
Electrical Synapses and
The Neuromuscular Junction
Lecture 3
McGehee

Synapses are specialized zones of contact between cells. Each CNS neuron receives
about 1,000 synaptic inputs, although some neurons receive many more.
Synapses can be electrical or chemical in nature. In the brain chemical synapses
are much more common. Electrical synapses are not as plastic as chemical synapses.
Electrical synapses dont show inhibition or long-lasting changes in efficacy. Chemical
synapses are quite plastic. Transmission can be modified dramatically.
Distance between pre- and post-synaptic membrane:
Electrical - 3.5 nm
Chemical - 30-50 nm

Electrical synapses show cytoplasmic continuity between pre- and post-synaptic cells.
Continuity established by gap junction channels. There is almost no synaptic delay in
electrical synapses. Transmission is usually bidirectional but sometimes rectification is
observed. Electrical synapses work best when pre-synaptic cell is same size or larger
than post synaptic cell.

Some electrical synapses rectify. That is they show electrical transmission in only

one direction.
For speed nothing beats a gap junction
synapse. In fact, the two neurons (preand post-synaptic) function almost as if
they were one cell. Gap junction
channels are found in cells that come
into contact with each other with gap
junctions frequently forming between
these cells. Gap junctions channels
couple these cells electrically. For
instance heart cells are coupled by gap
junction channels so they contract
synchronously. Gap junctions have a
large single channel conductance of
100 pS (1 pS = 1/1012 ohms). Gap
junction channels are usually open but
can be closed by their cytoplasmic
environment. They can be modulated
by pH, Ca2+, or by second messenger
systems activated by
neurotransmitters. Low pH or elevated
Ca2+ frequently close gap junction
channels (conditions that exist when
cells are damaged). Gap junction
channels that rectify (pass current
primarily in one direction) are voltagedependent. That is voltage will open or
close the channels depending on the
voltage.
Gap junction
channels are
formed when two
hemi-channels
(called hemigaps) come
together. The
channels meet in
the gap between
the two
membranes and
come together to
form a channel.
The
communicating
channels is ~ 1.5
2.0 nm
diameter hole that
connects the
cytoplasm of the
pre- and postsynaptic cells.

Each hemi-gap is called a connexon. Each connexon is made up of six identical protein
subunits called connexins which are each 75 in length. The six connexins come
together to form a hexagon. Gap junction channels are part of a gene superfamily. Even
though there are many connexons each member of this family has a lot of similarities.
All seem to have similar four hydrophobic domains that are probably membrane
spanning. Two extracellular domains that are thought to be involved in the hemi-gaps
recognizing each other to form complete gap junctions channels. The cytoplasmic
regions vary greatly which is why there is a lot of variability in how they respond to
modulatory agents (pH, Ca2+, kinases etc.). Gap junction channels are very important in
many cells for allowing communication between cells especially developmental or
regulatory signals. Compounds with molecular weight up to 100 can pass through gap
junction channels i.e. things like cAMP.

Chemical Transmission:
Synaptic clefts are normally wider than normal extracellular space around
neurons. Morphologically synapses are clear. The pre-synaptic region is filled with
vesicles containing neurotransmitter. In response to an action potential,
neurotransmitter is released into synaptic cleft, diffuses across the cleft and then binds
to receptors on the post-synaptic side where it exerts an effect, frequently opening or
closing an ion channel. Neurotransmitters also activate receptors that are not directly
linked to ion channels but rather activate second messenger machinery inside the postsynaptic neurons. Because of this sequence there is a synaptic delay (which can be as
short as 0.3 ms). Chemical transmission can amplify signals. Since each pre-synaptic
vesicle can contain thousands of molecules of neurotransmitter thousands of ligandgated ion channels can be opened. Thus in this system a small pre-synaptic neuron
can activate a large post-synaptic cell. Most neurons have pre-synaptic nerve terminal
active zones, but often neurotransmitter release occurs from regions that cannot easily
be identified as active zones. Frequently the same chemical neurotransmitter can have
multiple effects depending on the receptor it binds to.
ACh can be excitatory or
inhibitory depending on the neuron where it acts and the receptor to which it binds. For
instance at the neuromuscular junction, ACh opens nicotinic ACh receptors and
depolarizes the post-synaptic cells initiating action potentials i.e. it's excitatory. The
heart has muscarinic ACh receptors. ACh releases on the heart activates potassium

channels which makes the cells

very non-excitable. In fact, ACh
can almost completely stop the
heart from beating by activating
the muscarinic receptors.
Sympathetic neurons have a
different type of muscarinic ACh
receptor than does heart.
Activation of this receptor
inhibits a type of K channel
(called M channels). After the M
channels are inhibited the cells
become hyperexcitable. Very
small synaptic inputs cause
these cells to fire action
potentials. In the examples
listed above ACh has three
different effects on postsynaptic cells, dependent on
the post-synaptic neuron.
[ACh receptors have been
grouped into nicotinic or muscarinic classes depending on whether nicotine or
muscarine acts as an agonist at these receptors. So far 5 different muscarinic ACh
receptors have been identified and 9 nicotinic receptors].

As
mentioned above, receptors at synapses are of two types. Some receptors are
ionophoric. That is after they bind a neurotransmitter, an ion channel, which is part of
the receptor, opens. These receptors include, nicotinic ACh receptors, GABA receptors,
glycine receptors, and glutamate receptors. These receptors include both the
neurotransmitter recognition site and the ion channel. Ionophoric receptors have several
subunits that come togther to make the receptor. The total protein is quite large.
Responses to neurotransmitters are very rapid (millisecond time scale).
Other types of receptors are not ionophoric. Rather they couple to second messenger
systems inside the cell, rather than opening an ion channel directly. These receptors
include noradrenaline, serotonin and dopamine. These receptors are separate from ion

channels and communicate via GTP binding proteins

and second messenger cascades. Second
messenger linked receptors are single polypeptide
subunits. Responses are manifested much slower
(seconds to minutes). Responses can last for many
minutes or if the second messengers activate
transcriptional machinery, effects can last for days of
weeks. Rather than direct effects, second
messenger receptor activation produces modulatory
responses changing neuronal excitability.
Modulatory synaptic pathways often serve as
reinforcing stimuli in learning.
One of the best studies synapses is the
neuromuscular junction because it is easy to study
both the anatomy and physiology. Single muscle
fibers are usually innervated by one motor axon. The
neurotransmitter released in ACh which binds to
post-synaptic ionophoric nicotinic ACh receptors.
The motor neuron innervates a specialized region of
the

muscle called the end plate . The

motor axon loses its myelin coat near
the end plate and splits into fine
branches about 2 :m in diameter. At
the end of the branches are
varicosities called synaptic boutons
which lie over depressions in the
membrane called junctional folds. The
folds are lined by basement membrane
a network of connective tissue that
covers the muscle fiber. Both pre- and
post-synaptic cells secrete proteins
into the synaptic clefts and junctional
folds. The basement membrane brings
the appropriate pre- and post-synaptic
structures into register. The boutons
contain all of the machinery necessary
for release - active zones, synaptic
vesicles filled with ACh, and Ca
channels which trigger the release.
Ca2+ entering the pre-synaptic cell
during an action potential causes
synaptic vesicles to fuse with the
membrane at the active zone and
triggers release. Cleft is ~100 nm wide.

Active zones are

positioned opposite postsynaptic junctional folds. At the
top of the fold is a geometric
lattice of ACh receptors with a
density of ~10,000 receptors
per micron2. Each receptor is
about 8.5 nm in diameter. Near
the bottom of the folds Na
channel convert the end plate
potential to an action potential.
When the motor axon is
stimulated action potentials
invade the synaptic boutons,
Ca channels open Ca2+ enters
the pre-synaptic cells causing
fusion of vesicles with
membranes.
ACh binds to the postsynaptic membrane and
causes an end-plate potential
(excitatory). Usually a synaptic
potentials of ~70 mV is
produced by a single motor
neuron, enough to trigger an
action potential. In the
CNS most synaptic
potentials are ~1 mV,
thus many synapses
must activate to initiate
an action potential.
Synaptic
potentials are largest
at the site of initiation
and propagate away
passively, unless an
action potential is
initiated. Synaptic
potentials rise rapidly
and decay more
slowly. Once released
ACh diffuses across
the cleft rapidly to the
receptors. Not all ACh
molecules find the
receptors due to
hydrolysis by acetylcholinesterase and diffusion out of the cleft. Decay of current is due
to time course of binding ACh. The current increase is more rapid than change in

voltage due to the capacitance of membrane. It takes time for current to charge cell
capacitor. The ACh released does not stay in cleft long at all due to hydrolysis and
diffusion out of cleft.

ACh esterase
ACh 666666666666666666666 acetate and choline.
The choline is taken up by the pre-synaptic nerve terminal via a high affinity
uptake system.
When the ACh receptor opens it is permeable to both Na and K.
In voltage clamp experiments the reversal potential was found to be ~ 0 mV. No ions
known reversed at 0 mV, so it was thought that the ACh receptor channels must be
permeable to more than one ion.
INa = gNa * (Vm - ENa)
IK = gK * (Vm - EK)
IEPSP = gEPSP * (Vm - EEPSP)
INa + IK = 0 at the reversal potential
gNa * (EEPSP - ENa) + gK * (EEPSP-EK) = 0

If gNa=gK then EEPSP = (ENa + EK)/2

gNa/gK = (EEPSP - EK)/(ENa - EEPSP)

EK=-100 mV

Therefore gNa/gK = 1.8

ENa=+55 mV
In fact many cations go
through the channel because it is
so large but the main ones are Na
and K. Anions don't go through
because there are rings of negative
charge lining the channel. The
channel allows K to leave the cell
and Na to enter to enter the cell.
Nicotinic ACh receptor
channels are not selective among
cations, but anions do not go
through the channel. They are not
capable of producing regenerative
responses like Na channels. The
muscle ACh receptors are blocked
by "-bungarotoxin.

To repeat:
Presynaptic action potential 6
presynaptic Ca2+ influx 6 ACh
transmitter release 6 Diffusion of
ACh across cleft 6 opening of post-synaptic ACh receptor channels 6 End plate potential
(epsp) 6 Na channels open 6 action potential propagated in postsynaptic cell.
In the late 1970's
the technology to study
single ACh receptor
channels open and
close was invented.
Using patch-clamp
techniques we can
measure the
elementary currents.
When ~200,000 ACh
receptor channels open
we get the end plate
potential. At -90 mV the
current through a single
channel is about 2.7 pA
(10-12 amps), so the
single channel
conductance is ~ 30 pS. The channels open and close randomly. The mean open time is ~1
millisec. During a typical 1 millisec opening of one ACh receptor channel ~17,000 Na ions
rush into the cell. The reversal potential for the unitary current is the same as for the total end

plate current.

EEPSP = N x p0 x ( x (Vm - EEPSP)

N is the total number of ACh receptor channels activated.
p0 is the percentage of time the activated channel spends open
( is the conductance of the unitary channel
(Vm - EEPSP) is the driving force on the ions
Thus the end plate current depends on the total
number of end plate channels, the probability that the
channels are open, the conductance of the open channel
and the driving force. The probability that the channels are
open depends on the concentration of ACh. Each channel
opening cause about 0.3 :V of depolarization. The rapid
rising phase of the EPSP is due to the nearly synchronous

activation of ~200,000 ACh receptor

channels. The ACh concentration
falls in less than 1 ms due to
hydrolysis and diffusion of the
neurotransmitter. The ACh receptors
start to close and current goes down.
The apparent smooth decay of the
current is due to the closing of
thousand so f channels at random
intervals, each contributing a small
step of current.
At rest (-90 mV, for muscle) the ACh receptors open. Since we are near the potassium
reversal potential not a lot of potassium leaves the cell. Since we are far from the sodium
reversal potential a lot of sodium enters the cells and the cells depolarize (positive charge
enters the cell so inside of cell becomes more positive). As the cell depolarizes and reaches
0 mV the sodium influx matches the potassium efflux and so the potential is stable at 0 mV.

Nicotinic ACh receptors

are made up of 5
subunits . There are
two ", one $, one (,
and one *.
Molecular weight of
each subunit
" - 40,000
$ - 48,000
( - 58,000
* - 64,000
Total is 275,000. The "
subunits bind the ACh, thus 2 molecules of ACh need to be bound before the channel opens.
"-bungarotoxin binds to the " subunit as well. The subunits
are encoded by 4 distinct but related genes. 50% of amino
acids are identical or conservatively substituted, suggesting
that the function of all 4 subunits are similar. It's thought
they're all
derived from a common ancestor gene. It's thought that
there are 4 membrane spanning subunits per subunit, M1 M4.
It's thought that M2 and the segment connecting M2 and M3
lines the channel. Amino acid sequence suggests that
subunits are symmetrically arranged around a central pore.
Cation selectivity is achieved through rings of negative
charge that flank the M2 region (mostly glutamate residues).
There are negatively charged rings at both the cytoplasmic
and extracellular side of the channel. These tend to
concentrate cations near the channels and repel anions.
Replacing negative charges with neutral amino acids
reduces single channel conductance. About 6.0 nm of the
channel extends above the membrane bilayer. At the
external surface the channel has a wide mouth of ~2.5 nm in
diameter. Within the bilayer the channel narrows abruptly.
This is where M2 is thought to line the channel. The narrow region is quite short ~2.5 - 3.0 nm
in length corresponding to the length of M2 and the hydrophobic core of the bilayer. As the
channel emerges from the inner surface of the bilayer it widens again. Therefore there are
three regions to the channel. A large entrance, a narrow transmembrane pore and a large
internal membrane portion.

Major topics:
Electrical Synapses
Chemical Synapses
Neuromuscular Junction
Nicotinic ACh receptors

Synaptic Transmission in the CNS

Lecture 4
McGehee

Signaling in the CNS is more

complicated than at the neuromuscular
junction. CNS neurons get thousands of
inputs both excitatory and inhibitory
mediated by different receptors. Some
receptors are coupled to ion channels,
while others are coupled to GTP binding
proteins and second messenger
cascades. Few synaptic inputs in the
CNS give large enough PSPs to initiate
action potentials by themselves. Many
synaptic signals must summate to get
an action potential. The central neurons
must integrate a diverse set of inputs
into a coordinated response.
For instance:
This simple circuit simultaneously
excites the quadriceps while inhibiting
the hamstring so that only one system
works at any given time. If we stimulate
a single DRG cell body all we get is ~0.3
mV of depolarization in the motor neuron. A lot of DRG neurons need to activate
simultaneously to fire the motor neuron. Even if there are sufficient excitatory inputs to fire the
cells, inhibitory inputs can keep cells from firing.
In the CNS excitatory
transmitters open ion channels
permeable to Na and K. These are
the glutamate receptors.
The size of an EPSP is:
VEPSP = IEPSP/gm
Because most transmitter
gated channels are voltage
independent, the number of channels
activated depends on the
concentration of neurotransmitter.
IEPSP = gEPSP x (Vm - EEPSP)
As the cell is made more negative the
driving force increases.
Most neurons have a resting potential
in the range -55 to -70 mV.
The threshold for firing an action

potential in central neurons is quite low, usually

between -55 and -50 mV.
There are three different types of glutamate
receptors, defined on the basis of the
pharmacological agonist that activates the receptors,
and each one is in fact a family of receptors. The
major excitatory action in the CNS is produced when
glutamate binds to kainate and quisqualate
receptors.
1. AMPA/ Kainate (also called non-NMDA)
2. NMDA receptor
3. Metabatrophic glutamate receptor
AmpA/ Kainate areceptors are permeable to
both Na and K. Some of these channels are
permeable to Ca2+ as well. Both receptor channels
are low conductance.
Metabatropic receptors are linked to second
messenger cascades via G-proteins

(phosphoinositide cascade) and not to ion channels

directly.
NMDA receptors (N-methyl-D-aspartate) are
another type of glutamate receptor that is directly
linked to a high conductance (50 pS) ion
channel. Pore is permeable to Na+, K+, and Ca2+.
The channel is selectively blocked by APV
(aminophosphonovalerate). The channel is also
blocked by PCP, and probably represents the main
locus of action of PCP in the CNS.
Although NMDA receptors are ligand gated
channels they show many of the properties of
voltage gated channels. Near the resting potential (65 mV), the channels are blocked by the Mg2+
present in CSF. The channels are thus non
conductive even though they have bound agonist
(NMDA or glutamate). As the cell is depolarized 2030 mV by the activation of different excitatory
receptors, the voltage forces the Mg2+ out of the
NMDA receptor channel and it becomes conductive
to Na, K and Ca2+. Therefore the channels need both voltage and ligand to open effectively.

At the single channel level the

following is observed.
AMPA/ kainate receptors are
responsible for the most rapid EPSPs
produced by glutamate. NMDA
receptors turn on more slowly than
do AMPA receptors so it provides the
late current in the EPSP, if the EPSP
is large enough to unblock the NMDA
receptors. The early fast current
observed is due to AMPA receptors.
Ca2+ entry via NMDA
receptors is important for activating
Ca2+-dependent second messenger
cascades, which are important in triggering long-term biochemical changes leading to
modification i.e. memory.
Excessive amounts of
glutamate are toxic to neurons.
Glutamate is the major excitatory
transmitter in the brain. Almost all
neurons have receptors for it.
Nonetheless, prolonged exposure
to glutamate produces neuronal
cell death. In fact after tissue
cultured neurons are exposed to
glutamate briefly, many die. Most of
the effect is due to Ca2+ entry via
NMDA receptors. Ca2+-dependent
proteases are activated and Ca2+
entry leads to increased production
of toxic free radicals. Glutamate toxicity contributes to the neuronal cell death observed after
stroke, persistent epileptic seizures and in degenerative diseases like Huntington's chorea.
Agents that that block NMDA receptors may protect
against the toxic effects of glutamate and are being extensively tested worldwide. Other
glutamate antagonists are neuroprotective as well as are anti-oxidants.
In most central neurons inhibitory neurotransmitters open Cl- channels. These
channels represent the target molecule for many drugs active in the CNS. About half of the
synapses in the CNS are inhibitory. If inhibitory synapses are blocked animals go into
convulsions. The other inhibitory channels in the CNS involve K channels. Remember that EK
is ~ -80 mV and ECl is ~ -70 mV. Therefore when each type of channel is activated the cell
potential is kept near the reversal potential for that ion.

In some cells the

resting potential is at
ECl, therefore when Cl
channels open there is
no change in potential.
But the Cl channels
opening shunts
excitatory inputs and
clamps cell at ECl.
VEPSP = IEPSP/ gm
IEPSP depends
on the driving force on
the excitatory input
and the concentration
of neurotransmitter (i.e. how many channels are opened). As we make gm larger (ie. by
opening GABA receptor channels), there is a smaller change in VEPSP and now threshold is
no longer reached. Thus activating Cl- channels makes response to excitatory inputs smaller.
To repeat: Normally when glutamate receptors are activated neurons depolarize to 0 mV.
When GABA receptors are activated neurons want to stay at -70 mV. When both are open
the potential reached is somewhere between the two, but frequently not depolarized enough
to reach threshold for an action potential.
The opening of Cl or K channels inhibits neurons in three ways.
1) Neurons are hyperpolarized and moved away from threshold,
2) By increasing conductance
the cell is clamped near the
reversal potential of the
inhibitory ion.
3) The increase in membrane
conductance shunts the
EPSP.
Cl channels are
frequently not influenced by
voltage (there are some
voltage-dependent Cl
channels). Cl channels are
usually activated by GABA or
glycine (spinal chord and
brain stem). Both
neurotransmitters open similar Cl channels. GABA receptors are locus of action for
benzodiazepines (valium and librium) and barbiturates.
GABA receptors, glycine receptors & glutamate receptors are multisubunit
transmembrane proteins that link the receptor and the ion channels together. GABA

receptors have at least three subunits

", $, (. All three bind GABA although
the " subunit does so with the highest
affinity. ( binds barbiturates. " and $
bind benzodiazepines.
GABA and glycine are similar
to Ach-activated channels. They have
4 transmembrane segments (M1, M2,
M3, M4). AMPA receptors are similar
with 4 transmembrane segments but
have almost no sequence homology
with ACh receptors. GABA and
glycine are 35% - 40% similar and
about 15% - 20% to ACh receptors.
The M2 region of GABA and glycine
receptors also lines the pore but
contains basic amino acids (arginine
and lysine) so it has poitive rings of
charge and thus attracts Cl and
repels cations.
All voltage and ligand-gated channels are thought to arrange subunits around a core to
form a gated water filled pore. The switch
from close to open is
thought to involve a slight tilting of
subunits and not radical realignment.
Different signals activate different
channels. K channels that are always
open generate the resting potential.
Voltage-gated K channels
repolarize the membrane during an action
potential. Second messenger gated K
channels can hyperpolarize the
membrane in some inhibitory synapses.
Excitatory and inhibitory signals
are integrated in a common trigger zone,
in interneurons and motor neurons, called
the axon hillock. This region has the most
Na channels per unit area and thus has
the lowest threshold for activity. Neurons
can have thousands of inputs. Some
inputs at at tip of apical dendrites, some on proximal dendrites and some on cell bodies
(soma) etc. At the axon hillock all of the signals are integrated. 10 mV of depolarization will

frequently produce an action potential.

At the cell body 30 mV of depolarization
is required to produce an action
potential.
Some cortical neurons have
trigger zones within the dendritic tree.
Ca2+ action potentials can be observed
in the dendrites of cortical neurons.
Then these action potentials are
passively conducted to the cell body
and axon hillock. Integration of signals
is not just the linear summation of
signals (although inear summation is
important).
Time constant and space
constant are important properties for
summation. Signals are propagated or
not depending on the passive properties
of these neurons.
Synapses can be axo-axonic,
axosomatic or axodendritic (spines or
shafts). Dendro-dendritic and
somasomatic synapses are found but
they are relatively rare. Proximity of the
synapse to the trigger zone is important
in determining the effectiveness of the
synapse. The closer it is the larger the
effectiveness. Synapses on cell bodies
are often inhibitory, where they will have
the greatest effect.
Synapses on dendritic spines are
often excitatory (they use glutamate).
Every spine has at least one synapse. In
hippocampus the spines have
NMDA receptors which Ca2+ into the
spines. Spines also have lots of Ca2+/
calmodulin kinase, which can be
activated by Ca2+ entering postsynaptic
cell via NMDA receptors.
Synapses on axon terminals (axo-axonic) indirectly affect activity of post-synaptic cell
by controlling amount of transmitter released.

Many central neurons

have 20-40 main dendrites
that branch into even finer
processes. Each branch has
two sites for synaptic input,
the shafts and the spines.

Most AMPA receptors are not permeable to Ca2+.

But there are exceptions. If the AMPA receptor
does not contain any GluR2 subunits then it is
Ca2+-permeable, or if all the subunits were not
edited it is Ca2+ permeable. The editing replaces a
glutamine with an arginine. Even a single subunit
containing arginine prevents Ca2+ flux through the
receptor.

Major topics:
Central Nervous system synapses
Glutamate synapses - excitatory
GABA/ Glycine synapses - inhibitory
spatial and temporal summation

Fox

Synaptic Transmission Mediated by Second

Messengers
Lecture 5
McGehee

Receptors gate or modulate channels indirectly. Most operate via GTP binding protein
intermediates called G-proteins. Family includes "- and $-adrenergic receptors, most serotonin
receptors, dopamine receptors, muscarinic ACh receptors, GABAB receptors, receptors for
neuropeptides, metabotropic glutamate receptors, odorant receptors, rhodopsin etc.
As mentioned above these receptors are linked to G-proteins (there are also receptor tyrosine
kinases). These are proteins that take signal, a conformational change in the receptor, and carry it into
the cell to activate a transducer (the G-protein). These activate effectors. Frequently the effector is a
second messenger system itself (i.e. cAMP, cGMP etc.). This activates a biochemical cascade
resulting in phosphorylation or release of intracellular Ca2+ stores. In some instances G-proteins or
second messengers (cAMP, cGMP) can act directly on an ion channel or other final effector. These
second-messenger linked receptors produce effects which are usually slow. The onset of effect is
usually slow (tenths of seconds to minutes). The effects of activating the receptors can last a long
time. Contrast this to the neurotransmitters that directly gate ion channels i.e. nicotinic ACh
receptors, glutamate receptors, GABAA receptors. There onset of effect is frequently less than one
msec and effect may last for ~10-100 ms. Many different receptors couple to the same second
messenger cascade. For instance, $-adrenergic receptors, CGRP receptors, D1-dopamine receptors,
and A2 adenosine receptors all usually activate the cAMP second messenger system.
These receptors have seven transmembrane
RECEPTOR
segments and activates a G-protein (see Fig. 2).
GProtein

Direct
Effect
Direct
Effect

2nd Messenger

Ion
Channel

Biochemical
Cascade

Figure 1- Multiple effects of receptor

activation

Figure 2 Receptors have 7 TM segments

Figure 3 cAMP cycle

$-adrenergic receptor couples to the G-protein GS to activate adenylyl cyclase to increase activity of
the enzyme, resulting in increased cAMP production which then goes on to activate protein kinase A.
cAMP is a water soluble second messenger system which can diffuse within the cell. Therefore it can
act at a distance from where it is made.
G-proteins are not integral membrane proteins. They are associated with the inner leaflet of the
plasma membrane. G-proteins are heterotrimeric molecules, that is they are composed
of three different subunit proteins called ", $, and ( There are at least 15 different " subunits of Gproteins known so far and these couple to different membrane receptors (5 and 14 ) . Sometimes Gproteins work on opposite sides of a reaction. For instance "-adrenergic receptors or certain
muscarinic receptors activate the G-protein called Gi which acts in an antagonist fashion to GS.

The G-protein concentration in the brain is very high,specially concentration of the G-protein
called GO. Certain naturally occurring toxins target G-proteins to produce their effects. GS is
permanently activated by cholera toxin (which is the first step in the pathogenesis of cholera). In
contrast the G-proteins called Gi and Go are inactivated by pertussis toxin, which causes whooping
cough. Fewer $( subunits exist and these are more tightly coupled to the membrane. G-proteins
amplify the signals arriving at the receptors as one activated receptor can activate many G-proteins.

Fig. 4 Activation of Protein Kinase A

Cells have more G-protein molecules than individual receptors. For instance, activating a few
receptors can then activate many G-proteins which then will activate many adenylyl cyclase

molecules.
The tetrameric holoenzyme R2C2 is inactive. After binding cAMP the catalytic subunit of the kinase is
released and is active. Normally the regulatory subunits inhibit the catalytic subunits and thus prevent
them from phosphorylating substrate. But when they bind cAMP they change conformation and no
longer bind catalytic subunits. Catalytic subunits can then phosphorylate substrate (in the presence of
ATP) serine threonine residues.
Catalytic subunits of kinases
have features that are similar
to each other. They are very
highly conserved. Each one
has an ATP binding site and a site that recognizes the substrate (specific amino acids). Regulatory
subunits usually bind to substrate recognition site.
Phosphodiesterase breaks down cAMP. As the levels of cAMP laws of mass action drive the
reaction above to the left and regulatory and catalytic subunits reassociate.
An important feature of kinase regulatory domains is that they all contain a sequence
similar to phosphorylation sequence. For protein kinase A (cAMP-dependent kinase) the sequence is
arginine-arginine-X-serine. Other nearby sequences contribute to binding. Thus this region of the
regulatory subunit serves as a pseudo-substrate. Artificial peptides which act as substrates can be
made. Regulatory subunits can frequently be phosphorylated which markedly changes their activity.
Other important kinases have regulatory and catalytic domains combined in one protein i.e. cGMPkinase, protein kinase C, Ca2+/ calmodulin kinase etc. Nonetheless, they work in many ways like
protein kinase A. These molecules bend 180E to form hairpin so regulatory subunit can interact with
catalytic subunit.
Figure 5 cAMP/ Protein kinase A cycle.

Figure 6 Protein kinases are related

Phospholipids also make second messengers. Two specific enzymes phospholipase A2 and
phospholipase C are involved each of which is activated by G-proteins.

PIP2

PLC

IP3 + DAG
(PKC)

Ca Channels

When phospholipase C is activated IP3 is

formed. IP3 combines with specific receptors to release Ca from endogenous stores. Also IP1, IP2,
IP4, IP5 are released. Some work as second messengers. Phosphatases remove phosphate groups
leaving inositol which is re-incorporated into membranes. DAG (diacylglycerol) is also produced by
phopholipase C. DAG stays within the membrane. Phospholipids are also required for activation of
2+

Figure 7 2nd Messengers activated by lipid hydrolysis

PKC (protein kinase C). There are at least 9 isoforms for PKC. Major forms of PKC require Ca2+ for
activation while the minor forms do not. Inactive PKC is found in the cytoplasm. Active PKC is
translocated to membrane where it is functional.
Arachidonic acid can activate certain forms of PKC. When phospholipase A2 is activated
arachidonic acid is released and is rapidly converted to a family of active eicosanoid metabolites.
There is cross-talk between second messenger systems. Frequently proteins can be
phosphorylated on more than one site by different kinases. For instance Ca channels have sites for
PKA and PKC.

K channels which are open at rest can be closed by phosphorylation. Thus small depolarizing
currents would produce large depolarizations as the channels that are normally active at rest are
inhibited.
Muscarinic ACh Receptors (10 minutes)
ACh
Nicotinic ACh Receptors (20 msec)

As we said before second

messenger signals are much slower than
ligand gated channel signals. For

instance:

Figure 8- Modulatory locations.

Slow synaptic actions typically modulate excitability. They can affect the threshold for spike
generation, amplitude and duration of action potential.
Sometimes G-proteins interact directly with ion channels. ACh greatly decreases the heart rate.
When this occurs the cell is much less excitable.

Fig. 9 Fast and slow synaptic transmission.

Figure 10- Hippocampal neuron excitability is greatly increased by diminishing Ca2+-activated K

currents.
Other channels are modulated directly by second messengers cAMP, cGMP or arachidonic
acid metabolites. Phosphorylation is not required.
cGMP 6666 Opens cation selective channels in photoreceptors.
cAMP 6666 Opens cation selective channels in olfactory bulb.
Receptors usually (but not always) desensitize. That is prolonged exposure to
neurotransmitters decreases efficacy, until transmitter has no effect at all.
Second messengers also regulate gene expression and thus can make long-lasting changes to
synaptic transmission.

Figure 11 Both short and long-term effects mediated by chemical transmitters.

Major topics:
G-protein linked receptors
Second messenger cascades
Slow modulatory responses
Extra Figures

The Physiology of Muscle

Jim OReilly
Office 426 BSLC
oreilly@uchicago.edu

Skeletal Muscle
You will recall that muscle is one of the four great cohorts of tissue (with neural tissue,
connective tissue and epithelia). Muscles are biological motors that convert the
chemical potential energy in high-energy phosphate bonds into force that is used to do
work and generate mechanical power. Muscle tissue will shorten when active, can be
extended under an external load and is capable of storing elastic potential energy. Like
all motors, muscle is not %100 efficient and an active muscle always produces copious
amounts of heat as well as force, work and power.
Humans have three distinct types of muscle: skeletal muscle, cardiac muscle and
smooth muscle. Skeletal muscle (as the name implies) is attached to and works with
the skeletal system to produce motion and maintain posture. It is innervated by somatic
motor neurons and can be brought under voluntary control by the motor cortex (i.e.,
voluntary movements). It can also be recruited from
the brainstem (e.g., respiration when you are asleep)
and directly from the spinal chord (e.g., spinal
reflexes).
Motion is generally the first function of skeletal muscle
that comes to mind but it also plays a critical roll in
maintaining posture, driving venous return in the
peripheral circulation and heat production.

SKELETAL MUSCLE ORGANIZATION

Muscle > Fascicle > Muscle Fiber (= Muscle Cell) >
Myofibril > Sarcomere > Filament
The terms muscle and fascicle are applied
somewhat arbitrarily. A single muscle can be
functionally integrated with and always recruited in
concert with other nearby muscles (e.g. the collective
external rotators of the hip) or can include several
anatomically distinct parts (e.g., the triceps brachii or
serratus anterior) that tend to function as a unit. Other
muscles appear anatomically homogeneous yet are
composed of distinct or overlapping regions that are
used for different actions (e.g., the temporalis, pectoralis
major or trapezius). A fascicle is a bundle of muscle
cells that are parallel in orientation and tend to stay
together as a muscle is dissected. Fascicles are readily observed in well-cooked beef
(such as in a stew).

A skeletal muscle is an organ that is composed of a variety of tissues in addition to

skeletal muscle tissue itself. This includes satellite cells (stem cells that regenerate
damaged muscle), the ends of motor and sensory nerve fibers, blood vessels and an
extensive connective tissue framework. This connective tissue is termed the investing
fascia and it defines the surface of the muscle, all of its major compartments, and
extends onto the surface of every individual muscle fiber. The part of the deep fascia
defining the surface of the muscle and its major compartments is termed the epimysium.
The perimysium defines fascicles and the endomysium covers the surface of each
individual muscle fiber. The investing fascia functions to anchor the muscle cells to each
other, and anchor the fascicles to tendons and bones. This investing fascia also acts as
a series elastic component of the organ as a whole that is capable of storing elastic
potential energy and releasing it to improve the energy efficiency of cyclical movements
and amplify muscle mass specific power output in explosive, episodic movements.
MUSCLE FIBER STRUCTURE AND ORGANIZATION
Skeletal muscle fibers are syncytia, arising from numerous myoblasts that fuse together
during development. As a consequence, each muscle fiber has numerous nuclei that are
located in its periphery. Fibers are long and cylindrical, ranging from about 10-100 microns
in diameter and from around 600mm (sartorius) to 1mm (stapedius) in length.
The major components of muscle fibers include myofibrils, the t-tubule/sarcoplasmic
reticulum network, and mitochondria. Myofibrils are composed of single row of
sarcomeres, stacked end to end and running the entire length of the fiber. The sarcomere
is the fundamental contractile unit of skeletal and cardiac muscle. Individual sarcomeres
have a banded appearance and the sarcomeres of adjacent myofibrils are aligned such
that the tissue itself has a banded appearance under a light microscope. This is why
skeletal muscle is also called striated muscle. Each myofibril is connected directly to the
cell membrane (sarcolemma) of the muscle fiber via invaginations termed transverse
tubules (= t-tubules) and surrounded by sarcoplasmic reticulum. The roll of the t-tubule/SR
system in controlling muscle contraction will be discussed later. Mitochondria (=
sarcosomes in muscle) are the membrane-bound organelles that generate ATP used to
fuel muscle contraction. They form branching networks between the myofibrils that can
rapidly hypertrophy or atrophy in response to exercise or lethargy.

SARCOMERE ORGANIZATION
Sarcomeres are composed of overlapping filaments that interact to generate force.
Actin and Associated Proteins
Actin monomers (globular or G-actin) bind to form actin filaments (F-actin). Two
strands of F-actin organize into a helix that has binding sites for myosin.
Tropomyosin dimers also form a long filament. The dimer lies on the edge of the
groove of the two actin strands across seven actin monomers. In the resting state,
tropomyosin blocks the myosin binding site on the F-actin.
Troponin has three subunits: Troponin T (TnT) binds to tropomyosin, troponin I and
troponin C. Troponin C (TnC) is calcium-sensitive, and each TnC will bind with up to 4
calcium ions. Troponin I (TnI) binds to actin and inhibits the interaction between actin
and myosin when in close proximity to the myosin binding site.

Myosin
Heavy chain = helical tail each attached to a globular head that includes a
binding site for ATP (adenosine triphosphate). There are two heavy chains per
myosin molecule.
Light chain located at the neck (connection between heavy chain myosin head
and tail). There are two per myosin head and four per myosin complex.

Actin-Myosin Organization and Overlap

In the sarcomere actin filaments with their associated proteins (also called thin
filaments) extend longitudinally from the Z-line or Z-disk, a disk-shaped meshwork of
filaments including -actinin. Long, thin nebulin filaments (called the forth filament
system) stabilize actin filaments and connect them to the Z-disk. Adjacent Z-disks
represent the margins of an individual sarcomere.

Myosin molecules aggregate to form thick filaments. Myosin tails form the trunk of the

filament while the myosin heads stick out the sides. They extend from the M-line toward the
Z-disks. Myosin is connected to the Z-disk by the protein titin (called the third filament
system) that provides elasticity and support. The regions of the sarcomere are often
described as bands.
The A band (A for anisotropic) extends the full length of the thick filament.
The I band (I for isotropic), is a band that only includes the region of the thin
filaments that dont overlap with myosin. It reaches from the tip of one think
filament to the next (so it spans parts of two sarcomeres and crosses the Zdisk).
The H band includes the region of myosin that does not overlap with actin (so it
crosses the M-line).

SKELETAL MUSCLE CONTRACTION

Cross-bridge cycling - The sliding-filament model describes the mechanisms of muscle
contraction. Actin and myosin move past each other and cause sarcomere contraction
through cross-bridge cycling.

1. At rest: ATP binds to the ATPase site on myosin. Tropomyosin/troponin complex sits over
the high-affinity binding site for myosin preventing interaction.
2. Initiation of cross-bridge cycling: Cycling is initiated when calcium floods into the
myofilaments. Calcium binds to TnC causing tropomyosin to shift into the actin groove
exposing the high-affinity myosin binding site.

3. Formation of the cross bridge: Myosin plus ATP binds to actin. ATP splits into ADP and
Pi and the myosin head rachets along the actin with the dissociation of Pi.
4. Cross bridge release. ADP separates from myosin and a new ATP binds at which point
actin is released.
5. Continuing Contraction. Once myosin is separated from actin and the myosin head
positioned appropriately, the cycle can start again.
6. Ending contraction. Calcium uptake prevents the tropomysin/troponin shift on the actin
filament blocking the myosin binding site and ending the contraction.

The force generated by a sarcomere

depends on the number of actin- myosin
crossbridges. As the sarcomere begins to
shorten, force increases until there is
complete overlap between actin and the
region of the thick filament that contains the
myosin heads. At this point, force
generation plateaus. If contraction
continues so that actin filaments from the
two ends of the sarcomere overlap or
myosin reaches the Z- disks, force
decreases precipitously and the sarcomere
may be damaged.

CALCIUM RELEASE AND MUSCLE ACTIVATION

Calcium is critical for muscle function and the muscle cell is well adapted to deliver
calcium to the myofilaments during muscle contraction and to sequester calcium in order
for the muscle to relax.
The muscle cell
membrane, the
sarcolemma, extends
into the muscle fiber
forming transverse
tubules (T-tubules) that
branch around the
myofibrils at boundaries
of the A-I bands.
Enlargements of the
sarcoplasmic reticulum
(SR), terminal cisternae,
border the T-tubules
forming the triad. The
SR is a major calcium
storage organelle.

Membrane depolarization travels along the sarcolemma and T-tubules. At the triad,
depolarization activates mechanisms for calcium release. In skeletal muscle, ryanodine
receptors (RyR1) on the SR are activated via dihydropyridine receptors causing calcium
release from the SR through electromechanical coupling. Calcium is passively
released from the SR. At the end of the membrane depolarization, calcium is actively
pumped back into the SR.

MUSCLE FIBER TYPES.

Muscle fibers have different characteristics that are related to their function.
Skeletal Muscle Fiber Types
Fibers can be fast contracting or slow contracting. This is due to differences in
speed of cycling of different myosin heavy chain isoforms. Fast muscle has a fast
isoform, slow has a slow isoform. This can be determined with antibody staining or
staining for myosin ATPase that differs with pH between the isoforms.
Fibers can be aerobic (use oxidative metabolism) or anaerobic (get energy through
glycolysis). Aerobic muscle tends to be darker than anaerobic muscle because it has
a much higher density of mitochondria, capillaries, and myoglobin. Succinate
dehydrogenase stain can be used to determine oxidative capacity.
With these characteristics, we generally classify muscle into three different fiber types:
Fast glycolytic (FG), Fast oxidative glycolytic (FOG) and slow oxidative (SO) fiber types.
FG fibers are fast but quick to fatigue as they deplete glycogen reserves, SO fibers are
slow but can work for longer with the continuing generation of energy through oxidative
metabolism. FOG fibers are intermediate.
In mammals, muscles are a mix of these different fiber types; however, depending on
muscle use or location in a muscle, one type may be more prevalent. Having
heterogeneous populations of fiber types allows he muscle to work in a range of
conditions. All muscle fibers in a given motor unit are of the same fiber type. This makes
sense functionally as those fibers will be activated together during movement.

MOTOR UNITS HAVE

HOMOGENEOUS FIBER
TYPES
All of the skeletal muscle
cells innervated by a single
lower (brain stem or spinal
cord) motor neuron are called
a motor unit. A single motor
neuron may innervate from
around 10 to over 1000
fibers. With few exceptions,
a given skeletal muscle fiber
is innervated by only a single
motor neuron. All of the
muscle fibers in a given
motor unit are recruited in
unison and are the same
fiber type.

SKELETAL MUSCLE
GROWTH AND CHANGE

Skeletal muscle is a resilient

and responsive tissue. It has
an impressive ability to
change in response to many factors including, for example, injury or disuse, aging and
training. Skeletal muscle also has some ability to repair itself with satellite cells,
(myogenic precursor cells) and muscle side population cells that have some of the
characteristics of stem cells.
Skeletal muscle changes due to:
Disuse. Many factors including the lack of innervation or excitation by a motor neuron or
other incapacitating illnesses can lead to acute muscle atrophy. Specific atrophic
changes include decrease in muscle fiber size and in overall muscle mass. During acute
atrophy, fibers tend to shift toward faster fiber types. In the case muscle fiber atrophy
due to loss of innervation, it is possible for muscle to be re-innervated by other healthy
motor neurons. When this happens the re-innervated fibers take on the fiber type
characteristic of that motoneurons motor unit. Unlike normal human muscle in which
fiber types are mixed, re-innervation can result in patches of muscle of a single fiber
type. In cases of disuse in which there is no nervous system damage, rehabilitation can
restore normal muscle morphology and function.

Aging. Muscle experiences chronic atrophy during aging. Unlike atrophy associated with
injury, chronic atrophy involves decrease in fiber numbers as well as fiber size and fiber
numbers. Also, unlike acute atrophy, faster fiber types seem to be selectively lost during
chronic atrophy. Some of these differences, such as the loss of muscle fibers, are due to
the decrease in a muscles ability to repair itself with aging.
Training. Training can lead to muscle fiber hypertrophy, an increase in the size of muscle
fibers or in the oxidative capacity of SO fibers. In some cases, training can also cause

changes in fiber type. In particular, myosin heavy chain isoforms can switch leading to
changes between FG and FOG fiber types but, in general, is not associated with
changes between slow and fast fiber types.
SKELETAL MUSCLE FUNCTION
FORCE GENERATION BY
MUSCLES MOVEMENT AND
POSTURE.

We looked at how muscle

generates force during shortening
of a sarcomere and that
can be extrapolated to an entire
muscle. Muscle can also generate
force when it is not shortening and
even when it is extending.
Concentric Contraction contraction during shortening. The
force applied to the muscle is less
than the force being generated by
it and the muscle shortens.
Isometric Contraction contraction at a constant length.
The force applied to the muscle is
the same as the force generated
by it.
Eccentric Contraction contraction during lengthening.
The force applied to the muscle is
greater than the force being
generated by it and causes
muscle extension.

Concentric and eccentric contraction can also be thought in terms of the work performed
by a muscle.
Work = Force * Distance.
Muscles can do positive and negative work: Positive work = overall more work
performed during concentric contraction. Negative work = overall more work performed
during eccentric contraction.

Work loops are useful for understanding the work

done by a muscle. A work loop plots length on
the X-axis vs. force on the Y-axis over an entire
contraction cycle. The area within the resulting
loop represents the overall work performed
during the cycle. Is it positive or negative work?
Without arrows on the work loop to indicate the
direction of force and length change over time, it
is impossible to know whether overall work
performed during the cycle is positive or negative.
A counterclockwise loop = positive work, A
clockwise loop = negative work.

This is simple to see when the cycle involve only

concentric or eccentric contraction but what if the
muscle performs both concentric and eccentric
contraction during a cycle?
A work loop still results and the overall work
performed is either positive or negative.
When a muscle generates positive work it is said
to be acting as a motor, when it generates
negative work it is said to be acting as a brake.

Much less is known about how myosin and actin

work in eccentric contraction than in concentric
contraction but that type of contraction is known
to be more damaging to muscle than concentric
contraction. There is some evidence that the
damage from eccentric contraction promotes
muscle growth through the repair process but this
hypothesis is under debate. It is thought that rather than releasing when ATP binds to
the myosin head (as in concentric contraction), much of the separation of myosin from
actin during eccentric contraction is due to mechanical pulling apart of that bridge. The
damage that occurs to the muscle cell during this process is likely a prime cause of
delayed onset muscle soreness that is particularly common after eccentric exercises. It
is unclear what causes this soreness an inflammatory response, remodeling or other
factors. It is also unclear how the nervous system controls eccentric contractions but
appears to involve different patterns of motor unit recruitment and levels of excitation of
the muscle.
MUSCLE ARCHITECTURE
There are many ways to arrange muscle fibers in a skeletal muscle. Parallel (or strap)
muscles have fibers/fascicles run in nearly the same orientation, in series with their
tendon. Convergent muscles have fibers/fascicles arranged in a fan shape,
converging on a single tendon. Circular muscles have fibers/fascicles that form a ring
around an opening. Pennate muscles have muscle fibers that insert onto a central
tendon at an angle: Unipennate muscles have fibers that insert on the tendon from
one side, bipennate muscles have fibers that insert on the tendon from two sides, and
multipennate muscles have fibers that insert on a tendon from multiple sides, may
also include multiple tendons.

10

While for some muscles it is necessary to generate high force, others may require less
force but need to contract over a longer distance. The organization of muscle fibers
relative to their tendons can help optimize for force or displacement. The two prime
contrasting examples are parallel fiber muscles and pennate muscles. In general,
pennate muscles can generate more force because, for a muscle of a given size, many
more fibers can insert onto a tendon. Although force production per fiber is decreased in
relation to their angle to the tendon, the large increase in fiber number leads to higher
total force output. Because muscle fibers in the pennate arrangement are shorter, they
cannot contract as far and because they are at an angle to the tendon (and direction of
pulling), only a fraction of the length change of an individual fiber will translate to
displacement of the tendon. In a parallel fibered muscle, fewer fibers can insert onto its
tendon but those fibers can run the full length of the muscle. Because there are many
fewer fibers, force will be lower but because the muscle fibers (and thus sarcomeres) are
in series with the tendon, contraction of the muscle fiber allows the muscle to generate
force and shorten over a much greater distance than would be allowed with a pennate
arrangement.
HEAT PRODUCTION
Muscles produce heat we experience this regularly, with its compensatory sweat,
during exertion. Although there are other tissues that can generate heat such as brown
adipose tissue in newborns - As endotherms, we rely fundamentally on muscles as heat
generators to maintain a relatively consistent body temperature. Where does the heat
come from? Heat is given off as a bi-product of cycling of calcium back into the
sarcoplasmic reticulum by the calcium-ATPase pump, from mitochondria as a bi-product
of ATP production and from other sources, including friction of muscle cells during
contraction.
THERMOGENESIS
Shivering thermogenesis is the generation of heat using minor repeated muscle
contractions that dont lead to effective force generation. Shivering is mediated by
involuntary mechanisms and is often augmented by piloerection or goosebumps,
involving activation of the arrector pili muscles associated with each hair follicles. The
contraction of these muscles causes your hair to stand up. This behavior serves to
increase the thickness of the boundary layer of air between body and the external
environment in animals with thick fur coats. It probably still serves this function on our
scalp, but would seem to offer little help in retaining heat over the rest of our body (at
least for most of us).
Non-shivering thermogenesis is heat production that does not rely on muscle
contraction of shivering. Brown adipose tissue is not muscle but does contain a very
high density of mitochondria that can produce heat. This tissue is highly vascularized to
allow the circulatory system to both provide sufficient oxygen to the mitochondria and
circulate heat produced throughout body. In humans, this tissue is primarily seen in
newborns.

10

Cardiac Muscle
Cardiac muscle cells are incredible workhorses, contracting rhythmically without
voluntary control 24/7. For a 23 year old, a good resting heart rate is around 60 70
beats per minute and 150 or so during vigorous exercise. Even with a 60 bpm heart rate
and resting 24 hours a day, the heart (and thus the cardiac cells) would have to contract
86,400 times in 24 hours. Add in even a little movement and it easily goes above 100K.
Over a lifetime this adds up to billions of contractions. This is particularly amazing as
cardiac muscle does not have the regenerative properties of skeletal or smooth muscle.
So, not only does the heart have to beat many millions of times, but individual muscle
cells also have to meet these same demands.
In this lecture we will examine cardiac muscle. We will start with A. the overall
organization of cardiac muscle cells in the heart but will spend most of the time at
the tissue level examining B. the histology of cardiac muscle cells and how they
function. Specialized signal conducting cells and cardiac muscle cells inherent ability to
relay signals are critically important for activating and coordinating heart contraction. We
will discuss C. Excitation of cardiac muscle through gap junctions and specialized
conductive cells. At this point we will focus on the anatomical perspective but you will
have detailed physiology of heart function later in the course. Disorders and diseases of
the heart are a major cause of hospitalization and death. If there is time at the end of
class, we will explore examples of how cardiac muscle cells are compromised by
disease and research on treating the damaged heart at the cellular level.
To understand cardiac muscle fibers and how they work, we need to understand how
they fit into the overall architecture of the heart. The cardiac muscle cells are organized
into the muscular layer of the heart called the myocardium. The myocardium is
sandwiched between connective tissue and epi-/endothelium that protect it and provide
support.

Pericardium: External to the myocardium are several connective tissue and

epithelial/mesothelial layers together called the pericardium. The pericardium surrounds
the heart and provides support and stabilization. It connects to other structures in the
thoracic cavity. Between pericardial layers there is a fluid-filled space. The innermost
layer of the pericardium, the epicardium, is tightly connected to the myocardium and
forms part of the heart wall.
Internal to the myocardium is the endocardium, a layer of connective tissue lined by an
endothelial layer that separates the myocardium from the blood it pumps.

CARDIAC MUSCLE ORGANIZATION.

The heart is an amazing structure and very different from the other muscular systems in
the body. Like the skeletal muscle, cardiac muscle is organized into fascicles but those
fascicles arent organized to pull on stiff skeletal structures but instead to squeeze the
spaces within them and, as a result, pump the blood from those spaces.

11

Ventricles: Fascicles spiral around the ventricles allowing them to squeeze and pump
the blood within. Unlike skeletal fascicles, cardiac fascicles are not independent as many
cells cross between them as well as from more superficial to more deep layers of the
myocardium. The fiber orientations vary through the depth of the myocardium with the
deepest fibers running at significantly different angles from the superficial fibers. The left
ventricle additionally has a thick middle layer of the myocardium with a distinct
circumferential orientation. The biomechanics of this complex organization has not been
investigated in depth.
Atria: Cardiac muscle fibers associated with the atria are also organized into fascicles.
However, the myocardium is thinner and does not seem to show the complex changes
in fiber angle with depth as seen in the ventricles.
ANATOMY AND FUNCTION OF CARDIAC MUSCLE CELLS.
Cardiac muscle cells share some characteristics with skeletal muscle cells and others
with smooth muscle. They also have their own unique identifying features. Compare and
contrast the structure of these three muscle cell types in relation to how they function in
the organism.
Cardiac muscle cell summary of characteristics.
15-35 microns (m) or so in diameter, 85 115 m in length. 12 nuclei located centrally in the cell.
Cardiac muscle have irregular shapes and often branch. Along with the
overlapping organization of fascicles, this helps generate an
integrated heart contraction. Rather than pulling along one axis, as generally
occurs in skeletal muscles, this organization helps the heart to squeeze the
heart chambers and the blood within them.
Cardiac cells are striated.
Contractions are involuntary.
Cells are electrically coupled.
SR-T-tubule are organized in diads rather than triads.

Membrane structure.

Membranes of cardiac muscle cells have a number of interesting features that are
intrinsic to their function. Cardiac muscle fibers connect end-to-end through
intercalated disks. The disks can have transverse (run perpendicular the fiber) and
longitudinal (run parallel to the fiber) portions. Actin filaments adjacent to the
intercalated disk are connected to it through the fascia adherentes. One of the
important actin binding proteins at the fascia adherentes is N-RAP (nebulin-related
anchoring protein) which appears important for both connecting t o adjacent cells and
for myofibrillogenesis. Maculae adherentes (desmosomes) bind adjacent cardiac
muscle fibers through cadherins. Gap junctions are found in a number of different
tissues. In cardiac muscle, they allow electrical coupling between cells to propagate
waves of muscle contraction that squeeze heart chambers.
Structures that function in contraction
For the most part, the same basic mechanism and types of proteins that drive skeletal
muscle contraction are also important in cardiac muscle contraction.

12

Sarcomere structure

Sarcomeres are organized serially in the muscle fiber with the same banding pattern as
in skeletal muscle They are composed of actin, myosin and other proteins also found in
skeletal muscle; however, in some cases, the protein isoforms in cardiac muscle are
different (for example, there are cardiac specific myosin heavy chain isoforms and
troponin isoforms). Despite these similarities in overall sarcomere structure, cardiac
muscle acts over a much narrower range of length change during contraction.
To understand the physiology of the heart and how cardiac muscle contracts to generate
pumping, it is important to understand the relationship between muscle contraction and
heart pumping.
The Frank-Starling law states that the greater the amount of blood that enters the
heart in a cycle, the greater the amount of blood that is pumped out. This implies that
the contractile mechanisms are able to generate a more forceful contraction when the
heart is more full. In fact, in cardiac muscle, the more the muscle fibers are stretched
as would happen with increases in the hearts blood volume the more sensitive they
are to calcium and the more forceful their contractions become. This is a fantastic builtin regulatory mechanism to modulate heart pumping with variation in blood volume.

13

Several important differences between skeletal and cardiac muscle:

1. SR: As mentioned above, rather than having a triad structure with two SRs flanking a
t-tubule, a single SR and t-tubule form a diad.

2. Calcium stores: while in skeletal muscle the calcium needed from contraction has
been shown to come primarily from intracellular stores, cardiac muscle relies heavily
on extracellular calcium.

3. Proteins associated with calcium release: Calcium channels on the sarcolemma,

similar to dihydropyridine receptors, allow significant extracellular calcium to enter. That
calcium triggers a cardiac version of the ryanodine receptor, RyR2, to release calcium
from the SR in a process called calcium induced calcium release.

As might be expected by its constant activity, cardiac muscle is highly oxidative and
has a high density of mitochondria to generate ATP.

EXCITATION OF CARDIAC MUSCLE THROUGH GAP JUNCTIONS AND

SPECIALIZED CELLS.
Gap junctions. In cardiac muscle gap junctions provide a mechanism for cells,
independent of innervation, to coordinate their activity. Gap junctions tend to be located
at the ends of cells, connecting in the longitudinal axis so excitation spreads along the
length of fibers and fascicles more rapidly than in the transverse direction. Gap junctions
are critical for normal cardiac function and abnormalities in these junctions are
associated with arrhythmic contraction.

Other excitatory and conductive cells. In addition to the conductive ability of

contractile myocytes (due to their gap junctions), other cells in the heart have been
specialized to form a network of cells that generate and conduct electrical signals. You
examined this system that includes SA and AV nodes as well as specialized m u s c l e
fibers when covering heart anatomy. We just recently marked the 100th anniversary of
the comprehensive description of this system. Only relatively recently, cells of hearts
electrical system have been shown to be derived from embryonic muscle precursor cells
(although this had been suspected by some researchers many decades earlier).
Purkinje cells are a good example of conductive cells that are relatively
straightforward to see in lab. They can frequently be observed between the contractile
muscle cells of the myocardium and the endocardium. Purkinje cells are larger than the
contractile myocytes and have large nuclei. They are organized together into bundles
that have been suggested to improve conduction speed. Often light staining of few
myofilaments can be seen near the periphery of the cell. This contrasts strikingly with
contractile muscle cells that are dominated throughout their cross-section by
myofilaments.

14

Smooth Muscle
Smooth muscle functions in many internal organs including structures of the
gastrointestinal tract, the reproductive tracts and the circulatory system as well as the
uterus, urinary bladder, and iris of the eye. Like cardiac muscle, smooth muscle is
involuntary and there is generally direct inter-cell communication through gap junctions
that allows electrical signals driving contraction to pass along the tissue; however,
overall smooth muscle histology and contraction is strikingly different from both skeletal
and cardiac muscle. We will start today by examining A. The morphology of smooth
muscle cells and their contractile mechanisms. We will also look at broader
organization to examine B. the tissue-level organization of smooth muscle in
relation to function as exemplified in several organ systems and C. its innervation.
THE ORGANIZATION AND CONTRACTION OF SMOOTH MUSCLE CELLS
Smooth muscle cell summary of characteristics:
are smooth not visibly striated
are typically around 20-100 microns long and 2-10 microns in diameter.
have a fusiform shape
have a single, elongate, centrally located nucleus
have involutary contractions

In histological sections, the most striking characteristic of smooth muscle is that it

doesnt have the banding pattern that is so clear in skeletal and cardiac muscle cells.
This difference reflects the lack of sarcomeric organization in smooth muscle. Although
actin and myosin are still the key myofilaments in smooth muscle contraction, they are
arranged in a very different way than in other muscle types. In smooth muscle actin is
anchored to the membrane of the cell and to dense bodies within the cell. The dense
bodies are made in part of -actinin that bind to both actin thin filaments and
intermediate filaments. Smooth muscle fibers contain an extensive array of
intermediate filaments that form the cytoskeletal structure. The dense bodies and
intermediate filaments act to transmit force through the cell. Remember back to the role
of -actinin in the z disk of the sarcomere, it serves a similar role anchoring actin here.
Relative to the numbers of actin filaments in the cell, there are many fewer myosin thick
filaments in smooth muscle (15 actin: 1 myosin vs. 6:1). Myosin in smooth muscle does
not assemble into the bipolar organization of the thick filament of striated muscle
(relative to the medial M-line). The organization of myosins into a filament is more
variable and less understood than in striated muscle. However, individual myosin
molecules do have a similar organization of heavy chains and light chains, albeit with
smooth muscle specific protein isoforms. Unlike skeletal muscle, formation of cross
bridges requires the phosphorylation of one of the myosin light chains.
The other two main filament systems of the sarcomere titin and nebulin are not present
in smooth muscle.
There are other proteins that play roles in smooth muscle contraction. While there is no
troponin, tropomyosin is still important on the actin filament. Although its role is still under
investigation, tropomyosin is believed to block the actin- binding site for myosin and
stabilize actin filaments as in striated muscle. Other protein, particularly calmodulin

15

and caldesmon, are important to the position of tropomyosin. In the inactive state,
caldesmon is associated with actin and tropomyosin and believed to prevent
tropomyosin from shifting off of the myosin- binding site. When calcium ions enter the
cytosol of the cell, they bind to calmodulin (4:1). The calcium-calmodulin complex
interacts with caldesmon and is thought to cause it to loose its association with the actin
complex freeing tropomyosin to shift on the actin filament and allowing myosin to bind
and cross-bridge cycles to occur. When calcium levels decrease and calcium dissociates
from calmodulin, caldesmon returns to actin and myosin binding is blocked.
The calcium-calmodulin complex is also important for activating the myosin molecule,
allowing phosphorylation of the myosin light chain via activity of myosin light chain
kinase and, as a result, ATPase activity on the myosin heads.

Caldesmon may have an additional role in inactive muscle. It can bind to both actin and
myosin and may stabilize the relative positions of the filaments at rest by latching them
in place.

While, as in other
muscles, contraction
relies on increases
in concentration of
intracellular calcium,
the elaborate
structure of t-tubules
and SR in striated
muscle is not
present in smooth
muscle. Like cardiac
muscle, voltage
gated calcium
channels in the
sarcolemma and
ryanodine receptors
are important for
calcium release
through calciuminduced calcium release. As in cardiac muscle, sarcolemma calcium channels allow a
small increase in calcium inside the cell. This calcium causes the ryanodine receptor on

16

the SR to release large amounts of calcium that activate contraction. Although the overall
mechanism is similar, the coupling between calcium release by calcium channels in the
sarcolemma and by ryanodine receptors on the SR is much more loosely coupled than in
cardiac muscle.
Smooth muscle cells are able to work effectively over a much larger range of lengths than
skeletal muscle and cardiac muscle allowing the muscle greater range of lengthening and
shortening. This gives muscles organized around tubes or bladders, the ability to
accommodate considerable volume change and still be able to function.

Reticular fibers outside of the smooth muscle cells form a robust network, supporting
and connect smooth muscle cells to one another. During contraction, these fusiform cells
may take on a corkscrew shape that is also reflected in the deformation of its elongate
nucleus. When contraction ends reticular fibers and the cytoskeleton act to return the
muscle cells to their original shape.

ORGANIZATION OF SMOOTH MUSCLE CELLS INTO SMOOTH MUSCLE TISSUE.

Skeletal muscle often is organized into agonist-antagonist pairs. A simple example is the
biceps and the triceps muscles in our arms. The two muscles have complementary
functions, the biceps flexes our arms at the elbow and the triceps extend the arm
returning it to a straighter position. Smooth muscle is also frequently organized into
antagonistic muscles but those muscles are organized into layers rather than having
complementary insertions onto a skeletal element.

In the gut tube, generally smooth muscle occurs in pairs of layers, an inner circular layer of
muscle and an outer longitudinal layer. These two layers are coordinated, the circular
layer constricts and lengthens the tube while the longitudinal layer expands and shortens it.
Acting in concert with longitudinal waves of activation, they generate peristalsis and movement
of gut contents along its length. In the stomach, where considerable mixing occurs, a third
oblique layer is added. The uterine tubes similarly have an inner circular layer and outer
longitudinal smooth muscle layer. The vas deferens has three layers; two longitudinal layers
separated by a middle circular layer.
Another important location of smooth muscle is in the eye. In the iris, antagonistic circular
and longitudinal muscles are finely coordinated to control aperture size.
Contraction of radially arranged dilator pupillae pulls the iris open and increases the aperture
size while contraction of sphincter pupillae muscles act like a purse string constricting the iris
and decreasing the size of the aperture

17

SMOOTH MUSCLE ACTIVATION

Smooth muscle activation varies considerably with the function of the tissue.
Multiunit smooth muscle is smooth muscle in which muscle cells are organized into
motor units, like skeletal muscle. However, unlike skeletal muscle, smooth muscles cells
may be innervated by more than one motor neuron. Multiunit smooth muscle is used
when fine motor control is needed, as in the iris of the eye.

When fine control is not needed, as in visceral smooth muscle, there is less direct
innervation and some cells are not connected to nerves at all. Instead, these muscles
rely heavily on gap junctions to spread activation from a few nerves in a wave across the
tissue. Adjacent muscle layers (i.e. circular and longitudinal) do not connect via gap
junctions as happens in cardiac muscle so that each layer is independently controlled.
Some smooth muscle contraction can also occur in the absence of any innervation.
Hormones, oxygen levels, and other chemical cues can cause contraction of smooth
muscle. Smooth muscle can also be excited to contract mechanically through stretching
of the cells as a result of activation of stretch dependent ion channels in the
sarcolemma.
Some smooth muscle tissue also has intrinsic rhythmicity to its excitation. The cells,
located between muscle layers, are called pacesetter cells or interstitial cells of Cajal.
They generate sub-threshold waves of excitation that pass through the muscle and
transmit excitation from nerves. They are believed to be specialized smooth muscle cells
but this is still under investigation.

18

Lecture Notes
Module 2
Cardiovascular Physiology
Beiser, Poston, & Sattar

THE UNIVERSITY OF CHICAGO

DIVISION OF BIOLOGICAL SCIENCES AND PRITZKER SCHOOL OF MEDICINE

TO:

Students of Cell & Organ Physiology

FROM:

David Beiser, MD
Jason Poston MD
Husain Sattar, MD

RE:

Cardiovascular Physiology Module

Welcome to cardiovascular physiology! We hope you will enjoy learning about the circulation as
much as we will enjoy teaching you about it.
Please note that the lectures will in general follow the handouts closely. We encourage you to
try and read the handouts in advance of the lectures in order that you may focus on
understanding the concepts that are emphasized during the lectures. We have included a
reference sheet listing the equations and normal ranges for a number of circulatory parameters.
We believe that most of you will benefit from some supplemental reading from one of the
suggested physiology textbooks but will not expect you to know anything not covered in the
handouts or in the lectures. The handouts include figures from a number of sources, including
the physiology textbooks by Levy & Pappano and by Boron & Boulpaep.
Compared with some other subjects you are studying, there are relatively few facts to learn. The
chief difficulty in cardiovascular physiology lies in being able to integrate the material. We will try
several approaches to help you do this, including provocative questions throughout the lecture
notes, problem sets and vignettes posted on Chalk, a healthy dose of clinical correlation, review
sessions with your teaching assistants, and laboratory sessions. The first of these lab sessions,
the Cardiovascular Physiology Laboratory, will provide you with an opportunity to explore
important physiological principles using the simulation program SimBiosys. This session will
formally cover the integrative response to Hemorrhagic Shock and Cardiac Tamponade. The
second laboratory session (Applied Physiology: Case Series) will provide you with additional
opportunities to work through physiology problems. Finally, we will several review sessions
including one during the regularly scheduled lecture time the day before the exam.
Again, welcome to cardiovascular physiology!
Sincerely,
David Beiser, MD

Jason Poston, MD

Husain Sattar, MD

Beiser/Poston

CV Overview & Cardiac Pump

Cell & Organ Physiology: Cardiovascular

OVERVIEW OF THE CARDIOVASCULAR SYSTEM

&
THE CARDIAC PUMP
Recommended reading
Levy & Pappano:
Chapter 1: Overview of the circulation, blood, and hemostasis, pp. 1-4.
Chapter 4: The cardiac pump, especially pp. 64-79.
KEY CONCEPTS
The main elements of the cardiovascular system include the cardiac pump, an array of
distributing (arteries) and collecting (veins) tubes, and a vast network of small vessels
(capillaries).
Increased myocardial fiber length, as occurs with an increase in ventricular filling during
diastole (preload), results in an increase in the force of ventricular contraction. The heart
gets its preload from the systemic vessels (e.g. the systemic vessels play a critical role in
the control of the cardiac outputmore on this later).
Contractility is the performance of the heart at a given preload and afterload, and is chiefly
determined by intracellular Ca++.
Afterload, or the load against which the ventricle contracts, is chiefly regulated by changes
in the amount of peripheral resistance present in the arterioles.
The cardiac cycle is the temporal sequence of pressure, volume, and flow events during one
contraction-relaxation cycle. It looks pretty complicated. But you just have to think your way
through it a few times. Really.
INTRODUCTION (A brief overview of the cardiovascular system)
The cardiovascular system delivers the essential ingredients for cellular metabolismnutrients
absorbed from the gut and oxygen taken up by the lungs to the tissues and eliminates their
metabolic waste products. The circulation is also involved in a number of homeostatic
processes including regulation of the arterial blood pressure, the transport of hormones and
other circulating substances to their target sites, regulation of body temperature, and the varied
adjustments required to respond to altered physiologic states such as exercise and
hemorrhage.
The main elements of the cardiovascular system include the cardiac pump, an array of
distributing (arteries) and collecting (veins) tubes, and a vast network of small vessels
(capillaries) that permit the rapid exchange of substances between the blood and tissues (see
Figure 1-2 below). The heart receives dark (deoxygenated) venous blood returning to the right
atrium and ventricle and pumps it through the lungs via the pulmonary circulation, where
oxygen is added to the blood and carbon dioxide is eliminated. The left atrium and left ventricle
receive this red (oxygenated) blood via the pulmonary veins and pump the blood to the tissues
of the body via the systemic circulation. During ventricular contraction (systole), more blood
is ejected into the aorta than runs off through the peripheral resistance located in the more
distal small arteries and arterioles, causing the walls of the aorta and its branches to be
distended outward. The recoil of these walls inward during ventricular relaxation (diastole)
propels blood through the peripheral circulation, thereby dampening the pulsatile flow created
by the heart and providing continuous blood flow at the capillary level. Arteriolar smooth muscle
tone can be adjusted through a variety of neurohormonal and metabolic mechanisms to regulate
the arterial blood pressure and to distribute blood flow to different organs according to their
metabolic needs. As a result, the arterioles have been called the stopcocks of the circulation.

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

Figure 1-4. Schematic diagram of the parallel

and series arrangement of the vessels
composing the circulatory system. The capillary
beds are represented by thin lines connecting
the arteries (on the right) with the veins (on the
left). The crescent-shaped thickenings proximal
to the capillary beds represent the arterioles
(resistance vessels). (Redrawn from Green HD:
In Glasser O, editor: Medical physics, vol 1,
Chicago, 1944, Mosby-Year Book.)

Because the total number of capillaries is enormous, the cross-sectional area of the capillary
bed is very large, despite the small size of each vessel. The velocity of blood becomes quite
slow as a result, permitting effective exchange of substances across the vessel wall. Blood
drains from the capillaries sequentially into venules, small veins, large veins, the vena cava, and
the right atrium, accelerating as the total cross sectional area decreases (see Figure 1-3 below).

Figure 1-3. Phasic pressure, velocity of flow,

and cross-sectional area of the systemic
circulation. The important features are the
inverse relationship between velocity and crosssectional area, the major pressure drop across
the small arteries and arterioles, and the
maximal cross-sectional area and minimal flow
rate in the capillaries. AO, Aorta; LA, large
arteries; SA, small arteries; ART, arterioles;
CAP, capillaries; VEN, venules; SV, small veins;
LV, large veins; VC, venae cavae.

Approximately 2/3 of the total blood volume resides in the veins. A critically important point is
that while the cardiac pump provides the energy required for blood flow through the circulation,
the cardiac output is controlled in normal individuals chiefly through the control of tone in the
veins, which controls the amount of blood returning to the right heart and therefore its preload
(vide infra). If you can appreciate this principle by the end of this course you will know
something important about the cardiovascular system that many practicing physicians do not.
This ventricular-vascular coupling will be explored in a future lecture, while other lectures will
consider other extracardiac facets of the cardiovascular system related to hemodynamics, the
autonomic nervous system, and various aspects of the arterial system, peripheral circulation,

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

and microcirculation. The heart is importantwho would deny it?but it is worth remembering
that the name of this course is Cardiovascular Physiology, not cardiac physiology.
With this is mind, well begin with the heart. The remainder of this lecture will deal with the
cardiac pump.
THE CARDIAC PUMP
Force of cardiac contraction; also preload, contractility, and afterload
You will recall from Dr. Hales lectures that the force of cardiac contraction depends upon the
resting length of the myocardial fibers, with an increase in initial sarcomere length resulting in an
increase in the force of contraction. The longer the myocyte, the greater the overlap of thick and
thin filaments and the greater the number of crossbridge attachments. In addition, the sensitivity
of the contractile apparatus to calcium increases when the muscle is stretched.
You will also recall that excitation-contraction coupling is mediated by calcium. Calcium enters
the cell during excitation and stimulates the release of calcium from the sarcoplasmic reticulum
(calcium dependent calcium release). Calcium binds to troponin C, and the Ca++-troponin
complex interacts with tropomyosin to permit myosin and actin crossbridge cycling. A reduction
in extracellular calcium results in decreased contractile force.
Experimental evidence supports the extrapolation of the above concept to the intact heart, with
an increase in myocardial stretch (reflected as an increase in ventricular end-diastolic volume)
resulting in an increase in the force of ventricular contraction (measured as ventricular
pressure). This is the Frank-Starling relationship. Imagine an experimental situation in which
the aortic valve is kept closed by a very high pressure afterload (vide infra) in the aorta. In this
circumstance, ventricular systole is isometric: there is no ejection of blood and no change in
ventricular volume during systole. The maximal isometric pressure generated by the ventricle
during systole at each degree of filling can then be plotted. Figure 4-4 below illustrates this
concept.

Figure 4-4. Relationship of myocardial resting fiber length

(sarcomere length) or end-diastolic volume to developed
force or peak systolic ventricular pressure during ventricular
contraction in the intact dog heart. (Redrawn from Patterson
SW, Piper H, Starling EH: J Physiol 48:465, 1914.)

The figure below further illustrates this relationship, while ignoring the decrease in developed
force that occurs when myocardial fibers are stretched beyond their optimal length (the
downward sloping rightward portion of the systolic curve above). Notice that ventricular pressure
rises along the line ABC (the end-systolic pressure-volume curve) as initial ventricular volume

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

increases along the curvilinear line 123. This lower line is the left ventricular diastolic pressurevolume curve.

Ventricular Pressure

A
3

Ventricular Volume (ml)

Notice that left ventricular diastolic pressure does not exceed zero until a certain volume has
been added (approximately 50 ml). This is the unstressed volume. Subsequently, diastolic
pressure rises in a curvilinear fashion as further increments of volume are added (the stressed
volume). The point on this diastolic pressure-volume curve to which the ventricle fills before it
contracts is called the preload, defined as the left ventricular end-diastolic volume (LVEDV).
Clinically, the LVEDV is sometimes estimated from the left ventricular end-diastolic pressure
(LVEDP). This may be done at the time of cardiac catheterization by measuring the pressure
within the left ventricle. The preload to the heart depends to a great degree on the amount of
venomotor tone that is present. This venomotor tone controls the amount of blood returning to
the heart, a concept which will be considered in more detail in a subsequent lecture.
The pericardium surrounds the heart loosely up to a given ventricular volume, but at greater
LVEDV it becomes stiff, limiting ventricular filling and imparting the pressure-volume relationship
seen on the rightward end of the curve above. This phenomenon is referred to as pericardial
constraint.
Clinical correlation: Certain conditions cause excess fluid to accumulate in the pericardial sac.
This pericardial effusion reduces the ventricular volume at which the pericardium becomes a
limiting membrane. In severe cases, cardiac filling is so impaired as to cause shock or even
death. This condition is called cardiac tamponade. Therapy involves drainage of the fluid
collection.
Bonus: Why is it illegal to perform pericardiectomies on greyhounds in the state of Florida?

Certain diseases may impair cardiac contractility, or the performance of the heart at a given
preload and afterload. For instance, a patient with myocardial ischemia due to an acute
coronary artery thrombosis may exhibit a significant reduction in myocardial contractility. The
cardiac function curve in such a patient would be shifted downward and to the right, as in the
panel on the left below (dashed line). Substances such as epinephrine or digitalis enhance
contractility and shift the end systolic volume-pressure curve upward and to the left (dotted line).
Certain conditions may impair diastolic filling of the ventricle, reflected by a shift in the diastolic
volume-pressure relationship upward and to the left, as shown in the panel on the right below
(dashed line). For instance, myocardial ischemia impairs diastolic relaxation, while longstanding
hypertension causes the left ventricle to grow abnormally thick and stiff (left ventricular

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

hypertrophy). Both diseases impair diastolic filling, and in both conditions, an increase in filling
pressure is required to maintain an adequate LVEDV.

Ventricular Pressure

Ventricular Pressure

Ventricular Volume (ml)

Ventricular Volume (ml)

Afterload is the load against which the heart must contract to eject blood. In plotting the
systolic volume-pressure curves above we have considered an artificial situation in which the
afterload is sufficiently high as to prevent ventricular ejection of blood. This experiment allowed
us to determine the maximum ventricular pressure that could be generated for a given preload
and contractility. In reality, left ventricular afterload varies according to the peripheral resistance,
which is chiefly regulated through the modulation of smooth muscle tone in the arterioles.
Stroke volume is the amount of blood ejected from the ventricle per beat, while ejection
fraction is the ratio of stroke volume to end-diastolic volume. A reduced ejection fraction
which can be calculated noninvasively with the use of echocardiography (ultrasound of the
heart utilizing Doppler flow)is a sign of impaired cardiac contractility. THE THREE MAIN
DETERMINANTS OF STROKE VOLUME ARE PRELOAD, AFTERLOAD, AND
CONTRACTILITY! Anything that increases preload and contractility will increase stroke volume
for a given afterload. Similarly, anything that increases afterload will reduce stroke volume,
given the same preload and contractility.
The cardiac cycle
The cardiac cycle consists of the sequential contraction and relaxation of the atria and
ventricles. The temporal sequence of pressure, volume and flow events is actually fairly
intuitive, but requires close study of the commonly shown figure below. Each panel in the figure
is correlated in time with the other panels and with the electrocardiogram at the bottom. The
cardiac cycle is divided into seven different phases. Sounds pretty complicated, right? IF YOU
TRY TO LEARN THIS CYCLE AS IF YOU ARE MEMORIZING SOMEONES CALENDAR YOU
WILL GET INTO TROUBLE! Instead, concentrate on trying to understand what is going on that
leads to these tracings.
In general, the following sequence focuses on the left side of the heart.
Atrial systole begins shortly after the electrical activation of the atrium, indicated by the P wave
on the electrocardiogram. Atrial contraction propels blood through the low-resistance mitral and
tricuspid valves into the left and right ventricles, respectively, which have already been passively
filled during ventricular diastole. This event is inscribed as an a wave on the left atrial and
venous pressure tracings and as a small increase in the ventricular pressure tracing. The atrial
booster or kick contributes relatively little (approximately 10%) to left LVEDV under normal
conditions, and many patients with complete atrioventricular block or atrial fibrillation have few
symptoms at rest. However, the atrial kick becomes more important at fast heart rates (e.g.

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

during exercise), when ventricular diastole is shortened, or when the ventricle is stiff or hard to
fill, as when left ventricular hypertrophy is present.

Figure 4-11. Left atrial, aortic, and left

ventricular pressure pulses correlated in
time with aortic flow, ventricular volume,
heart sounds, venous pulse, and the
electrocardiogram for a complete cardiac
cycle in the dog.

The onset of ventricular contraction is signaled by the peak

of the R wave on the electrocardiogram. The ventricles
contract to raise ventricular pressure and close the
atrioventricular valves (mitral valve and tricuspid valve). This
first phase of ventricular systole, between the closing of the
atrioventricular valves and the opening of the semilunar
(aortic and pulmonary) valves is called isovolumic
contraction because ventricular volume is constant. This
pressure increase is transmitted across the closed valves
and inscribed as a c wave on the left atrial and venous
pressure tracings.
Eventually, left and right ventricular pressures rise above
that of the aorta and pulmonary artery, respectively, and the
semilunar valves open. The left ventricle continues to
contract forcefully, leading to an increase in both LV and
aortic pressure to a peak systolic pressure. The early, short
phase of ventricular ejection is called rapid ejection and is
characterized by a rapid increase in aortic blood flow and a
rapid decrease in LV volume. Note that left atrial pressure
falls during this phase; this is due to atrial stretch from rapid
descent of the base of the heart. The pressure generated by the LV begins to fall as ventricular
volume decreases. Blood flow from the aorta to the periphery exceeds blood flow from the LV
into the aorta during this phase, causing the pressure in the aorta to decline. During this
reduced ejection the pressure in the aorta actually exceeds the pressure in the ventricle due to
the storage of potential energy in the distended aorta. Flow continue from the LV into the aorta,
however, because of momentum (think of shooting a bullet or a missile from a low pressure
weather system into a high pressure systemwould the bullet suddenly stop?), although aortic
blood flow decreases rapidly as a result of this reversal in pressure gradient. Left atrial and
venous pressures rise throughout this period as blood continues to flow into the atria, inscribing
a v wave.
Once LV pressure falls below aortic pressure, the aortic valve closes, inscribing a notch or
incisura on the aortic pressure tracing because of a reflected pressure wave. This marks the
end of ventricular systole and the beginning of ventricular diastole. The first phase of ventricular
diastole is isovolumic relaxation, during which ventricular pressure falls rapidly while
ventricular volume remains constant. Left atrial and venous pressures continue to rise

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

throughout this period until they exceed the rapidly falling ventricular pressures, and the mitral
valve opens. Rapid ventricular filling occurs as blood flows from the left atrium to the LV,
aided by suction created by the still relaxing left ventricle. The next phase of ventricular filling,
diastasis, is marked by a gradual increase in left atrial, left ventricular, and venous pressures
as blood continues to return to the heart from the pulmonary circuit and from the systemic veins.
Blood flow continues from the aorta to the periphery throughout ventricular diastole, falling to a
nadir just prior to ventricular ejection (vide supra).
Events are similar on the right side of the heart, but occur at lower pressures because of the
lower resistance of the pulmonary circulation. Similarly, tricuspid valve closure occurs after
mitral valve closure, and pulmonic valve closure occurs after aortic valve closure.
Relating the cardiac cycle to the clinical examination
Four sounds are typically produced by the heart: S1, S2, S3, and S4. Typically only twoS1
and S2are audible with a stethoscope. S1 and S2 are caused by oscillation of blood and
vibration of the chamber walls caused by abrupt closure of the atrioventricular valves and
semilunar valves, respectively. S2 is somewhat higher in pitch than S1.
S1 = lub
S2 = dub
S3, or the third heart sound, is due to rapid filling of the ventricle with sudden termination of
ventricular distension and deceleration of blood. This sound can be heard in children with thin
chest walls and in adults with left ventricular failure, the latter case due to stretching of volumeoverloaded ventricles.
S4, or the fourth heart sound, is caused by atrial contraction. It can indicate an abnormally stiff
left ventricle and may be heard in many patients with left ventricular hypertrophy caused by
years of high blood pressure.
Valves that are narrowed or incompetent (leaky) can cause murmurs that may be heard by the
astute clinician. For instance, mitral regurgitation typically produces a holosytolic murmur (e.g. a
murmur heard throughout systole) that is best heard at the cardiac apex and radiates to the
axilla. We might have time for me to play an example for you in class.
Inspection of the internal jugular vein can allow estimation of central venous pressure (and
therefore right atrial pressure) and is valuable clinically. This tracing looks very similar to the left
atrial pressure tracing but occurs sooner than the letter with respect to the electrocardiogram.
Close inspection of the jugular vein may reveal discrete a, c, and v waves.
Clinical correlation: The diagnosis of congestive heart failure can frequently be made at the
bedside. For instance, the physical examination findings of an S3, an elevated jugular venous
pressure, and peripheral edema support the diagnosis of congestive heart failure.
There are a number of excellent websites that have examples of murmurs. Remember this
when you do physical diagnosis next year. For instance, Cardiologysite.com
(http://www.cardiologysite.com/index.html) has numerous examples of murmurs linked to the
electrocardiogram and pressure tracings.

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

Pressure-volume curve
The pressure-volume curve for the left ventricle for a single cardiac cycle is shown below.

Pressure-volume loop of
the left ventricle for a single
cardiac cycle.

Below are pressure-volume loops depicting alterations in the 3 determinants of stroke volume:
contractility, preload, and afterload. I will show a real-time example of a pressure-volume loop in
class using the SimBiosys program. This program will be used during the laboratory sessions.

Increased contractility (Figure B) allows ejection to a smaller end-systolic volume.

The end-systolic pressure-volume curve is shifted to the left, reflecting increased
contractility (note also the increased systolic pressure). Increased preload (Figure
C) increases SV by ejecting from a greater LVEDV to the same LVESV (note again
the increased systolic pressure, in this case due to the Frank-Starling mechanism).

Beiser/Poston

Cell & Organ Physiology: Cardiovascular

Increased afterload (Figure D below)

reduces SV through an increase in LVESV.

MEASUREMENT OF CARDIAC OUTPUT

The equation for cardiac output is:
CO = HR x SV
where CO = cardiac output, HR = heart rate, and SV = stroke volume. There are several
methods for measuring cardiac output. One approach is uses a pulmonary artery catheter and
is called the indicator dilution technique. The pulmonary artery catheter is a long, slender
catheter with a small balloon near its tip. This catheter is inserted into a large central vein like
the subclavian vein. Inflation of the balloon allows passage of the catheter tip along with the
venous return (like a boat on a stream) through the heart and into a branch of the pulmonary
artery. A small quantity of cold saline at a known temperature is injected into the right atrium
through the catheter. A small thermistor at the tip of the catheter detects the temperature
change downstream. Blood flow can be calculated from the resulting thermodilution curve:

See Levy & Pappano for further

details if you are interested. For
our purposes, you need only be
aware of this principle.

David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

Cardiac electrophysiology I: Cardiac Action Potential, Automaticity, & Conduction

Recommended reading
Levy & Pappano 9th Edition:
Chapter 2: Excitation: The Cardiac Action Potential
Chapter 3: Automaticity: Natural Excitation of the Heart (pp. 33 45)
Objectives
Review cardiac E-C coupling, with close attention to calcium handling.
Describe the specific ionic currents underlying the cardiac action potential (slow & fast).
Understand key differences between cardiac and skeletal muscle action potentials (APs).
Understand absolute and relative refractory period designations.
Describe the ionic basis of automaticity and the role of automaticity in normal physiology,
sinoatrial (SA) node dysfunction (sinus arrest) and AV block.
Become familiar with the mechanisms of cardiac automaticity modulation.
EXCITATION: THE CARDIAC ACTION POTENTIAL
Cardiac muscle cell contraction occurs through a stereotypical sequence known as
excitation-contraction (E-C) coupling. As with striated and smooth muscle, E-C coupling
begins with depolarization of the sarcolemmal membrane by an action potential.
Excitation-Contraction (E-C) Coupling (REVIEW). The concept of E-C coupling was
introduced to you during lectures covering skeletal and cardiac muscle physiology. To
review, E-C coupling involves the following events:
1. Action potential (AP) depolarization of the sarcolemmal and T-tubule system.
2. Membrane depolarization triggers the influx of Ca2+ via L-type Ca2+ channels.
2+
o (NOTE: Unlike skeletal muscle, cardiac E-C coupling requires extracellular Ca )
3. Ryanodine receptor 2 (RyR2, cardiac type) channels in the sarcoplasmic reticulum (SR)
are activated by the initial rise of intercellular [Ca ] , thus amplifying the Ca signal by the
further release of Ca from SR
stores so called calciuminduced calcium release
(CICR).
4. Intracellular Ca associates
with troponin C in the
sarcomere and stimulates
contraction (cardiac systole).
5. Release of Ca from the
sarcomere causes relaxation
(cardiac diastole) and its
reuptake into the SR
compartment by SERCA.
6. Remaining excess intracellular
Ca2+ (an incredible 28%) is
transported to the extracellular
space via Na/Ca exchange.
2+

2+

2+

2+

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2+

David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

The 5-Phases of the Fast-Response Cardiac Action Potential

Atrial and ventricular muscle, along with the His-Purkinje conduction system, exhibit a fastresponse cardiac action (AP) potential which has 5 distinct phases. As with skeletal muscle,
the cardiac action potential begins with a rapid membrane depolarization (Phase 0) via
inward Na+ currents (INa) conducted through voltage-gated Na+ channels. Following this
upstroke, there is a brief period of partial repolarization (Phase 1) mediated by outward K+
currents, followed by a plateau period (Phase 2) of sustained depolarization dominated by
inward Ca2+ currents (ICa) conducted through L-type (long-lasting) Ca2+ channels. The
membrane potential is then rapidly repolarized (Phase 3) by an outward K+ current (IK) via
delayed-rectified K+ channels until the resting membrane potential is achieved (Phase 4).
Excess intracellular Na+ is exchanged for extracellular K+ via Na/K ATPase exchangers.
Similarly, excess intracellular Ca2+ is eliminated an ATP-driven Ca + pump.

Phase 0 Depolarization (Upstroke): In the

fast response a rapid upstroke is primarily
produced by an inward INa conducted through
voltage-gated Na+ channels. Similar to
skeletal muscle, voltage-dependent Na+
channels are activated (1-2 ms) as the
membrane potential (Vm) suddenly
depolarizes across the cardiac cells threshold
potential (about -65 mV). At this point Na+,
driven by a large concentration gradient and
electrostatic forces, rushes into the cell,
producing an inward INa current. As the Vm
crosses 0 mV, electrostatic forces are
neutralized (actually they reverse direction);
however, the inward INa current persists briefly
(due to a continued Na+ concentration
gradient) producing an overshoot in
membrane potential. Immediately after
activation, Na+ channels become inactivated
(recall the Hodgkin & Huxley model from
skeletal muscle) which lasts approximately
100 to 200 ms.
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David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

Phase 1 Early Partial Repolarization: Atrial, His-Purkinje, and ventricular cells

display a notch (partial rapid repolarization) after the depolarization upstroke peak. This
early outward current is mediated primarily by voltage-dependent K+ channels (Kv4.3),
which rapidly inactivate.

Phase 2 Plateau: Following Phase 1, the membrane potentials of all excitable cardiac
cells (except the SA node cells) plateau around 0mV for a period of 200-400 msec. This
plateau is maintained by a delicate balance between inward and outward currents.
o Inward Plateau Currents: By far, the dominant Ca2+ channels, which are inward
current during Phase 2 is that of the long-lasting (L-type) initially triggered during
Phase 0 as Vm reaches a threshold potential of -20 mV. However, L-type Ca2+
channels have a slow response and dont begin to open until the latter part of Phase
0. The inward INa currents (of Phase 0) make a minor/brief contribution to the inward
plateau, though they (as discussed above) rapidly inactivate.
Clinical Correlation
The activity of L-type Ca2+ channels can be inhibited by calcium channel antagonists
such as verapamil, nifedipine, and diltiazem. L-type Ca2+ can also be potentiated by
the -adrenergic signaling of catecholamines, thus increasing contractility (the details
of autonomic control will be discussed in a later lecture).
o

Outward Plateau Currents: Outward currents play a minor role during the plateau
period. Despite large concentration gradients and electrostatic forces, only small
outward IK currents are produced initially. However as the plateau period
progresses, one-way delayed-rectified K+ channels gradually open, producing
gradual repolarization. NOTE: The K+ channels open during the resting Phase 4
(see below) are inwardly-rectifying and thus do not contribute to repolarization
during this period.

Phase 3 Repolarization: Delayed rectifier K+ channels (e.g. HERG, KvLQT1,

KCNQ1) which began opening during the plateau, come on-line in full force during Phase
3. As these outward currents overtake the declining inward Ca2+ currents, rapid
depolarization occurs.

Phase 4 Resting (time between action potentials): In the fast-response tissue of the
atrial and ventricular muscle; and the cells of the His-Purkinje conduction system,
resting membrane potential is determined primarily by the high conductance of inwardly
rectifying K+ channels (e.g. IK1), which close during depolarization and only re-open
during late repolarization, thus driving Vm towards the reversal potential of K+ (-94mV).
A small inward Na+ current is also present which slightly depolarizes Vm to a resting
potential of -90 mV.

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David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

3 KEY differences between the cardiac and skeletal muscle action potentials

Plateau Potentials Cardiac action potential (AP) has long duration (~ 300 ms) as
compared to the skeletal muscle AP (~ 5 ms). This is due to the plateau potential, which is
primarily mediated by L-type calcium channels. The long duration precludes the fusion of
individual twitch contractions and tetany in the heart.
Cell-to-Cell Conduction Cardiac AP is conducted directly from cell-to-cell via gap
junctions.
Automaticity Specialized cells within the cardiac conduction system have intrinsic
pacemaker activity and can thus spontaneously self-generate an AP without an external
trigger (e.g. synaptic motor end-plate of skeletal muscle).

Cardiac AP of Slow-Response Tissue: The ionic basis of automaticity

The AP of pacemaker cells in the
atrioventricular (AV) and sinoatrial (SA) nodes
is characterized by a slow-upstroke (Phase 0)
and a spontaneously-depolarizing (up-sloping)
Phase 4. Also, in the slow response AP, Phase
1 (partial repolarization) is absent. Phase 2
(plateau) is brief and not flat and is blended with
Phase 3 (repolarization). For slow-response
tissue, focus on the following phases:

Phase 0: Pacemaker cells have few, if any,

Na+ channels and thus do not rapidly
depolarize. Instead, they depolarize in a
much slower fashion via inward ICa
mediated by voltage-dependent (longlasting, L-type) Ca2+ channels. Accordingly,
the Phase 0 depolarization is much less steep and smaller magnitude.

Clinical Correlation
+
Like skeletal muscle, activation of Na channels in the heart can be blocked by puffer fish toxin
+
tetrodotoxin (TTX). Blocking Na can convert the upstroke in fast-response cells to a slow
response.

Phase 3: Tends to be less steep than in fast-response fibers.

Phase 4: Pacemaker cells exhibit an unsteady resting potential which gradually

depolarizes eventually reaching the threshold for L-type Ca2+ depolarization. Several
ionic currents are thought to contribute to the slow depolarization including:
o Inward Na+ current known as If (for funny), conducted through HCN1 channel, is
thought to be primarily responsible for this gradual depolarization. It is induced by
hyperpolarization at the end of Phase 3.
o L-type Ca2+ are triggered towards the end of Phase 4 and thus begin to contribute
to this slow depolarization.
o K+ outward currents (which oppose depolarization) diminish towards the end of
Phase 4, and thus also contribute to gradual depolarization.
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David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

Absolute Refractory Period (ARP) and Relative Refractory Period (RRP)

ARP: (aka Effective Refractory Period, ERP) Following the initial upstroke (Phase 0) of
a cardiac action potential, there is an absolute refractory period during which time the
cell cannot fire another AP. This period represents the time it takes for voltagedependent Na+ channels to recover from
inactivation and extends midway into Phase 3
where the Vm repolarizes to approximately 50mV. This refractory period precludes
summation of action potentials which could
result in tetanic contraction of cardiac muscle,
thus allowing the heart muscle to relax
between beats (diastole). Before enough Na
channels recover, however, calcium channels
can generate an inward current and this can
produce a slow upstroke event, which can
sometimes trigger extra beats.

RRP: Recovery from inactivation is a stochastic event, with the probability of recovery
increasing as a function of time and degree of repolarization. During this period known
as the relative refractory period, APs can be triggered, but require a stronger than
normal depolarizing stimulus. In addition, APs during the relative refractory period tend
to have smaller magnitudes. The channel mechanisms underlying this period are more
diverse. It represents a time during which the potassium conductance is larger than it will
eventually be. This increase in K+ permeability, which time dependently diminishes, can
be "overcome" if more inward current is present to counteract the tendency of the K+
channels to keep the potential negative.

AUTOMATICITY: NATURAL EXCITATION OF THE HEART

Unlike skeletal muscle, some cardiac muscle cells exhibit automaticity (the ability to initiate
its own contraction) and rhythmicity (the regular contractions). These properties, while
normally associated with the sinoatrial (SA) node, are also exhibited (albeit at a lower
frequency) by the atrioventricular (AV) node and at times by cells of the His-Purkinje system.
This underlying property of cardiac tissue provides an important back-up pacemaker
system in disease states where the SA node fails to initiate a sinus beat.

SA Node: During normal sinus rhythm (60-100 bpm), the cardiac beat originates from
cells in specialized region of the right atrium known as the SA node as well as 1-2 other
neighboring atrial sites which together comprise the atrial pacemaker complex. Cells of
the SA node normally display the highest frequency of natural excitation. As this sinus
wave of depolarization spreads across the atria, it suppresses automaticity in other cells
in the atria (and ventricles) thus determining heart rate. This phenomena which allows
the SA node to be the dominant pacemaker is known as overdrive suppression the
suppression of automaticity by high-frequency excitation.

Ectopic Atrial Foci & Atrial Escape Rhythms: Occasionally, other cells within the atria
or specialized cells within the atrial conduction system display automaticity. These latent
pacemakers can serve as an important safety measure, triggering escape beats when
the SA node fails to fire due to disease or suppression by drugs or parasympathetic tone.
In the case of persistent impairment of the SA node ectopic atrial foci will produce a
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David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

series of escape beats yielding a protective escape rhythm. Latent pacemaker cells can
also trigger premature atrial depolarizations (ectopic atrial beats) or continuous rhythm
disturbances such as paroxysmal atrial tachycardias (e.g. atrial fibrillation). We will
discuss arrhythmias more in Electrophysiology III.
Clinical Correlation
For those gunning for a cardiology electrophysiology (EP) fellowship, note that cells
in and around the pulmonary veins are often the source of ectopic beats leading to
common atrial arrhythmias such as atrial fibrillation. EPs utilize intravascular
catheters to map the location of these aberrant cells and isolate them from the rest
of the atrium through precision electrocautery to form insulating scar tissue barriers.

AV Node: Pacemaker cells within the atrioventricular (AV) node display natural
excitation at a rate of around 40 60 bpm. In the absence of SA node excitation (e.g.
sick sinus syndrome), the AV node may become the dominant pacemaker.
Purkinje Fibers: When conduction from the atria to the ventricles is blocked at the level
of the AV node (e.g. secondary to ischemia), idioventricular pacemakers within the
specialized Purkinje conduction fibers of the ventricles become the dominant pacemaker
though at an extremely low rate (30-40 bpm) that generally does not result in adequate
cardiac output. Low cardiac output states such as complete block of the AV node are
true emergencies that can quickly deteriorate into cardiac arrest.

Modulation of Pacemaker Rate: The firing rate of pacemaker cells can be modulated by a
variety of synaptic, circulating factors, and pathophysiological conditions such as acidosis
and ischemia. (The autonomic modulation of cardiac activity will be covered in detail in a
later lecture. Here we introduce you to a few of the concepts).

Autonomic synaptic efferents and circulating catecholamines: Unlike skeletal

muscle, the triggering of pacemaker cells in the SA node does not require synaptic input;
however, synaptic inputs from the autonomic nervous system (sympathetic and
parasympathetic), provide short-term modulation of intrinsic pacemaker rates through
ligand-gated channels. Catecholamines (norepinephrine released from sympathetic
nerve endings or circulating epinephrine from the adrenal medulla) increase pacemaker
rates by decreasing conductance of HCN1 (K+) channels through cAMP-mediated 2nd
messenger signaling cascades. Catecholamines also increase slow inward Ca2+ and If
funny Na+ currents. These changes increase the slope of Phase 4 such that the
pacemaker cell Vm more rapidly reaches the threshold for action potential generation.
Conversely, pacemaker firing rate is slowed by acetylcholine released from the vagal
nerves.

Hormones: Pacemaker activity is also altered by hormones. For example, excess

circulating thyroid hormone (T3) in hyperthyroidism induces tachycardia while
hypothyroidism can produce bradycardia.

Serum ion concentrations: Changes in the serum concentration of ions, particularly

potassium, can cause changes in SA nodal firing rate. Hyperkalemia induces
bradycardia or can even stop SA nodal firing. Hypokalemia increases the rate of phase 4
depolarization and causes tachycardia.

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David G. Beiser, MD, MS

Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

Clinical Correlation
During cardiac bypass surgery, cardiothoracic surgeons often temporarily stop the heart
+
using a cardioplegic solution that contains a high concentration of K .
Question: In which phase of E-C Coupling (systole or diastole) does the heart stop?

Cellular hypoxia: Hypoxia (usually due to ischemia) depolarizes the membrane

potential causing bradycardia; severe hypoxia completely stops pacemaker activity
inducing sinus arrest.

Drugs: Various drugs used as antiarrhythmics also affect SA nodal rhythm. Calciumchannel blockers, for example, cause bradycardia by inhibiting the slow inward Ca++
currents during phase 4 and phase 0. Drugs affecting autonomic control or autonomic
receptors (e.g., beta-blockers, muscarinic antagonists) directly or indirectly alter
pacemaker activity. Digitalis causes bradycardia by increasing parasympathetic (vagal)
activity on the SA node; however, at toxic concentrations, digitalis increases automaticity
and therefore can cause tachyarrhythmias. This toxic effect is related to the inhibitory
effects of digitalis on the membrane Na+/K+-ATPase, which leads to cellular
depolarization, increased intracellular calcium, and changes in ion conductances.

CONDUCTION OF FAST AND SLOW ACTION POTENTIALS

The conduction of action potentials through a cardiac muscle fiber occurs over the surface of
individual cells as action potentials in one region of a cell depolarize adjacent membrane
such local circuit conduction is also known as electrotonic (passive) conduction. The
ends of cardiac cells are mechanically-anchored to adjacent cells by intercalated disks
When the wave of depolarization reaches the end of a cell, it is conducted to neighboring
cells via gap junctions which are non-selective, high conductivity, ion channels composed of
proteins known as connexins that form electrical connections between cells. Electrotonic
conduction velocity is primarily determined by the resistive/capacitive properties of cell
membranes, gap junctions, and cytoplasm.

Current Flow through Gap Junctions: An AP conducting from left to right causes
intracellular current to flow from fully depolarized cells on the left, through gap junctions,
and into cell A. Depolarization of cell A causes current to flow from cell A to cell B (IAB).
Part of IAB discharges the capacitance of cell B (depolarizing cell B), and part flows
downstream to cell C.

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Cardiac electrophysiology I

Cell & Organ Physiology: Cardiovascular

Conduction of the Fast Response: In atrial muscle, ventricular muscle, and Purkinje
fibers, a wave of depolarization triggers APs in muscle cells along the length of a cardiac
fiber. The conduction velocity of this propagating wave of depolarization is proportional
to the rate of change in membrane potential during Phase 0 (dVm/dt). Thus rapid
depolarization favors rapid conduction. In addition, conduction velocity is inversely
proportional to resting membrane potential during Phase 4, with lower membrane
potentials resulting in faster conduction velocities.

Phase 0 upstroke velocity and magnitude of depolarization

depend on the recovery of inactivated Na channels. The
probability of recovery is related to both time and degree of
Vm repolarization. Thus, APs arriving during Phase 3 will
produce slower upstrokes of smaller magnitude or no
activation at all (effective refractory period).

Clinical Correlation
Factors which influence the dynamics of Phase 0 or resting membrane potentials during
Phase 4 (e.g. catecholamines, ischemia, ionic concentrations) can drastically alter the rate of
+
depolarization in the heart. Question: Predict the impact of increased extracellular K
concentration on conduction velocity?

Conduction of the Slow Response: Electrotonic spread of is also responsible for

propagation of the slow response within the SA and AV nodes; however, the conduction
is much slower (0.02 0.1 m/s). By comparison, conduction of the fast response is 0.3
1 m/s in myocardial cells and 1 4 m/s in the specialized conduction fibers of the
Purkinje system.

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

Cardiac Electrophysiology II: The Surface Electrocardiogram

Recommended reading
Levy & Pappano 9th Edition:
Chapter 3: Automaticity: Natural Excitation of the Heart (pp. 45-54)
Mohrman & Heller: Lange Series: Cardiovascular Physiology 6th Edition (optional)
Chapter 4: The Electrocardiogram (optional, though well-written)
Boron & Boulpaep:
Chapter 20: Cardiac Electrophysiology and the ECG (great figures)
Objectives
Understand the structure and function of the major components of the hearts conduction
system.
Describe the propagation of cardiac action potential during the normal cardiac cycle
Describe the orientation of the hearts dipole moment vector during different phases of
the ECG
Derive frontal or precordial lead projections given the dipole moment vector
Conversely, calculate the orientation of the mean electrical axis given a frontal lead ECG.
Diagnose the discussed common dysrhythmias related to impulse initiation and AV
conduction.
CARDIAC CONDUCTION PATHWAYS:
Depolarization and subsequent repolarization of the hearts chambers follows a stereotypical
sequence that is determined by the structure of its conduction system.
Structure + Function
SA Node (slow conduction ~ .05 m/s):
During sinus rhythm, pacemaker cells of the
sinoatrial (SA) node initially fire as
described in our last lecture. SA Node firing
is localized to a small region of the atrium.
SA node firing is not evident on the surface
EKG (due to its small dipole moment vector
as explained below).

Atrial Pathways (fast conduction ~1 m/s):

During normal sinus rhythm, APs spread
radially from the SA node pacemaker
throughout the right atrium via regular atrial
muscle fibers. Simultaneously, a
specialized conduction pathway (interatrial
myocardial band, aka Bachmanns
bundle) conducts this depolarizing wave rapidly to the left atrium. The existence of a
fibrous (non-conductive) atrioventricular ring precludes the spread of the atrial impulse
directly to ventricles. Instead, internodal pathways rapidly conduct the signal to the AV
node. The spread of atrial excitation is reflected as the P-wave on the surface ECG.
Clinical Relevance: Many abnormalities in atrial excitation and conduction can be
diagnosed by analysis of the P-wave. For example, though we cannot see the activation
of the SA node, we can infer normal activity of the SA node by looking at shape of the Pwave.

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

AV Node (slow conduction ~ 0.05 m/s): Approximately 0.01 seconds after its origination
at the SA node, the wave of depolarization arrives at the atrioventricular (AV) node,
situated posteriorly on the right side of the interatrial septum and just above the
atrioventricular ring. AP propagation is greatly slowed as it traverses the AV node
imparting a slight delay between atrial and ventricular AP propagation. The slow
response tissue of the AV node contributes to this delay as conduction velocity is
proportional to upstroke velocity (dVm/dt) during Phase 0. In addition, the small fiber
diameter within the AV node increases its resistance further slowing conduction
velocity. Functionally, this delay has hemodynamic advantages, providing the optimal
delay to allow blood in the atria to empty into the ventricles (colloquially the atrial kick)
prior to ventricular contraction. Clinical Relevance: This AV node delay (PR Interval)
largely accounts for the delay between the onset of the P-wave (spread of atrial
excitation) and the QRS complex (spread of ventricular excitation) the so-called PR
interval.

Bundle of His (fast conduction ~ 1 m/s): The bundle of His, which emerges from the AV
node on the right side of the interventricular septum, is the proximal portion of the
ventricular conduction system.

Bundle Branches (fast conduction ~ 1 m/s): The bundle of His divides into the right and
left bundle branches, which carry the signal to the muscle of both ventricles. The right
bundle branch conducts the electrical signal down the right side of interventricular
septum to the right ventricle. The left bundle branch perforates to the left side of the
interventricular septum and then most frequently divides into two main branches-the left
anterior fascicle (or hemibundle) and the left posterior fascicle.

Purkinje Fibers (rapid conduction ~ 4 m/s): Both bundle branches ultimately divide into
a complex network of rapidly conducting Purkinje fibers that invest the ventricular walls.
Purkinje fibers are large diameter (i.e. fast conducting) cells and rapidly spreads the wave
of activation throughout both ventricles. The Purkinje network is also the major locus of
ventricular escape pacemakers (idioventricular pacemakers).

Ventricular Depolarization: Frontal Plane Overview

In order to understand the genesis of the
surface electrocardiogram it is helpful to step
back and view the depolarization of the
ventricles within a frontal plane crosssection of the heart. Keep in mind that this
pattern of depolarization is made possible by
the conduction anatomy described above.
1. SA node fires, depolarizes atria and then
AV node.
2. After a short delay, the signal emerges via
the bundle of His and depolarizes the
interventricular septum from left to right.
3. The anteroseptal region depolarizes via
the bundle branches.
4. The myocardium depolarizes from the
endocardium (the cells lining the
ventricles) toward the epicardium (cells on

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

the outer surface of the heart). The left ventricle depolarizes at the apex, while the
Purkinje fibers are still in the process of conducting the action potential toward the base
of the left ventricle.
5. Depolarization spreads from the apex toward the base, carried by the Purkinje fibers.
This spread to the base begins even as the signal in the "apex" is still spreading from the
endocardium to the epicardium. The last region to depolarize is the posterobasal region
of the left ventricle.
6. The ventricles are fully depolarized.
THE SURFACE ELECTROCARDIOGRAM: The surface electrocardiogram (ECG or EKG)
provides an inexpensive and highly-repeatable measure of heart status. Clinically, the ECG
can provide a wealth of insight into a variety of cardiac parameters including:
heart rate
rhythm
conduction
anatomic orientation of the heart (axis)
chamber size (magnitude of wave)
extent, location, and magnitude of ischemic myocardial damage
In addition, ECGs can also assist in the diagnosis of a wide variety of other classically noncardiac diseases/disturbances related to (for example): pulmonary function, endocrine
function, toxic exposure, drug overdose, trauma, temperature, infection, and inflammation.
Rather than measuring the electrical signal of individual cardiac APs, the ECG provides a net
measure of the small extracellular signals (local circuit currents) produced by the movement
of action potentials (depolarization/repolarization) through cardiac myocytes. The surface
ECG provides a representation of the timing and direction of cardiac action potential
propagation through the heart projected onto 2 orthogonal (i.e. perpendicular) planes.
In order to obtain a standard 12-lead ECG, two electrodes are placed on the upper
extremities (RA, LA), two on the lower extremities (RL, LL), and six on standard locations
(V1, V2, V3, V4, V5, V6) across the chest. In various combinations, the electrodes on the
extremities generate the six limb leads (three standard and three augmented), and the chest
electrodes produce the six pre-cordial leads. In a lead, one electrode is treated as the
positive side of a voltmeter, and one or more electrodes as the negative side. Therefore, a
lead records the fluctuation in voltage difference between positive and negative electrodes.
By varying which electrodes are positive and which are negative, the ECG machine records
a standard 12-lead ECG. Each lead records the heart from a unique angle and plane, that is,
from what is essentially a unique point of view.
The Prototypical ECG:
Before tackling the physics of the ECG, we will consider a prototypical ECG signal. There
are three waveforms and 3 intervals and 2 segments in the ECG.
P Wave represents depolarization of the atria. There is an isoelectric period after the P
wave, when all the atrial cells are on in Phase 2 (plateau) and the ventricles have yet to
be depolarized.
QRS Complex (80 100 msec) represents ventricular depolarization. This
depolarization triggers contraction of the ventricles. The QRS duration is the time it takes
to depolarize both ventricles. This activation is coordinated in a specific pattern by the

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

Purkinje system. Clinical relevance: Diseased tissue typically decreases conduction

rates within the Purkinje system widening the QRS complex.

T Wave is repolarization of the ventricles.

Repolarization of the atria takes place during the
QRS, and it, therefore, is usually buried in the
QRS signal.
PR Interval (120 200 msec) is measured from
the beginning of the P wave to the beginning of
the QRS. It corresponds to the conduction time
from the onset of atrial depolarization and
conduction through the AV node and the HisPurkinje system, ending when the first ventricular
cells are activated.
RR Interval (rate dependent, 100 - 300 bpm =
600 - 200 msec) is the distance between
successive R waves and represents the ventricular rate.
QT Interval (300 450 msec) measures the time between the start of the Q wave
(ventricular depolarization) and the end of the T wave (ventricular repolarization). As you
might guess, this interval is quite sensitive to drugs that impact the length of Phase 2 or
Phase 3. QT interval is inversely proportional to heart rate and thus must be corrected
(adjusted) in the clinical setting. In general it is less than 50% of the RR interval.
PR Segment: Represents the isoelectric period between full atrial depolarization and the
onset of ventricular depolarization
ST Segment: Represents the isoelectric period between full ventricular depolarization
and repolarization.

The Surface ECG Records the Dipole Moment Vector: Electrotonic conduction of the
action potential between adjacent cardiac cells is mediated by local circuit currents which are
driven by the potential difference between depolarized (positive charge) and resting
membranes (negative charge) through the conductive extracellular matrix. To understand
how these events are reflected in a surface ECG it is useful to invoke the concept of dipoles
and dipole moment vectors.
A dipole is a pair of positive and negative charges separated by a distance that have a
particular orientation in space. A dipole creates an electromagnetic force known as a dipole
moment vector whose magnitude is determined by the amount of charge and degree of
charge separation (the concept of a dipole moment vector and dipole vector is used
somewhat interchangeably in the texts, so dont get too caught up in the distinction).
The magnitude of the hearts dipole moment vector is determined by the extent of
depolarized tissue (amount of charge) and the size of the depolarized region (charge
separation). The net dipole vector is also determined by the consistency of orientation
between individual dipoles as dipoles oriented in opposite directions cancel each other out.
Thus depolarization of a small amount of tissue within a small region (e.g. SA node) creates
a tiny dipole moment (which as mentioned before is not sensed by the surface ECG).
Conversely, simultaneous depolarization of a large mass of tissue across a large region (e.g.
left ventricle) creates many dipoles oriented in a similar direction and a resulting large
dipole moment vector. Note, that when all of the heart is either depolarized (Phase 2) or
resting (Phase 4), no boundary exists thus no dipoles are present this period is also
known as the isoelectric point (or period) on the ECG tracing.

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

As the cardiac action potential

propagates through the heart, a
Ventricular
wave front of dipoles forms at the
Isoelectric
repolarization
boundary between polarized and
point
(T wave)
resting tissue creating an
instantaneous dipole moment
vector. At any instant within the
cardiac cycle, the surface ECG
Atrial
Depolarization
measures the net dipole vector
Ventricular
(P wave)
which represents the vector sum
depolarization
(QRS)
of all individual dipole moment
vectors within the heart. As the tip
Mean electrical
of this vector rotates around the
axis
isoelectric point, it traces a set of
Typical frontal plane vector cardiogram.
complex loops in 3-dimensional
space that can be displayed on an oscilloscope screen a technique known as vector
cardiography. The mean electrical axis represents the instantaneous dipole vector during
the most peak phase of ventricular depolarization (aka R-wave peak of the QRS complex).
Understanding the concept of a rotating dipole vector is key to understanding the ECG.
Einthovens Triangle: Tracking the hearts net dipole in the frontal plane
As discussed above, at any instant in time, the net electromotive forces of the heart can be
represented by a dipole moment vector having both a 3-dimensional direction and a
magnitude within the chest. As mentioned above, the tip of this vector can easily be
visualized using vector cardiography; however, this technique is not commonly applied
clinically. Instead, a standard 12-lead ECG is used to record the projection of this vector on
two perpendicular planes the frontal plane (defined by limb leads aka Einthovens Triangle)
and a transverse plane (defined by precordial leads). For his discovery of the mechanism of
the electrocardiogram, Willem Einthoven was awarded the 1924 Nobel Prize in Physiology or
Medicine.

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Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

Standard Limb Leads (I, II, III): Einthovens Triangle is the idealized frontal projection
plane defined by the placement of 3 limb electrodes (RA, LA, and LL). Each side of the
triangle defines a lead, separated by 60, which measures the potential difference
between two bipolar electrodes. Each of these leads provides a somewhat unique view
of the dipole vector over time. The leads are defined electrically as follows:
Lead I = VLA VRA
Lead II = VLL VRA
Lead III = VLL - VLA

Augmented Limb Leads (aVR, aVL, aVF): Additional virtual (or augmented) leads are
defined by the use of unipolar electrodes which measure potential relative to the center of
the chest. These leads (e.g. aVR, aVF, aVL) provide additional perspectives on the 3dimensional electrical vector by measuring the projection of the dipole vector along a line
between the limb electrodes (RA, LA, LL) and a point known as the central terminal of
Wilson though an oversimplification, this essentially involves measuring the potential of
a single limb lead (e.g. RA for aVR) relative to the other 2 leads (e.g. LA and LL).
Derivations of the augmented leads can be found in the text.

Converting Dipoles into the QRS Complex:

ECG leads have a defined
direction and polarity. As the
dipole vector rotates through
space, each lead senses the
component of this vector which
projects along the lead and
subsequently provides a negative
or positive deflection on a scalar
tracing. When the vector points
along the lead a positive deflection
is produced and vice versa. To
better understand this concept,
consider the depolarization
sequence of the ventricles (see
figure) from the perspective of
Lead I. As the septum depolarizes
left-to-right, this produces a
leftward dipole, thus inducing a
small negative deflection (Q wave)
on the Lead I tracing. Next, as
the impulse travels down the
septum and into the ventricles, a
large net dipole is created inducing
an upward (R wave) in all 3 limb
leads. Finally, depolarization of
the left ventricle is completed
producing a small positive (S
wave). Finally, the dipole vector
The QRS complex is the projection of the dipole moment
disappears once the entire
vector on each of the standard limb leads.
ventricle is depolarized an
isoelectric period. Note that the
projection of the dipole vector is
slightly different for each lead.

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

The Mean Electrical Axis: The position of the dipole moment vector during the peak of
ventricular depolarization (peak of R-wave)
is referred to as the mean electrical axis.
o Normal Axis (-30 to +90):
Normally the mean electrical axis of
the ventricles points within the lower
left (anatomically speaking)
quandrant of the frontal plane.
o Left Axis Deviation (-30 to -90):
can indicate a more transverse
anatomic orientation of the heart,
left-ventricular hypertrophy, or a
decrease in right ventricular
depolarization.
o Right Axis Deviation (>90): can
indicate a more longitudinal
orientation of the heart, right
ventricular hypertrophy, or a leftventricular conduction issue.

During the depolarization of ventricles (represented by the

QRS complex), the mean electrical axis of the heart in the
frontal plane is normally +60 relative to Lead I (+ =
clockwise, opposite to mathematical convention). The
Mean electrical axis during ventricular depolarization is
influenced by the anatomic position and size of the heart.
Changes in ventricular size (as can occur in heart failure
and high blood pressure) can alter the size direction of this
vector. The direction of the mean electrical axis can be
easily measured on a vector cardiogram; however, on a
standard ECG, it requires a bit of vector math. Here are a
few methods for calculating the mean electrical axis:
o Vector Addition Method: Vector addition can
be performed easily by plotting the amplitude of
leads I and II (or any frontal leads) along the
appropriate lead direction on and drawing the
resultant vector.
o Equal R-Wave Method: In this method, identify
2 frontal leads with R-waves of approximately
the same magnitude (and direction). The mean
electrical axis is midway between these two leads. For
example, identical R-waves in leads II and III would suggest
an axis of +90 (i.e. along aVF)
o Inspection Methods: Identify the largest R-wave the axis
likely is fairly close to this lead. Conversely, identify the lead
with the smallest R-wave this lead is roughly perpendicular
to the mean electrical axis.
o Geometric Method: (optional, see Boron & Boulpaep p. 500)

II
Vector addition method

Though you should be able to calculate the mean electrical axis by at least one of these methods, in
practice, the axis is usually calculated by the ECG machine.

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David G. Beiser, MD, MS

Cardiac electrophysiology II

Cell & Organ Physiology: Cardiovascular

Ventricular Repolarization The T-wave conundrum (optional material):

Considering the upright shape of the R-wave (depolarization of ventricles), it should
surprise you that repolarization of the ventricles produces an upright T-wave indicating
a dipole moment in the same direction as repolarization. If repolarization occurred along
the same path as depolarization (down the septum and into the ventricles) we would
expect the T-wave to be inverted (because repolarization produces a dipole of reverse
polarity). Instead, repolarization is not quite as well coordinated as it depends on both
the channels in the cells locally and on flow of current from adjacent cells. Two
observations have been floated to explain the upright T-wave:
o

Though not well-understood, the last ventricular cells to depolarize are actually
the first cells to repolarize thus this reverses the order of repolarization.

APs of the epicardial cells are shorter than those in the endocardium, so the main
repolarization starts at the epicardium and moves to the endocardium through the
main wall of the left ventricle (opposite to depolarization). Therefore, the T wave
tends to be in the same direction as the main QRS.

Note, the septal and right ventricular repolarization is sufficiently disorganized that it provides
no coordinated wavefront. The T wave is perhaps the most variable part of the ECG
showing sensitivity to many parameters such as temperature, pH, electrolytes (e.g. K+), and
ischemia.

Converting Dipoles into P Waves: As mentioned before the dipole moment of the SA
node is too small to be measured by the ECG; however, the dipole of the atria as they
depolarize, points primarily along the Lead II axis. Accordingly, Lead II is generally the
best lead for finding an upright P wave of consistent morphology.

Precordial Leads: Six leads (V1, V2, V3, V4, V5, and V6) provide a picture of the dipole
moment as it progresses in the transverse plane. Similar to the augmented frontal leads,
these unipolar leads measure changes relative to a point located in the center of the
heart (see figure). Dipole moments directed towards these electrodes produce positive
deflections while those directed away produce negative deflections. The precordial leads
are closer to the heart than the limb leads and consequently are more sensitive to
changes in dipole (and heart muscle) size. Thus for V1 and V2 (which sits far from the
left ventricle, along the sternum) only a small R-wave is produced as the dipole moment
is largely
perpendicular to the
line between the
center of the heart
and V1.By contrast,
the V6 lead (which is
situated close to the
left ventricle along the
midaxillary line),
records a large
positive R-wave as
depolarization
spreads down the
septum and outward
towards the left
ventricle.

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Cardiac Electrophysiology III: Mechanisms of Cardiac Arrhythmias

Recommended reading
Review cardiac conduction in Cardiac Electrophysiology I lecture
Objectives
Understand the cellular mechanisms of conduction block & reentrant conduction.
Understand cellular mechanisms, anatomic defects, and EKGs for common
tachyarrhythmias & bradyarrhythmias.
Diagnose the discussed common dysrhythmias related to impulse initiation and AV
conduction and reentry.
A FEW COMMON DYSRHYTHMIAS
Dysrhythmias are cardiac rhythm abnormalities that reflect disturbances of either impulse
propagation or impulse initiation. While a detailed discussion of the specific diagnostic
criteria is beyond the scope of this lecture, here we will introduce you to a few general
common dysrhythmias.
Sinoatrial Rhythms
Normal Sinus Rhythm: This refers to a
beat emanating from the SA node at
characteristic rate between 60 100 bpm
(beats per minute) with a normal PR
interval.

Sinus Arrhythmia: This variation in heart

beat is actually a normal response to the
respiratory cycle. It is often quite
pronounced in kids.

Sinus Tachycardia:
Sinus tachycardia
refers to a sinus rhythm
(i.e. emanating from the
sinus node) that is
faster than 100 bpm.
This can occur as a
Sinus Tachycardia. Rate > 100 bpm (~ 125 bpm).
normal autonomic
response to exercise;
however, as discussed in later lectures, can also reflect a response to variety of
pathophysiological states such as hemorrhage, hypoxia, fever, or infection.

Sinus Bradycardia: Defined as a sinus rhythm less than 60 bpm. Sinus bradycardia
can occur in the setting of ischemia or severe hypoxia. In addition, trained athletes often
exhibit a profound resting bradycardia.

Sinus Arrest: While the depolarization of the SA node is not reflected in the ECG, loss
of the SA node (as can occur in ischemia) is usually diagnosed by a change or loss of the
P-wave, signaling the existence of an escape pacemaker.

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Premature Atrial Contractions: PACs are P-waves which emanate from an ectopic
atrial pacemaker in between normal sinus beats. Following a PAC, the ventricles will
depolarize normally as the ectopic impulse still travels through the AV node to reach the
ventricles. PACs generally produce odd or inverted P-waves reflected a change in the
atrial dipole.

AV Transmission Blocks: The conduction of an impulse is blocked when it reaches a

region of the heart which is electrically unexcitable. This can occur at a variety of levels
between the atria and ventricles or within the conduction system of the ventricle itself.

1 AV Block reflects a slowing of

conduction through the AV node. On the
ECG, this appears as a long PR interval
(> 200 ms).

2 AV Block is an intermittent conduction

block, in which the tissue conducts some
impulses but not others, of which there
are two types.
o Mbitz Type I (aka Wenckebach block): Refers to progressive prolongation of
the PR interval on consecutive beats that is followed by a complete block of AV
conduction resultling in a dropped beat (QRS complex). It almost always
suggests disease within the AV node.
o

Mbitz Type II, is a partial block in which the PR interval is constant from beat to
beat, but every nth P-wave fails to conduct to the ventricles resulting in a
dropped beat. The figure below shows 2:1 block.

3 AV Block refers to complete AV

conduction block where no atrial
impulses conduct to the ventricles. In
this case, the atria and ventricles are
triggered by separate (and independent)
pacemakers producing an ECG
characterized by P-waves and QRS
complexes with no apparent relationship
a situation called AV dissociation. In
this case, escape pacemakers within
the Purkinje fibers, which are quite slow and unreliable. Depolarization of the ventricles
may or may not follow normal conduction pathways (so the QRS complex is often wide
and misshapen) depending on the location of the block, and location of the escape
pacemaker this is a medical emergency!

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Ventricular Conduction Blocks:

Another form of conduction block occurs
in the large branches of the His-Purkinje
fiber system ("bundle branch block).
With failure of the His-Purkinje fiber
system, the impulse is left to spread
slowly and inefficiently through the
ventricles by conducting from one
myocyte to the next. This altered
conduction changes the rapid and
coordinated spread of the AP
throughout the ventricle and thus
impacts conduction. In addition, it alters
the direction and magnitude of the ventricular depolarization vector (QRS complex) as
imaged by the surface ECG.
Reentrant Conduction: Under certain conditions, a cardiac impulse may produce selfsustaining circuits of excitation known as reentry loops. Reentry underlies many common
dysrhythmias of ordered and random (e.g. atrial fibrillation, ventricular fibrillation)
conduction.

Normal Conduction: To understand reentry, imagine a conduction pathway (see figure

below) involving a single Purkinje conduction fiber which bifurcates into two branches
which are then connected back to each other by a third bundle or a group of conducting
myocytes this creates a closed conduction loop. Normally, when an impulse arrives, it
will propagate down both arms leaving a zone of recently depolarized (and thus
refractory) cells in its wake. When these impulses later rejoin each other within the
connecting bundle, propagation of around the loop is extinguished as two fronts of
recently depolarized (and thus absolutely refractory) tissue meet this is known as
bidirectional block.

Reentrant Conduction: Reentrant conduction requires closed conduction loops,

unidirectional block, and sufficiently long propagation times.
o

Unidirectional block is a type of partial conduction in which impulses conduct in

one direction but not the other. Normal cardiac tissue conducts action potentials
in both directions. Injured tissue has a greater resistance, and thus slows
conduction and attenuates a wave of depolarization. To get an intuitive
understanding of unidirectional block, consider an asymmetric tissue lesion in
which many more healthy cells may exist on one side of the lesion than the other
(Panel B below). In this situation, depolarization of the large group of healthy
cells (to the right of the lesion) is sufficient for triggering an AP in the small group
of cells underlying the lesion; conversely, depolarization of the small group of cells
underlying the lesion is not sufficient for bridging the wave of depolarization past
the injured area resulting in unidirectional block.

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Long propagation times: The effective refractory time of reentered tissue

adjacent to a unidirectional block must be less than propagation time around the
loop. Such a situation can arise, for example, when tissue is injured (depressed
tissue has slower conduction). In addition, longer propagation times can be
created by increasing the length of a circuit which can occur if the surface area of
the atria or ventricles increases (e.g. secondary to dilated cardiomyopathy).

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Reentrant Tachycardias: Reentrant tachycardias can occur within above the ventricles
(Supraventricular tachycardia) or within the ventricles.

Supraventricular Reentrant Tachycardias: Reentrant circuits above the level of the

ventricles can include the atria (atrial flutter, atrial fibrillation), AV node (atrioventricular
nodal reentrant tachycardia (AVNRT)), accessory pathways (or bypass tracts) along the
groove of tissue between the atria and the ventricles (AV reentrant tachycardia AVRT) or
almost any combination of these. In most cases (except those involving bypass tracts),
these tachycardias are categorized as narrow-complex tachycardias since they display
normal QRS duration. A detailed description of these will be presented in the 2nd year
curriculum. For now, we will focus on atrial tachycardias.
o

Atrial Flutter: Atrial flutter is characterized by rapid and regular atrial activity at a
rate of 180 350 bpm. Thankfully, many of these beats arrive at the AV node
during its refractory period and thus do not conduct to ventricles thus resulting in
a slower ventricular rate. Commonly observed ECG patterns include 2:1 block
(e.g. atrial rate 300 bpm with ventricular rate of 150 bpm), 3:1 block, or variable
block (changing ratio beat-to-beat). From the surface ECG, atrial depolarization
takes on a saw-tooth like pattern reflecting a relatively large and fixed reentrant
circuit within the atria.
Flutter waves: atrial rate ~ 300 bpm (1 large box)
(note, some p-waves are buried in the QRS and T-waves)

Atrial Flutter with 3:1 block

Atrial fibrillation: Atrial fibrillation is characterized by irregularly irregular (i.e.

no random) ventricular beats without discernable P-waves. This randomness is
quite distinctive when palpating a radial pulse while talking to the patient. The
random p-wave morphology reflects the wandering or chaotic nature of the
reentrant atrial circuit. Such random activation does not result in coordinated
contraction of the atrial and thus results in a loss of the atrial kick which leads to
a loss of cardiac output. While the AV node blocks most of these atrial impulses,
further loss of cardiac output leading to hypotension can occur if the ventricular
rate becomes too fast to allow for effective diastolic filling.

Atrial fibrillation: Irregularly irregular narrow complex without P-waves

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Ventricular Arrhythmias: The most common ventricular arrythmias are (1) premature
ventricular beats, (2) ventricular tachycardia, and (3) ventricular fibrillation. Ventricular
arrhythmias are typically more dangerous because they can lead to a significant
reduction in cardiac output or cardiac arrest. As ventricular tachycardias often involve
conduction circuits outside the normal His-Purkinje system, the QRS duration is typically
prolonged. In addition, loss of coordinated conduction leads to a loss of coordinated
ventricular contraction which can lead to decreased (ventricular tachycardia) or no
(ventricular fibrillation) cardiac output. Once again, a full discussion of these rhythms will
be presented next year.
o

o
o
o
o

Premature Ventricular Beats: Clinically, these are often referred to as

premature ventricular contractions (PVCs). Similar to what occurs in the atria,
PVCs are common among healthy, asymptomatic, individuals and are often
benign in course. PVCs appear as additional wide-complex QRS complexes
between normally conducted narrow complex beats.

can occur in healthy individuals

Ventricular Tachycardia:

Unifocal (i.e. same ectopic focus) Premature Ventricular Contraction (PVC)

Ventricular Tachycardia: VT is a series of 3 or more PVCs. Arbitrarily, if it

persists for more than 30 seconds, produces symptoms (e.g. fainting aka
syncope), or requires termination, then it is designated sustained VT. Selfterminating episodes are known as nonsustained VT. Unlike PVCs, patients
with VT usually have underlying structural heart disease or electrical, valvular, or
congenital cardiac abnormalities. Like the atrial flutter, ventricular tachycardia
often exhibits a fixed morphology (monomorphic VT) reflecting a large and
relatively stable underlying reentrant circuit. Polymorphic VT results in QRS
complexes which continually change in shape suggesting multiple ectopic foci.
The clinical significance of VT depends on the rate, symptoms and patient. If it is
relatively slow, it can often be well-tolerated. When rapid, it can quickly devolve
into ventricular fibrillation and cardiac arrest.

Monomorpic Ventricular Tachycardia

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David G. Beiser, MD, MS

Cardiac electrophysiology III

Cell & Organ Physiology: Cardiovascular

Ventricular Fibrillation: VF is an immediate life-threat which leads to complete

loss of cardiac output, cardiac arrest, and death untreated. The VF ECG reflects
wandering reentrant ventricular circuits which cause the ventricles to quiver
rather than contract in a coordinated (effective) fashion. Though usually forgotten
(and buried within the ventricular ECG signal) the atria continue to contract
normally during VF. The etiology of VF can often be traced to structural heart
disease, acute myocardial infarction (ischemia), acidosis, electrolyte
abnormalities, hypoxemia, electrical injury, drug/medications, or familial
myocardial channelopathies such as Brugada Syndrome. The cornerstones of
VF treatment include rapid access to 911, early defibrillation, high quality
cardiopulmonary resuscitation (CPR), and advanced cardiac life support (ACLS).
Cardiac arrest is responsible for as many as 300,000 deaths in the U.S. each
year.

Ventricular fibrillation: chaotic & polymorphic

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

The Peripheral Circulation

Recommended reading
Levy & Pappano:
Chapter 6: Hemodynamics
Mohrman & Heller: Lange Series: Cardiovascular Physiology 6th Edition (optional)
Chapter 6: The Peripheral Vascular System (pages 93-108)
Objectives
1. Gain familiarity with the layout of systemic circulations
2. Understand structure/function of peripheral vessels
3. Develop intuitive understanding of hemodynamic forces and their clinical implications
a. Understand the determinants of vascular resistance
4. Understand how Ohms Law applies to cardiac output, SVR and MAP
a. Understand the functional implications of series vs. parallel resistances
THE PERIPHERAL CIRCULATION: Capillary Beds in Parallel & Series
1) To a first approximation, the
peripheral arterial system is a
network of parallel capillary beds
created by successive generations
of branching arteries & arterioles
from a main trunk (the aorta).

2) Typically, oxygenated arterial blood

flows through a single capillary bed
before entering the venous system.
3) However, in some branches (e.g.
renal circulation) blood flows
through two capillary beds in series
before entering the venous system.
4) In still others (e.g. portal circulation)
blood flows through a path
characterized by parallel and
sequential capillary beds.

2
4

5) In contrast, deoxygenated venous

blood from the right heart can only
take a single pathway through the
pulmonary artery and into the lungs
capillary beds. The lungs
circulation (to be covered in detail in
a later lecture) itself branches
distally into a massively parallel
network of capillaries.
Clinical Correlation: A large blood
Figure 1-4: Schematic of Peripheral Circulation
clot in the pulmonary artery can stop the flow of blood through the heart.

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

HEMODYNAMICS:
Compliance
Analogous to capacitance in physics, compliance is defined as the change in volume that
occurs for a given change in pressure (Compliance = V/P). Thus highly compliant
vessels (e.g. inferior vena cava) can receive a large amount of additional volume with
relatively little change in venous pressure. Conversely, the small changes in volume
produces large changes in pressure within non-compliant (i.e. stiff) vessels such as an
artery.
Flow rate Velocity
It is important to appreciate the distinction between blood velocity and flow rate. Simply
stated

Velocity (V) = fluid speed expressed as distance/time (e.g. cm/s)

Flow Rate (Q) = volume flux expressed as volume/time (e.g. cm3/s, ml/s)

Conservation of Mass/Volume
One of the central physical laws of hemodynamics (and
more generally fluid dynamics) deals with the idea of
conservation of mass. Simply stated, the volume of an
incompressible fluid (e.g. water or blood not air) entering
a conduit (e.g. a non-leaky copper pipe or blood vessel)
exactly equals the volume exiting. This implies that the
average flow rate within a conduit does not change along
its length. Stated mathematically:

Q = (Velocity)(Area)
(cm2)

A=2

10

Q = 10 cm3/s
V=5

1
(cm/s)

10

Conservation of Volume: Qin = Qout

Qin = Qout
As a result of this physical law, its apparent that blood velocity varies inversely with vessel
cross-sectional area: Stated mathematically:
V = Q/A
Limitations: This simple relationship breaks down at very small time scales or when we add
the biologic complexity of pulsatile flows in distensible (i.e. compliant) and leaky (e.g.
capillaries) vessels; however, it works well for understanding simple hemodynamics.
Ohms Law Governs Blood Flow
R
To a first approximation, the physical
V
R
I
Pi
Q
Po
factors that govern blood flow are
analogous to those describing the flow of
Ohms Law
electrical current in a resistive circuit
V
P P
I
=
Q= i o

aka Ohm's Law, which states that current

R
R
(I) flow equals the voltage difference (V)
divided by circuit resistance (R). Drawing
the analogy to fluid flow, the voltage difference is the pressure difference (sometimes called
the pressure gradient or perfusion pressure), the electrical resistance is the resistance to
flow (R) of the blood vessel, and the current is the blood flow rate (Q).

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

Systemic Vascular Resistance (SVR) (aka total peripheral resistance, TPR). SVR refers
to the total resistance to blood flow presented by all of the systemic (excluding pulmonary)
vasculature between the aortic valve and the right atrium. This number cannot be measured
directly in humans and thus we use an analogy to Ohms Law (V = I x R) to approximate it,
namely:
P arterial P venous MAP CVP
=
Q
CO

AP
M

SVR =

Parterial = mean arterial pressure (MAP)

Pvenous = mean central venous pressure (CVP)

CV
P

where :

SVR: systemic vascular resistance

CO: cardiac output (L/min)
MAP: mean arterial pressure
CVP: central venous pressure

Q = blood flow rate or cardiac output (CO)

Clinically, alterations in SVR primarily reflect net changes in factors that influence arteriolar
diameter/tone (and thus resistance) in individual vascular beds. Mechanisms that cause
vasoconstriction increase SVR, and mechanisms that cause vasodilation decrease SVR
(more on this in later lectures).
Mean Arterial Pressure (MAP) Standard textbook definition
So far we have ignored the fact that
arterial blood pressure is actually a
dynamic property that continuously
fluctuates with during the cardiac cycle.
Clinically, we utilize the blood pressure
cuff (sphygmomanometer) to measure
arterial systolic (peak) and diastolic
(trough) blood pressures non-invasively.
While these are convenient measures, the
mean arterial pressure (MAP) provides a
better estimate of the arterial pressure
when calculating perfusion pressure
across a tissue bed. Theoretically, MAP
represents the time-weighted average of
arterial pressure waveform. However,
clinically we do not typically have access to this measurement (which requires an invasive
arterial catheter and signal processing software). Instead, MAP can be estimated from the
clinically-available (and non-invasive) systolic and diastolic blood pressure using the simple
formula:

1
MAP Pdia + ( Psys Pdia )
3
where (Psys - Pdia) is defined a the pulse pressure

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

Mean Arterial Pressure (MAP) Beisers intuitive geometric definition

I have always had difficulty remembering random formulas
beyond those used in 10th grade geometry and physics.
Center of Mass
Recall that MAP is defined as the time-weighted average
height of the arterial pressure wave-form. Note also that
the arterial wave-form can be approximated by a triangle
1/3*PP
(representing the pulse pressure waveform) sitting on-top
of a rectangle (representing the diastolic blood pressure).
The average height of the pulse pressure triangle is equal
Pdia
to the height of triangle (aka the center of mass where half
the mass of the triangle is above and half below). Now
reaching back to your inner-10th grader, remember that the
average height of a triangle is 1/3 of its height. Of course
the average height the diastolic rectangle is the diastolic
blood pressure. Putting it together, MAP is defined as the
diastolic blood pressure plus the average height of the pulse pressure triangle.

PP

Physical Determinants of Resistance

Above we introduced an aggregate measure of hydraulic resistance known as SVR. We will
now discuss the physical parameters that determine hydraulic resistance (R) and discuss the
role of hydraulic resistance in determining blood flow rate. Interestingly, one of the
fundamental laws governing the flow of fluid through cylindrical tubes was empirically derived
not by a physicist (or plumber) but rather a French physiologist (Jean Poiseuille, 1797-1869).
Poiseuilles Law simply states that flow resistance increases with tube length (L) and blood
viscosity (); while decreasing with increasing tube radius (actually inversely as the 4th power
of the radius ~ think of it as the square of the conduit area). Strictly speaking, this law holds
only for laminar flows breaking down when turbulence is introduced (discussed below).
L1

Viscosity
L2
The study of blood rheology (essentially the
Hydraulic Resistance Eq.
RL
study of blood viscosity) is quite complex and
P P 8 L
R= i o =
is covered in some depth in Chapter 6 of L&P.
r1
1
Q
r4
The important concepts are summarized
R
r2
below. The viscosity of a Newtonian fluid
r4
(e.g. water) may be determined via Poiseuilles
R blood viscosity
Law by measuring the flow rate of a fluid
L=
tube
length, r = tube radius, R=resistance, Pi =
through a tube of known length and radius
inflow
pressure,
Po=outflow pressure, = blood
under a constant pressure gradient. Sadly,
viscosity,
Q
=
blood
flow
blood is not a Newtonian fluid. Instead, it is
actually a suspension of erythrocytes within a
high-protein fluid known as plasma. As a
suspension, blood viscosity depends greatly on the density of the suspension (i.e. hematocrit
ratio). Thus anemic (decreased red blood cells) blood has a lower viscosity while
polycythemia (increased red blood cells) increases viscosity. Paradoxically, one of the nonNewtonian properties of blood is that its viscosity decreases as vessel radius decreases in a
phenomenon known as shear thinning (see L&P Chapter 6 for details). The extent of this
decrease is partially dependent on the properties of the erythrocytes themselves.
Accordingly, poorly deforming erythrocytes (e.g. in setting of sickle-cell crisis or
spherocytosis) display less shear thinning and thus increased hydraulic resistance. Blood
temperature also inversely effects resistance as hypothermia decreases plasma membrane
deformability and thus increases blood viscosity.

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

To summarize, blood viscosity (and thus vascular resistance) is altered by:

1) Hematocrit ratio (anemia vs. polycythemia)
2) Vessel diameter (shear-thinning)
3) Erythrocyte shape (sickle cell crisis, spherocytosis)
4) Temperature (e.g. accidental or induced hypothermia)
Laminar vs. Turbulent Flow
Normally, blood flows through vessels in a smooth and efficient manner defined by laminar
flow. Laminar flow can be modeled as a collection of concentric tubes of blood sliding down
the length of the blood vessel. The outermost tube (touching the vessel wall) does not move
at all, while the innermost ring moves fastest. Laminar flow resistance follows Ohms Law
and thus increases linearly with increases in perfusion pressure.
Turbulent flow, which is characterized by chaotic flow eddies, results under certain
conditions of viscosity, velocity and fluid density (through a concept known as the Reynolds
number). Under conditions of turbulence, resistance increases exponentially with velocity.
In the peripheral circulation, flow velocity is probably the most important factor leading to
turbulence. Thus, turbulent flow can be generated by obstructions or irregularities along the
arterial system such as heart valves or carotid artery plaques. Such turbulence generates
sound waves that can be auscultated with a stethoscope. Because higher velocities enhance
turbulence, heart murmurs intensify as flow velocities increase. Elevated cardiac output,
even across anatomically normal aortic valves, can cause physiologic murmurs due to
small amounts of turbulence. This can occur in during the 3rd trimester of pregnancy with
associated increases in cardiac output and anemia (which decreases blood viscosity). Both
factors increase the Reynolds number and thus increase the likelihood of turbulence.

Vessel Cross-Sectional Area

In health, the bodys large/small arteries display very low resistance and thus are excellent
blood conduits. Accordingly, only a small drop in blood pressure is seen across the
large/small arteries. The largest drop in blood pressure occurs across the microvascular
network reflecting the high resistance of the arterioles. This illustration shows how the
arterioles, which determine blood flow into the capillary beds, are actually the points where
vascular resistance is the highest.

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

Velocity (cm/s)

Velocity/Pressure/Area Profiles of the Peripheral Circulation

The arterial system branches distally into successive generations of smaller vessels that
eventually each serve a single capillary bed. While individual arterial branches become
smaller with successive generations, the total number of vessels (and thus total crosssectional area) of each generation of branches actually increases thus blood velocity
decreases along the arterial path. Low capillary blood velocity (~ 1 mm/s) facilitates
gas/nutrient exchange.

50
40
30
20
10
(Mohrman & Heller)

Parallel Resistances: As described above,

Q1, R1
Pi
Po
the peripheral circulation can be thought of as
Qt
Qt
a closed-loop circuit made up of a network of
Q2, R2
resistive capillary beds arranged in a largely
parallel fashion through branches off of main
Q3, R3
trunk arteries (e.g. aorta). In this way, total
blood flow (Qt = 4-6 L/min in 70kg male) is
Qt = Q1 + Q2 + Q3
distributed across a myriad of capillary beds
Qt
Q3
Q1
Q2
supplying the bodys tissues. From
=
+
+
Pi Po Pi Po Pi Po Pi Po
conservation of mass, we know that the total
flow rate (Qt) through this type of circuit is the
1
1
1
1
=
+
+
sum of the flow rates through individual parallel
Rt R1 R2 R3
elements. If we divide this equation by the
perfusion pressure and apply Ohms Law to substitute resistance for this fraction we see
that the total resistance (Rt) of the network is less than the resistance of any individual
element. In hemodynamics we define the hydraulic conductance as the reciprocal of
resistance. Using conductances, we see that that total conductance is the sum of individual
conductances.
Thus, while the resistance of an individual capillary is quite high (due to its small internal
diameter), the branching architecture of the capillary network creates a massively parallel
resistive network (estimates of ~ 1010 capillaries in the peripheral circulation) which, when
aggregated, contributes negligible resistance to the average capillary bed.

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David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

Another way to conceptualize how parallel resistances add together is to recall a

simplified version of Poiseuilles Law (stated above) which states that resistance is roughly
inversely proportional to the square of the vessel cross-sectional area. This relationship can
be applied to the aggregate cross-sectional area of a network of parallel vessels to estimate
hydraulic resistance. For example, unlike arterioles, capillaries contribute little to the total
resistance. To understand why, consider that the total cross-sectional area presented by the
entire capillary network (estimates range 1300 -- 4500 cm2) is approximately 10 20 times
larger than that of the arteriole resistance vessels ( estimated range 50 500 cm2). If we
assume that the majority of the bodys capillaries are arranged in parallel to each other, we
can apply Poiseuilles Law to estimate that capillary resistance is approximately 100 400
times lower than that of the arterioles under basal conditions!
Clinical Correlations:
In a massively parallel system large increases in resistance within an individual
branch (e.g. cross clamping a femoral artery) have a relatively small impact on total
resistance and thus little impact on blood pressure.
In shock states (e.g. hemorrhagic shock) the body attempts to shunt blood to vital
organs by dramatically increasing the resistance of non-vital (e.g. skin, skeletal
muscle) tissues.
Series Resistances: Some capillary beds (e.g. renal peritubular/glomerular) are arranged in
a sequential fashion.
Total resistance (Rt) in this type of arrangement equals the sum of individual
resistances.
Clinical Correlation: In the renal capillary beds, the peritubular capillary network is
anatomically connected in series with the glomerular capillary bed through the
efferent arteriole such that changes in the physical determinants of renal GFR will
critically influence the hydraulic and oncotic pressures in the peritubular capillaries.
As a consequence of this anatomic relationship, the hydraulic pressure in peritubular
capillary is significantly lower than that of the post-glomerular efferent arteriole,
allowing for re-absorption of filtered plasma.

Q Pi

R1
P1

R2
R2

R3
P2

Rt = R1 + R2 + R3
Vessel Structure + Function
Arteries (distribution, dampening)
Vessels such as the aorta and large
and small arteries serve as conduits for
distributing blood to regional capillary
beds. Compliant arteries (e.g. the
aorta) dilate during systole and contract
during diastole and thus serve as
hydraulic filters that dampen the
hearts pulsatile outflow to supply a
near continuous (and virtually nonpulsatile) flow of oxygenated blood at
the level of the capillary.

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Po

David G. Beiser, MD, MS

Peripheral Circulation

Med. Biology 303: Cardiac Physiology

Veins (distribution, storage) These thinwalled conduits are the major source of
compliance (defined in next section) in the
cardiovascular system. In fact, >65% of the
total blood volume resides within the large
veins. This high compliance system
dampens (i.e. attenuates) the influence of
total blood volume on venous return to the
heart (i.e. preload). In other words, large
changes in volume produce relatively small
changes in venous pressure. Clinical
Correlation: Large changes in intravascular
volume (e.g. during massive hemorrhage)
produce relatively modest changes in
central venous pressure. The effect of
hemorrhage on venous pressure is
minimized further by the autonomic nervous
system (discussed in later lectures), which
decreases the compliance of the venous
system leading to venous constriction and up to a 30% reduction in venous intravascular
volume. Venous constriction has very little impact on Systemic Vascular Resistance (see
Hemodynamics below for additional details).
Arterioles (resistance, stop-cocks) Arterioles (5-100 m diameter) are comprised of
an inner layer of endothelial cells is encased by a circular layer of smooth muscle cells
surrounded by adventitia, which
is innervated primarily by the
sympathetic nervous system.
Vessel resistance is modulated
by smooth muscle contraction
and relaxation. Changes in
arteriole resistance control the
systemic vascular resistance
(SVR) and direct the regional
distribution of blood throughout
the body (local and central
control mechanisms will be
discussed in later lectures.
Metarteriole (local tissue bed
distribution) Metarterioles (10-20 m diameter ) serve as thoroughfare conduits
connecting arterioles to venules (bypassing capillary beds). Their structures mirrors that
of arterioles except usually not innervated by autonomic nervous system.
Capillary (filtration/exchange) Capillaries (5-10 m dia, Length ~ 0.5-1.0 mm) are single
layer endothelial conduits devoid of smooth muscle (though capillaries do not contract,
they do change conformational shape in response to certain biochemical stimuli through
the action of actin/myosin fibers yielding larger, leaky, pores). High total surface area
and low flow velocity promote efficient tissue oxygen/nutrient delivery. Capillary density
(i.e. anatomical distribution) within a tissue varies directly with tissue metabolic activity.
Denser networks exist in heart vs. subcutaneous tissues.
Venules (fine-tuning of capacitance/resistance) Venules are post-capillary vessels with a
thin smooth muscle layer and less abundant nerve innervation. They provide
capacitance as well as additional resistance distal to capillaries, which plays a role in
regulating hydrostatic pressure within capillaries (discussed in Microcirculation lecture).

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

The Microcirculation, Lymphatics & Local Control of Blood Flow

Recommended reading
Levy & Pappano:
Chapter 8: The Microcirculation and Lymphatics
Chapter 9: The Peripheral Circulation and Its Control (p. 157-167)
Mohrman & Heller: Lange Series: Cardiovascular Physiology 6th Edition (optional)
Chapter 6: The Peripheral Vascular System (pages 93-108)
Chapter 7: Vascular Control (pages 117-133)
Objectives
1. Become familiar with structure/function of the microcirculation
2. Understand the transcapillary mechanisms of gas, water, and solute transport
3. Understand (and apply clinically) the forces of capillary filtration/re-absorption
4. Understand the local control mechanisms of the peripheral circulation (resistance)
a. Understand how intrinsic autoregulation regulates tissue blood flow
THE MICROCIRCULATION
From a reductionist biomedical engineering perspective, the human cardiovascular system is
a two-pump (left and right ventricles) two-exchanger (lung and end-organs) system. Given
our focus so far on hemodynamic measures such as cardiac output, compliance, resistance,
and blood pressure it is easy to lose sight of the primary function of the cardiovascular
system maintaining a suitable environment for cellular life through the delivery and
exchange of nutrients, gases, waste, and thermal energy between tissues and the external
environment. At the level of the lungs and other organs, this exchange is exquisitely
controlled by the arterioles, capillaries and venules constituting the microcirculation.

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Microcirculation Structure + Function

The microcirculation is made up of
distributed networks of arterioles, metaarterioles, capillaries, and venules. The
structure of each of these vessel types
(introduced in the Peripheral Circulation
lecture) determines their function.
The regulation of regional blood flow (and
thus gas/solute exchange) is primarily
achieved through dynamic changes in
pre-capillary resistance which is the net
sum of hydraulic resistance presented by
small arteries, arterioles, and pre-capillary
sphincters. Arteries and arteriole vessels
consist of endothelial layers wrapped by
thick layers of vascular smooth muscle
cells (VSMC), which are innervated by nerve endings from the autonomic nervous system.
Arteriole diameter can vary between complete obliteration by strong contraction and infolding
of smooth muscle (acting as an arterial stop-cock) to maximal dilation. Under basal
conditions, the majority of vascular smooth muscle cells maintain partial contraction (basal
tone). Passive stretch decreases vascular resistance while passive recoil increases
resistance. Pre-capillary sphincters are small cuffs of smooth muscle that are usually not
innervated but instead respond to local tissue conditions.
At their distal ends, true capillaries merge into venules (inner radius: 5-25 m), which carry
blood back into low-pressure veins that return blood to the heart. Venules have a
discontinuous layer of VSMCs and, therefore, can regulate local blood flow (though their
contribution to overall resistance is negligible). Venules may also exchange some solutes
across their walls.

Autoregulation

INTRINSIC (LOCAL) CONTROL OF SYSTEMIC VASCULAR RESISTANCE (SVR):

The cardiovascular system utilizes the control
Autoregulation
of SVR to deliver blood to tissues at a flow
rate that optimally matches tissue metabolic
demand for O2,and nutrients while
simultaneously carrying away CO2 and other
waste products. Ultimately, SVR is controlled
by a balance of intrinsic (autoregulatory) and
extrinsic (autonomic) mechanisms. The
relative importance of extrinsic vs. intrinsic
control varies across different tissue beds.
For example, autonomic control predominates
in the skin while the control of heart vessels
resistance is dominated by local intrinsic
Muscle blood flow immediately after change in
factors.

perfusion pressure (closed circles) and following

autoregulatory compensation (open circles).
Box = autoregulatory range.

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Autoregulation: Autoregulation is an intrinsic mechanism, or vessel property, by which

capillary blood flow through is adjusted to maintain homeostasis in response to arterial
transmural pressure, blood velocity, and changes in local tissue metabolic activity. In many
tissues (most notably skeletal muscle), autoregulation allows for relatively constant tissue
blood flow across a wide range (20 -120 mmHg) of mean arterial pressures (perfusion
pressures). Several autoregulatory mechanisms have been proposed to play a role in this
local control system:

Myogenic (stretch)

Myogenic mechanism (stretch):

Increases in transmural pressure
(i.e. difference between
intravascular and interstitial
hydrostatic pressures) stretches
smooth muscle in precapillary
vessels. Such stretching causes
stretch-depend ion channels to
open and trigger depolarization
and subsequent contraction of
smooth muscle. Such an increase
in transmural pressure might be
expected to occur during periods
of increased cardiac output.
Thus, at constant rates of tissue
metabolism, imposed changes in
arterial pressure are met with
changes in vascular resistance
that tend to maintain a constant
blood flow within a local tissue
bed. This mechanism does not
require the endothelium.

To summarize, the Myogenic Mechanism...

transmural pressure stretches smooth muscle opens ion channels triggers smooth
muscle contraction arteriole diameter resistance (R) attenuates impact of
pressure change on local tissue flow rate (Q)
(The opposite occurs in response to decreases in transmural pressure)

Endothelial release of Nitric Oxide (shear stress): In isolated coronary arteries,

perfused at constant transmural pressure, increases in flow velocity elicit vasodilation.
This vasodilation is mediated by nitric oxide (NO, formerly known as endotheliumderived relaxing factor or EDRF) and prostacyclin (PGI2) which are released by
endothelial cells in response to a velocity-related increase in shear stress. NO freely
diffuses into smooth muscle, activates guanylate cyclase, increased cGMP inhibits Ca++
release and influx which promotes smooth muscle relaxation. This response is ablated
by removing the endothelial layer (see figure below).

Schematically, shear stress impacts resistance as follows:

blood velocity shear NO/PGI2 arteriole diameter (R) blood velocity

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Endothelial (shear)

Metabolic mechanism: Arterioles maintain a degree of basal tone (i.e. vasoconstriction)

or partial contraction under physiologic conditions. A variety of tissue metabolites (e.g.
lactic acid, CO2, H+) have been proposed as locally-synthesized metabolic vasodilators.
An increase in metabolic rate (e.g. during exercise or increased temperature) increases
the production of these vasodilators and produces a subsequent increase in tissue blood
flow referred to as active hyperemia. In the setting of constant metabolic rate, increased
blood flow leads to wash-out of basal metabolites leading to compensatory
vasoconstriction. During periods of reduced blood flow or tissue ischemia, metabolite
build up promotes vasodilation and thus produce a reactive hyperemia which increases
blood flow following the resumption of blood flow.

Metabolic Mechanism
blood flow

[metabolites]

vasodilation

resistance

Reactive Hyperemia
(Mohrman & Heller)

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Capillary Filtration/Exchange Vessels: Functional Anatomy

As mentioned in the Peripheral circulation lecture, capillaries are single layer endothelial
conduits (5-10 m dia, Length ~ 0.5-1.0 mm), devoid of a smooth muscle outer layer. Single
cell-layer construction permits the efficient exchange of gases, solutes and water by 3
different mechanisms including diffusion, filtration, and transcytosis. Efficient exchange is
also enhanced by the vast number of capillaries which has been estimated to be in excess of
1010 in the peripheral vascular system. Capillary density within a tissue is closely matched to
tissue metabolic activity with denser networks in metabolically active tissues such as the
heart. Slow capillary blood velocities (~ 1 mm/s) also enhance this exchange by allowing for
equilibration between the intravascular and interstitial compartments.
Despite such flimsy single-cell layer construction, capillaries are able to withstand relatively
high transmural pressures without rupturing. This apparent paradox is explained by the Law
of Laplace, which describes wall-tension in thin-walled conduits:
T = Pr
where :
T = vessel wall tension
P = transmural pressure
r = vessel radius
Wall tension (T) is the force that ruptures a vessel wall. Small capillary radii yield
exceedingly small vessel wall tensions. Thus under conditions of equal transmural pressure,
the Law of Laplace suggests that wall tension in the aorta (2.5 cm diameter) is 5000 times
higher than that experienced by a capillary (diameter 0.0005 cm) wall!
Capillary Exchange of Gases and Solutes: Passive diffusion
Passive diffusion down concentration
gradients (as governed by the Ficks First
Law) is the key mechanism for promoting the
exchange of gases, substrates, and waste
products between the capillaries and tissue
cells.
Ficks First Law states that diffusion rate
depends on
1. concentration difference
2. vessel surface area for exchange
a. ~ 100 m2 (roughly a tennis court).
3. diffusion distance between cell & capillary
a. < 10m for most cells
4. permeability of the capillary wall to diffusing substance
The gases O2 and CO2 are lipid soluble and thus freely diffuse by a transcellular route
across the two cell membranes and cytosol of the endothelial cells of the capillary. Arterial
blood has a relatively high O2 level. As blood traverses a systemic capillary O2 diffuses
across the capillary wall and into the tissue space, which includes the interstitial fluid and the
neighboring cells. CO2 diffuses in the opposite direction from the tissue space into the
capillaries.

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Capillary permeability to small polar particles such as sodium and potassium ions is thought
to be mediated by small water-filled openings known as channels, pores, intracellular clefts,
and fenestration. As mentioned previously, capillary endothelial cells are unable to contract;
however, they are able to change conformational shape in response to certain biochemical
stimuli through the action of actin/myosin fibers yielding larger, leaky, pores. Individual
pores are thought to be about 40 as solutes greater than that size do not freely diffuse in
healthy capillaries. Thus albumin and other plasma protein are normally confined to the
capillary lumen.
Capillary Exchange of Solutes: Transcytosis
Large macromolecules can cross the capillary at low rates through pores; however, a second
mechanism for macromolecular translocation is known as transcytosis. Transcytosis
involves creation of pinocytotic vesicles at the luminal or extracellular side of the plasma
membrane which get pinched off, shuttle through the cytoplasm, fuse with other vesicles, and
finally fuse with the opposite plasma membrane to release their contents. The laws of
diffusion do not apply directly to this mechanism.
Capillary Exchange of Water (Filtration/absorption):
About 20 liters per day of water is thought to be filtered back and forth through capillary
endothelium through both water-selective channels known as aquaporins and through small
(clefts) pores between adjacent endothelial walls. The Starling Equation estimates the
direction and magnitude of net water filtration across the capillary wall to the interstitium.
The equation simply computes the algebraic sum of outward pressures (hydrostatic +
oncotic) and inward pressures (hydrostatic + oncotic) on water filtration and then and
multiplies this sum by a proportionality (or filtration) constant (k) to get the magnitude (and
units) correct:

Q f = k[(Pc + i ) ( Pi + c )]
(Outward) (Inward)
where...
Qf = rate of fluid movement from capillary lumen to interstitium (ml/min)
k = filtration constant (ml/min/mmHg)
Pc , Pi = hydrostatic pressure of capillary
lumen and interstitium (mmHg)
c , i = colloid osmotic (or oncotic) pressure
of plasma and interstitium

(Mohrman & Heller)

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Water is also subject to the laws of

diffusion governing solutes and gases.
While somewhat confusing to think
about, the diffusional exchange of H20
across the capillary beds is thought to
be on the order of 80,000 liters/day.
Thus, the diffusional exchange of H20
occurs at a much higher rate than
filtration. However, this diffusional
exchange is not thought to contribute
significantly to the next movement of
H20. In other words, 80,000 liters
diffuse out of the capillaries, and 80,000
liters diffuse back in. DONT GET
HUNG UP ON THIS POINT!
Lymphatic Drainage:
Water filtration at the arteriolar end of
capillaries exceeds reabsorption at the
venular end by 2 to 4 liters/day. Under
healthy conditions, the lymphatic system is
responsible for returning most of this net
fluid and solute back to the intravascular
compartment in order to maintain a steady
state. Lymphatic flow also returns ~ 2550% of total plasma proteins/day to the
vascular compartment each day. This flow
is augmented by skeletal muscle
contraction. Lymphatics are absent from some tissues (e.g., myocardium, brain). They are
most prevalent in the skin and the genitourinary, respiratory, and gastrointestinal tracts. The
large lymphatic vessels, like the veins, have valves, which restrict the movement of lymph in
the retrograde direction. These large lymphatics ultimately drain into the left and right
subclavian veins (via thoracic duct).

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David G. Beiser, MD, MS

The Microcirculation

Cell & Organ Physiology: Cardiovascular

Clinical Correlations: The Starling equation is never actually calculated in a clinical setting
because we do not have access to any of its variables; however, it is important to develop an
understanding of the forces involved in water filtration in order to develop an intuitive feel for
the impact of the multitude of therapies and disease states which have the potential to impact
filtration.
For example, disease states such as severe burns, trauma, sepsis, toxic exposure and
cardiac arrest increase capillary permeability, leading to significant increases in the filtration
constant, along with leakage of proteins into the interstitial space, increasing the interstitial
osmotic pressure (i) -- an outward force. In the setting of normal blood pressures, this often
leads to interstitial edema formation.
To enhance your filtration intuition, use the Starling relationship to predict the clinical impact
of the following diseases/therapies. Which conditions promote interstitial fluid (edema or
ascites) formation, vascular re-absorption, lymphatic flow or changes in filtration constant?
Write your answers schematically below:

Severe dehydration (think salt and water deficit)

Protein malnutrition (think plasma proteins)

Intravenous albumin infusion

Intravenous H20 infusion

Protein wasting disease state (e.g. nephrotic syndrome)

Hemorrhagic shock

Prolonged standing (why is standing different from walking?)

Lymphatic blockage (e.g. following radical mastectomy or elephantitis -beware Google Image search of this topic requires a strong stomach)

Inflammation (think increased capillary leakiness)

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Jason Poston, MD

Cell & Organ Physiology: CV physiology

CONTROL OF CARDIAC OUTPUT: VENTRICULAR-VASCULAR COUPLING

Recommended reading
Levy & Pappano:
Chapter 7: The arterial system
Chapter 10: Control of cardiac output: coupling of heart and blood vessels
KEY CONCEPTS
The arterial system acts as a hydraulic filter.
The compliance (change in volume per change in pressure) of the arterial system varies
from person to person, and tends to decrease with age.
The blood pressure is determined by the amount of blood in the arterial system and the
arterial compliance.
Pulse pressure is proportional to stroke volume, and inversely proportional to arterial
compliance.
The systemic vessels are responsible for providing the hearts preload, and thus play a
major role in controlling cardiac output.
Cardiac output and venous return are closely related and can only differ transiently.
So far weve discussed the heart and the blood vessels independently. Today we will stitch
them back together and begin to discuss how they interact to control the blood pressure and the
cardiac output.
THE ARTERIAL SYSTEM
The hydraulic filter
Lets begin with a brief discussion of the arterial system. Dr. Beiser has already described a
number of the properties of this system.
How does the body convert an intermittent cardiac output to a continuous flow at the capillary
level? It does so by ejecting the stroke volume into an array of elastic conduits in line with highresistance terminals. The energy stored in the walls of the aorta and similar conducting vessels
serves to propel blood into the periphery during diastole as seen in the panel on the left below.

Systole

Diastole

If, however, you remove the aorta and other large conducting vessels and replace them with
lead pipes, the capillaries will no longer receive flow during diastole. This is because the walls of

Jason Poston, MD

Cell & Organ Physiology: CV physiology

the lead pipes are not distensible, and therefore cannot store any of the stroke volume to be
subsequently propelled peripherally during diastole.
Aging causes a stiffening of the aorta (a true hardening of the arteries; see the panel on the
right above). This panel shows pressure-volume relationships for aortas obtained at autopsy
from humans in different age-groups. The pressure that results from the injection of a given
volume increases with age. This means that aging causes the aorta to become less compliant:
Compliance = volume
pressure
What makes a blood pressure?
The blood pressure is determined by the amount of blood in the arterial system and the arterial
compliance. As discussed above, arterial compliance varies between individuals, increasing
with age and with other conditions leading to hardening of the arteries. However, arterial
compliance is relatively constant for a given individual. Thus, blood pressure is regulated from
moment to moment chiefly by altering the arterial blood volume. This volume is determined by
the rate of inflow (the cardiac output) and the rate of outflow (the peripheral runoff). A sudden
increase in cardiac output will increase blood pressure (so long as peripheral resistance is
constant) because more blood is transferred from the venous circuit to the arterial system than
runs off from the arterial system to the venous circuit. Similarly, an increase in peripheral
resistance will increase the blood pressure (so long as cardiac output remains constant) by
holding more blood on the arterial side.
The following figure from Levy and Pappano describes the measurement of the blood pressure
with a sphygmomanometer.

Measurement of the blood

pressure. I still have my blood
pressure cuff from medical
school. For the most part, it has
been used on my medical
school roommates and my
family.

The relationship between pulse pressure and stroke volume

Dr. Beiser discussed how we can estimate the mean arterial pressure from the systolic and
diastolic blood pressures. Now lets consider another concept, the pulse pressure:
pulse pressure = systolic BP diastolic BP

Jason Poston, MD

Cell & Organ Physiology: CV physiology

An increased pulse pressuresay, from 50 mm Hg (BP 120/70) to 80 mm Hg (BP 160/80)

may indicate that the arterial compliance is reduced, as occurs in many older patients with socalled isolated systolic hypertension:

Figure 7-12. For a given volume increment (V2 - V1), a

reduced arterial compliance (compliance B compliance A)
results in an increased pulse pressure [(P4 - P1) &gt; (P3 P2)].

An increase in stroke volume may also increase the pulse pressure. Septic shock is an example
of this phenomenon. Imagine a patient with a reduced blood pressure (80/30) but a robust pulse
pressure (50 mm Hg). In this case, mean arterial pressure is reduced because of the sepsisinduced reduction in peripheral resistance. This reduced peripheral resistance decreases left
ventricular afterload and allows the ejection of a greater stroke volume, reflected by a wide
pulse pressure.
Clinical correlation: We apply this principle regularly in the intensive care unit when we evaluate
patients with shock. Clinically, the patient with shock due to sepsis (serious infection) presents
with signs of an elevated cardiac output and peripheral vasodilation, with warm extremities,
brisk capillary refill, bounding pulses, and a wide pulse pressure. Conversely, the patient with
shock due to hypovolemia or heart failure presents with signs of a reduced cardiac output and
peripheral vasoconstriction, with cool extremities, sluggish capillary refill, thready pulses, and a
narrow pulse pressure.
Bonus: In your evaluation of a patient in shock, you determine that the patient is suffering from a
low cardiac output form of shock. How can you distinguish hypovolemia from heart failure on
physical examination?

120

Aortic pressure tracing as seen in two

different clinical states. Pulse pressure is
proportional to stroke volume, and inversely
proportional to arterial compliance.

80
40
0

Low Cardiac Output

High Cardiac Output

Jason Poston, MD

Cell & Organ Physiology: CV physiology

CONTROL OF CARDIAC OUTPUT: VENTRICULAR-VASCULAR COUPLING

Introduction
This next part can be a little tricky. Lets take a moment to consider why this subject is worth
discussing.
What is the cardiac output?
Cardiac output = stroke volume x heart rate
What are the determinants of stroke volume?

Preload
Afterload
Contractility

Afterload is controlled through changes in arteriolar smooth muscle tone. Contractility, which
describes cardiac performance in the setting of a given preload and afterload, is an intrinsic
property of the heart, albeit one that can be modified by external influences such as sympathetic
stimulation or drugs (e.g. digitalis). Preload determines myocardial fiber length and thus the
force of contraction.
Because the systemic vessels provide the hearts preload, they play a major role in
controlling cardiac output.
The vascular function curve
Consider a simplified model of the cardiovascular system. Lets consider the heart as a single
pump. The heart pumps blood into the arterial system, which has high resistance, high
pressure, low volume and low compliance. Blood passes through this circuit into the venous
system, which has low resistance, low pressure, high volume, and high compliance. If the heart
suddenly stops, what will happen?

Pra

PA

A simplified model of the cardiovascular

system. Pra=right atrial pressure,
Pla=left atrial pressure, Ppl=pleural
pressure, PA=alveolar pressure.

Pla

CO2 O2
Ppl

CO2 O2

In the moment immediately following cardiac arrest, blood flow will continue from the arterial
system to the venous system, while the heart will no longer transfer blood from the venous side
to the arterial side. As a result, arterial pressure will fall, while venous pressure will rise.
Because the compliance of the venous system is approximately 20x that of the arterial system,

Jason Poston, MD

Cell & Organ Physiology: CV physiology

the venous pressure will rise 1 mm Hg for every 20 mm Hg fall in arterial pressure. Ultimately,
the arterial and venous pressures will become equal. The pressure that results (which
unfortunately has more than one name) is the mean circulatory pressure (Pmc) or mean
systemic pressure (Pms). This pressure is determined by the volume of blood in the system
and the compliance of the system.
Figure 10-5 The changes in arterial (Pa) and central
venous (Pv) pressures produced by changes in
systemic blood flow (Qr) in a canine right-heart
bypass preparation. Stepwise changes in Qr were
produced by altering the rate of a mechanical pump.
(From Levy MN: Circ Res 44:739, 1979.)

If the heart is restarted, what will happen? The heart will begin to transfer blood from the high
compliance, high volume venous system to the low compliance, low volume arterial side. The
pressure on the venous side will fall, but much more slowly than the arterial pressure will rise
(1/20th the rate, in fact). The mirror image of the above experiment is the result. In fact, this
experiment can be performed in dogs by replacing the heart with a mechanical pump, permitting
precise control of the cardiac output. The change in central venous pressure produced by
changes in cardiac output can be plotted on a vascular function curve.

Figure 10-3. Changes in central venous pressure produced

by changes in cardiac output. The mean circulatory pressure
(or static pressure), Pmc, is the equilibrium pressure
throughout the cardiovascular system when cardiac output is
0. Points B and A represent the values of venous pressure at
cardiac outputs of 1 and 5 L/min, respectively.

Pms is affected by changes in blood volume or venomotor tone. In fact, the regulation of
venomotor tone is one of the principal mechanisms by which the cardiac output is controlled.
The vascular function curve is shifted leftward or rightward in response to decreases or
increases in blood volume or venomotor tone, respectively (see panel on the left below). The
slope of the vascular function curve is affected by changes in peripheral resistance, with
increases in resistance resulting in a clockwise rotation of the curve (see panel on the right
below).

Jason Poston, MD

Cell & Organ Physiology: CV physiology

These curves are also called venous return curves. Venous return is really another way of
saying cardiac output, but applies to the blood flow returning to the heart. The equation for
venous return is:
Venous return = Pms RA pressure
Resistance to venous return
Pms thus is the driving pressure for venous return. An increase in Pms, as with transfusion or
increased venomotor tone, will increase venous return, as will a decrease in resistance to
venous return (RVR). An example of the latter is the opening of an abdominal arterio-venous
fistula between the aorta and inferior vena cava, causing a large fraction of the cardiac output to
traverse a low resistance circuit. Septic shock is another example of a condition characterized
by a reduction in peripheral resistance, when poorly understood metabolic factors cause a large
number of small, low-resistance, arteriovenous shunts to be opened. Conversely, an increase in
peripheral resistance will decrease venous return.
Ventricular-vascular coupling
You already know the cardiac function curve. It is an extrapolation of the Frank-Starling
relationship to the entire heart, and it describes cardiac output as a function of preloadin this
case, central venous pressure. It is possible to analyze the coupling between the heart and
systemic vessels by plotting the cardiac function curve and vascular function curve (also called
the venous return curve) on the same axis:

Figure 10-8. Typical vascular and cardiac function curves

plotted on the same coordinate axes. Note that to plot
both curves on the same graph, the X and Y axes for the
vascular function curves had to be reversed. The
coordinates of the equilibrium point, at the intersection of
the cardiac and vascular function curves, represent the
stable values of cardiac output and central venous
pressure at which the system tends to operate. Any
perturbation (e.g., a sudden increase in venous pressure
to point A) institutes a sequence of changes in cardiac
output and venous pressure that restore these variables
to their equilibrium values.

The equilibrium point occurs at the intersection of these two curves. At steady state,
cardiac output equals venous return. Perturbations in the system may cause transient
deviations from this point. Ultimately, however, a new equilibrium point is established. The
following panels illustrate perturbations in the system:

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Venous Return (CO) l/min

Blood transfusion. The vascular

function curve is shifted to the right.
The new equilibrium point (arrow) is
shifted upward and to the right, at a
higher cardiac output and central
venous (right atrial) pressure.
0

10

Venous Return (CO) l/min

PRA (mmHg)

Reduced myocardial contractility.

The cardiac function curve is shifted
to the right. The new equilibrium
point is shifted downward and to the
right, at a lower cardiac output and
higher central venous (right atrial)
pressure.

10

PRA (mmHg)

Lets take the example of reduced myocardial contractility and consider it in more detail in the
panel below. Immediately after a reduction in myocardial contractilitysay, from acute
myocardial ischemiathe cardiac output will be reduced (A to B). As a result, the transfer of
blood from the venous side to the arterial side will also be reduced. This net transfer of blood to
the venous side will increase cardiac preload, causing a consequent increase in cardiac output
(B to C). Because this point is still below the intersection point of the two curves, the driving
pressure for blood flow from the arteries to the veins across the peripheral resistance will
continue to transfer blood to the veins at a rate greater than the heart can transfer blood from
the veins to the arteries. With each subsequent beat, however, venous pressure rises, further
increasing the cardiac output (although not back to baseline), until the new equilibrium point is
reached.

Venous Return (CO) l/min

Clinical correlation: A patient with this condition may have physical examination signs of a
reduced cardiac output (e.g. reduced pulse pressure from reduced stroke volume) and elevated
right atrial pressure (jugular venous distension).

Reduced myocardial contractility.

See text for details.

D
C
B

10

PRA (mmHg)

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Heres a great example of how the systemic vessels control the cardiac output. Remember,
Pms is the driving pressure for venous return. Heres the equation again:
Venous return = Pms RA pressure
Peripheral resistance
As Pms is reduced, the driving pressure for venous return is reduced. As less blood returns to
the heart, the preload will fall, leading to a reduction in cardiac output. How might Pms fall? One
way would be to lacerate your carotid artery with a razor in a shaving accident. As Dr. Beiser will
discuss and as you will examine in the laboratory session, the body compensates for this acute
blood loss through a variety of mechanisms including an increase in sympathetic tone.
Venoconstriction reduces the compliance of the venous system, increasing Pms (remember, 2/3
of the blood is in the veins, so squeezing the veins can affect Pms). In addition, sympatheticallymediated constriction of the resistance vessels in the skin diverts blood flow away from the skin
and toward the general circulation and vital organs. This further increases Pms and mitigates
the adverse consequences of hemorrhage. You will see what happens when the autonomic
nervous system is deactivated in the laboratory.
If you put the two pumpsthe right and left ventriclesin series, the analysis becomes a little
more complicated. Still, it uses the same techniques we have just applied. Briefly, if left
ventricular function is suddenly reducedsay, by an acute reduction in blood flow due to
occlusion of the left anterior descending coronary arterythe immediate consequence will be
that left ventricular cardiac output will fall, while right ventricular cardiac output remains the
same. This disparity in ventricular outputs will result in a progressive increase in left atrial
pressure, tending to restore left ventricular cardiac output to normal through the Frank-Starling
mechanism. At the same time, there will be a progressive fall in right atrial pressure, decreasing
right ventricular cardiac output through a reduction in preload. Ultimately, a new equilibrium
point is achieved characterized by an increased pulmonary venous pressure and a reduced
but equalcardiac output for the two ventricles.
Clinical correlation: An increase in left atrial pressure can have serious clinical consequences.
This pressure is transmitted back to the lungs, causing a rise in capillary hydrostatic pressure
that, if sufficiently high, can lead to transudation of fluid into the lungs. This condition, called
pulmonary edema, can result in hypoxia and an increase in the work of breathing.
Remember the Starling equation from Dr. Beisers lecture?

David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Autonomic Regulation of the Heart and Circulation

Recommended reading
Levy & Pappano:
! Chapter 5: Regulation of the Heartbeat
! Chapter 9: Peripheral Circulation (pp. 170-177)
Mohrman & Heller (Lange Series): Cardiovascular Physiology 6th Edition (optional)
! Chapter 7: Vascular Control (pp. 129-135)
! Chapter 9: Regulation of Arterial Pressure (pp. 161-182)

Objectives
1. Describe cardiovascular autonomic nervous system anatomy/innervation,
2. Explain the effects of neurotransmitters/hormones on inotropy, chronotropy, and
vasomotor tone.
3. Compare & contrast autonomic vs. autoregulatory (intrinsic) control mechanisms
4. Predict response of individual autonomic reflexes to environmental stress
5. Predict integrated autonomic reflex responses to environmental stress
INTRODUCTION
As discussed in the Peripheral Circulation lecture, homeostatic autoregulation
mechanisms work independently to optimize local the tissue perfusion conditions in the face
of variations in flowrate and pressure. Accordingly, autoregulation mechanisms alone are
insufficient for the task of defending the perfusion in critical organs. Such coordinated control
is provided by the autonomic nervous system (ANS), which regulates blood pressure
through an elegant system of sensory organs and feedback control mechanisms. Here we
discuss a few of the major cardiovascular reflexes that provide short-term regulation of
systemic blood pressure through rapid changes in vascular tone, heart rate and myocardial
contractility.

CV
P

AP

CO = HR x SV

Determinants of Mean Arterial Pressure (review)

Recall from Ohms Law that mean arterial blood
pressure (MAP) is determined by cardiac output
(CO), central venous pressure (CVP) and
systemic vascular resistance (SVR).
Furthermore, recall that cardiac output is
determined by the product of heart rate (HR)
and stroke volume (SV).

SVR: systemic vascular resistance

CO: cardiac output (L/min)
MAP: mean arterial pressure
CVP: central venous pressure

The simplicity of these two formulae belies a

complex interaction of hemodynamic,
P arterial P venous MAP CVP
heterometric (i.e. ventricular-vascular coupling),
SVR =
=
autoregulatory, and autonomic factors that
Q
CO
ultimately determine their instantaneous
solution on a beat-to-beat basis. Today we will review the autonomic factors controlling heart
rate, myocardial contractility, venous capacitance and arterial vasoconstriction that govern
MAP.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

AUTONOMIC CONTROL OF THE

CARDIOVASCULAR SYSTEM
The autonomic nervous system (ANS)
provides short-term homeostatic
regulation of arterial blood pressure.
Afferent and efferent autonomic nerve
fibers link the CNS with peripheral
sensory organs (e.g. baroreceptors) and
visceral effectors (e.g. veins, arteries,
heart). ANS reflexes integrate sensory
input into homeostatic responses
through the regulation of vascular tone,
heart beat and myocardial contractility
and thus provide short-term control of
blood pressure.
The two efferent arms of the ANS
nervous the sympathetic and
parasympathetic divisions are made up
of cholinergic neurons (pre-ganglionic
neurons) located within the CNS that
innervate ganglia (for example, para- or
pre-vertebral sympathetic ganglia),
glands (adrenal glands) or neural
networks of varying complexity (e.g.
cardiac ganglionic networks) located
outside the CNS.
Medulla Oblongata: The Central
Controller
The balance of sympathetic and
parasympathetic tone is primarily
controlled by the medulla
oblongata across a collection of
nuclei traditionally referred to as the
medullary cardiovascular centers,
which integrate sensory data from
a variety of inputs including
peripheral and central vascular
sensory organs, the cerebral cortex
and limbic system into a coordinated
cardiovascular response intended to
achieve homeostasis. The neural
interconnections between these
medullary nuclei are not completely
mapped so we will focus on the
overall response of various
autonomic cardiovascular reflexes
rather than the exact neural
circuitry within the medulla.
RVLM= rostral ventrolateral medulla (sympathetic),
NTS=nuc. tractis solitarius, rn = raphe nuc. (parasympathetic),
na = nucleus
- 2 - ambiguous (parasymp) (Mohrman & Heller)

David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

The nucleus tractus solitarious (NTS) is the principle integrative center for circulatory control,
receiving afferent inputs from peripheral sensors (e.g. baroreceptors & chemoreceptors) via
the sensory portions of the vagus (CN X) and glossopharyngeal (CN IX) nerves. Neurons
from the NTS make polysynaptic projections to efferent neurons mediating parasympathetic
and sympathetic outflow.
Parasympathetic motor nuclei
The nucleus ambiguous (vagal motor nucleus) provides tonic parasympathetic tone to the
heart. Activation of the NTS by sensory afferents causes activation of interneuron
projections from the NTS to the nucleus ambiguous thus increasing parasympathetic
outflow. Parasympathetic activation also involves inhibition the tonically-active sympathetic
RVLM nucleus of the medulla.
Sympathetic vasomotor area
Cardiovascular sympathetic efferents originate in the tonically-active rostral ventrolateral
medulla (RVLM, or vasomotor area). The RVLM receives tonic inhibitory input from the NTS.
Modulation of these inhibitory inputs will increase/decrease sympathetic outflow.
To summarize, the medullary cardiovascular centers consist primarily of:
NTS input area projects interneurons to other medullary centers
Nucleus ambiguous (vagal motor nucleus)
o Tonic parasympathetic activation to heart (discussed below)
Rostral ventrolateral medulla (RVLM)
o Provides tonic sympathetic activation to CV system (discussed below)
o Primarily inhibited by NTS
Raph nucleus
o Inhibits spinal sympathetic outflow
Autonomic Cardiac Efferent Anatomy, Neurotransmitters, Hormones, Receptors,
Effectors and Responses
The heart receives tonic inputs from both the sympathetic and parasympathetic divisions of
the ANS; however, under normal resting conditions, parasympathetic activity generally
dominates. Fibers from both divisions project to the cardiac pacemaker cells of the sinoatrial
(SA) node, atrioventricular (AV) node, myocardium and vascular endothelium.
Parasympathetic fibers also invest the vessels of the cranial (head) and sacral (genitalia,
bladder and large bowel). The cardiac adrenergic (sympathetic) and cholinergic
(parasympathetic) receptors, effectors and responses are summarized in the table below:
Cardiac adrenergic/cholinergic receptors, effectors and responses

Cardiac Effector
SA Node
AV Node
myocardium
coronary vessels

Sympathetic (NE)

Parasympathetic (ACh)

Receptor (Response)
1 (tachycardia ++)
1 (conduction)
1 (contractility +++)
1 (constriction +++),
2 (vasodilation +)

Receptor(Response)
M2 (bradycardia +++)
M2 (conduction)
M2 (contractility +)
N/A

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Parasympathetic Efferent Anatomy

Efferent fibers from the vagal motor nucleus travel via the vagus nerve to synapse with postganglionic cells on the epicardial surface or within the myocardium, primarily in the region of
the sinoatrial (SA) and atrioventricular (AV) nodes the SA and AV nodes are the main
effectors of the parasympathetic cardiovascular response. Parasympathetic fibers also
project to a limited number of blood vessels in the cranial and pelvic regions.
Parasympathetic Efferent Response
The parasympathetic (cholinergic) response in the heart is mediated by acetylcholine which
is released by post-ganglionic neurons to bind to muscarinic, M2, receptors in the heart.
Binding of muscarinic receptors decreases heart rate, slows conduction and, to a much
lesser extent, decreases contractility.
Parasympathetic release of acetylcholine
1. Binds M2 receptors primarily in cardiac Sinoatrial (SA) node
a. Induces bradycardia (or asystole when activation is strong)
2. Decreased AV conduction (can cause heart block)
3. Partially antagonizes the release of norepinephrine from sympathetic nerve endings.
4. Decreases atrial contractility (& ventricular to small extent not so clinically relevant)
5. Vasodilation (primarily certain viscera such as the gut and pelvic organs)
Sympathetic Efferent Anatomy
Projections from the RVLM synapse with preganglionic neurons in the lower cervical and
upper thoracic segments of the spinal cord and synapse with post-ganglionic neurons at
either the stellate or middle cervical ganglia. Post-ganglionic sympathetic fibers synapse
within the myocardium, vasculature and nodal regions of the heart. Pre-ganglionic fibers
also project to the adrenal medulla which can release circulating catecholamines (e.g.
epinephrine and norepinephrine) to preserve blood pressure in response to environmental
stress (humoral response described below). Also of major importance to the cardiovascular
system, post-ganglionic sympathetic fibers invest
smooth muscle cells of the vast majority of the bodys
small arteries, arterioles and veins. Exceptions to this
rule are discussed in the lecture on Special
Circulations.
Sympathetic Efferent Response
Sympathetic outflow promotes increased blood
pressure and blood flow to vital organs (e.g. brain,
heart). The cardiac sympathetic response is primarily
mediated by 1- adrenergic receptors which
promote increased firing of the SA node, increased
conduction of the AV node and enhanced myocardial
contractility. Figure 5-20 displays the effect of
norepinephrine infusion on left ventricular stroke
work. Note that for a given left-ventricular enddiastolic pressure (preload) stroke work increases
following NE infusion. To a small extent, sympathetic
release of NE in the heart also binds coronary 1adrenergic receptors. However, the vasoconstrictive
effect of this binding is thought to be largely
attenuated by autoregulatory vasodilation of coronary
arteries.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Sympathetic release of NE in the heart

1. Increases heart rate by activation of SA and AV nodes 1-adrenergic receptors
2. Increases contractility via both 1-adrenergic receptors on cardiac cell membranes
and rate-related changes in intracellular Ca++ concentration.
3. Increases cardiac relaxation rate (i.e. lusitropy) during diastole
4. Increases Pms (mean systemic pressure) through venous vasoconstriction
5. NET RESPONSE: Increases cardiac output
Clinical Correlation: The normal resting
heart rate (~ 70 bpm) is determined
primarily by the firing rate of the
sinoatrial (SA) node. While local factors
such as temperature and atrial stretch
can impact SA node firing rate, it is
primarily determined by the balance
between tonic sympathetic and
parasympathetic outflow from the ANS.
Stimulation of the vagus nerve
produces instantaneous release of
acetylcholine from nerve endings which
can slow or stop SA node firing and
slow AV conduction. Most often, an
increase in either sympathetic or
parasympathetic tone is accompanied
by a concomitant reciprocal decrease in
the opposing division. In healthy
individuals at rest, parasympathetic
tone ordinarily prevails. This is
demonstrated in Figure 5-1 by blockade of parasympathetic tone (via atropine) which
produces marked tachycardia while blockade of sympathetic tone (using a beta-blocker)
reduces heart rate only slightly.

Sympathetic Vascular Receptors, Effectors and Responses

Much of the bodys small arteries, arterioles and veins are invested with efferent fibers from
the sympathetic division of the autonomic nervous system. These tonically-active
sympathetic fibers deliver a basal level of norepinephrine (NE) which produces smooth
muscle vasoconstriction through peripheral 1-adrenergic receptors or relaxation through
2-adrenergic receptors. While the end result is primarily vasconstriction, in some vascular
beds (such as skeletal muscle) the ratio 2 to 1 receptors is large and thus the end result is
vasodilation. The vessels of the brain and heart are thought to be only minimally responsive
to norepinephrine and epinephrine accordingly, increased sympathetic tone promotes
blood flow to these vital organs. Circulating (humoral) epinephrine, also plays an important
role in regulating vascular tone in response to environmental stress and will be discussed
below. NOTE: Only blood vessels in the cranial (head) and sacral (pelvic viscera) receive
parasympathetic innervation.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Sympathetic Humoral Response fight or flight

In addition to these organ-targeted projections, preganglionic neurons synapse with
chromaffin cells the adrenal medulla to control the release of humoral (epinephrine >>
norepinephrine) sympathetic mediators. Epinephrine binds to receptors with greater affinity
than receptors. Thus low to moderate concentrations of circulating epinephrine will
produce vasodilation while high concentrations lead to vasoconstriction.
Circulating epinephrine:
1. Binds to >> -adrenergic receptors
2. Increases heart rate and myocardial contractility (& CO)
3. Augments venous constriction to increase Pms.
4. Reduces systemic vascular resistance at low-moderate concentrations. While
somewhat confusing, this net decrease in resistance occurs because vascular
effects of epinephrine vary greatly in each bed depending on the proportion of 1receptors (constricting splanchnics, skin, renal vessels) and 2-adrenergic
receptors (dilating skeletal muscle vessels).
5. NET RESPONSE: Moderately increases mean arterial pressure (MAP)
Circulating norepinephrine:
1. Higher affinity for - than -adrenergic receptors
2. Primarily causes vasoconstriction
3. NET RESPONSE: Increases MAP more than epinephrine
Circulating hormones: A variety of hormones including thyroid hormone, insulin and
glucagon can act to directly increase cardiac contractility and heart rate (thyroid
1. Thyroid Hormone enhances myocardial contractility and increases heart rate
through the up-regulation of -adrenergic receptors.
2. Insulin has direct positive inotropic effect on the heart independent of glucose.
3. Glucagon is a potent inotrope which operates through mechanisms quite similar
to catecholamines
AUTONOMIC CARDIOVASCULAR REFLEXES
Autonomic reflexes maintain
cardiovascular homeostasis through
a variety of sensory receptors which
provide the medulla with input
regarding, for example, arterial and
ventricular pressure
(baroreceptors); arterial and central
(medullary) PCO2 (chemoreceptors)
and atrial stretch. The baroreceptor
and stretch reflexes are most
relevant to the control of cardiac
performance.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Baroreceptor Reflex:
Acute changes
(seconds to hours) in
arterial blood pressure
reflexively elicit
inverse changes in
heart rate and
contractility. This
reflex is mediated by
sensors
(baroreceptors)
located in the aortic
arch and carotid
sinuses. The
baroreceptor reflex
plays a key role in the
Baroreceptor Reflex control of arterial pressure. In this example, we
short-term regulation
assume that an increase in mean arterial pressure (violet box) is the
of blood pressure,
primary insult
providing a consistent
flow of blood to vital
organs including the brain under a variety of internal/external perturbations.
Baroreceptor Reflex Summary:
Carotid sinus and aortic arch mechanoreceptors
o Sense changes in mean arterial pressure (active above 60 mmHg)
o Sensitivity : Carotid sinus (brain perfusion pressure) > aortic arch
o Receptors adapt over time in the setting of hypertension
Project to the parasympathetic NTS
o Carotid sinus: via the glossopharyngeal nerve (IX)
o Aortic arch: via vagus (X)
Increases in pressure tend to
o Increase parasympathetic outflow to the heart (bradycardia)
o Decrease sympathetic tone of the heart (bradycardia) and peripheral circulation
o Lower blood pressure
Decreases in pressure tend to
o Decrease parasympathetic outflow (tachycardia)
o Increase sympathetic tone (tachycardia, contractility)
o Peripheral vasoconstriction redistributes peripheral circulation to vital organs such
as brain and heart.
Bainbridge Reflex/Phenomenon (atrial stretch)
This controversial mechanism (has only been documented in dogs) is thought to reflexively
increase heart rate in response to an intravenous infusion. Distension of atrial stretch
receptors, located in the venoatrial junctions, sends impulses centrally via the vagus nerve to
the medulla to increase sympathetic stimulation of the heart (tachycardia). The anatomic
relations are not well-understood (and not included in the above diagram). This reflex acts in
opposition to the baroreceptor reflex (which decreases heart rate when blood pressure rises),
thus the final change in heart rate following an increase in preload represents a compromise
between the two. When blood volume is increased, the Bainbridge reflex is dominant; when
blood volume is decreased, the baroreceptor reflex dominates (see figure below).

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Bainbridge Reflex dominates at normal volumes. At low

volumes, the response is dominated by the baroreflex.

Peripheral Chemoreceptor Reflexes:

In addition to the dominant baroreceptor reflex, a secondary reflex mediated by peripheral
chemoreceptors plays a role in short-term regulation of blood pressure. The peripheral
chemoreceptors lie close to the baroreceptors. There are two types of peripheral
chemoreceptors: the carotid bodies and the aortic bodies.
During normal physiology, this reflex is primarily involved in the regulation of respiration;
however, to a lesser extent (and potentially only during times of severe hypoxia/ischemia) it
regulates heart rate and vascular tone. Peripheral chemoreceptors respond to changes in
the arterial blood PCO2 (hypercapnia), pH (acidosis) or PO2 (hypoxia) via specialized sensory
neurons located in the base of the carotid arteries (carotid bodies) and the arch of the aorta.
The peripheral chemoreceptor reflex is unique in that it involves a mixture of sympathetic and
parasympathetic outflow. Specifically, primary stimulation of these receptors induces
simultaneous sympathetic vasoconstriction of peripheral blood vessels while increasing vagal
outflow to the heart (producing bradycardia). In contrast, baroreceptors exert a negative
drive on the medullary vasomotor center (causing vasodilation) while also decreasing heart
rate. When hypoxia and hypercapnia coexist (asphyxia) a more pronounced and synergistic
response occurs. Chemoreceptors also exist in the ventrolateral medulla (VLM) and raphe
nucleus. Central chemoreceptors respond primarily to changes in PCO2 and pH.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Primary Response to Chemoreceptor Activation: Ventilation fixed

The Chemoreceptor Paradox
Chemoreceptor-induced bradycardia is difficult to demonstrate and only occurs when
ventilation is fixed or inhibited (e.g. forced apnea or breath-holding). In fact, under real-life
conditions, hypoxia causes tachycardia. This is due to a complex interaction with the
pulmonary system whereby chemoreceptors trigger respiration which in turn stimulates
pulmonary stretch recepters, triggering a reflex tachycardia. Thus the net effect of hypoxia in
the intact animal is tachycardia (see below figure).

Clinical Correlation: In a patient requiring intubation for respiratory compromise, difficult

airway anatomy can occasionally lead to long periods of apnea while the physician struggles
to visualize, and correctly place, an endotracheal breathing tube in a patient with respiratory
failure. During this period, respiration is typically inhibited pharmacologically leading to

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

drops in arterial PO2 while PCO2 quickly rises thus triggering the chemoreceptor reflex
leading to profound bradycardia, hypoperfusion and occasionally cardiac arrest. Pretreating the patient with 100% oxygen and hyperventilation can forestall this response
dramatically. This response can also be ablated by atropine (frequently used in pediatrics).
Hormonal Reflexes (vasopressin and atrial natriuretic peptide)
Stimulation of the atrial stretch receptors reduces the secretion of vasopressin (antidiuretic
hormone) by the posterior pituitary gland thus leading leading to increased urine volume.
Synergistically with this action, atrial stretch causes the release of atrial natriuretic peptide
(ANP) which dilates resistance and capacitance vessels and promotes diuresis through
increased sodium/water excretion. Both of these actions serve to lower blood pressure.
EXTRINSIC CONTROL OF PERIPHERAL BLOOD FLOW:
Sympathetic Tone
Much of the bodys small
arteries, arterioles and veins
are invested with efferent
fibers from the sympathetic
division of the autonomic
nervous system. These
tonically-active sympathetic
fibers deliver a basal level of
norepinephrine (NE) which
produces smooth muscle
vasoconstriction through 1adrenergic receptors. A
small minority of vessels,
primarily those subserved by
cranial (head) and sacral
(genitalia, bladder and large
(Mohrman & Heller)
bowel) spinal segments
receive parasympathetic input
(although the parasympathetic division plays a prominent role in heart rate regulation to be
covered in a later lecture).
Sympathetic efferents originate from a complex of brainstem nuclei called the medullary
cardiovascular center. Within this center, broad subdivisions can be distinguished such as
the vasomotor area and a cardioinhibitory area. This area integrates data from a variety
of peripheral and central sources including peripheral vascular sensors, central
chemoreceptors, the cerebral cortex and limbic system and offers a coordinated
cardiovascular response via targeted neural efferent projections and humoral (i.e. circulating)
factors (e.g. endogenous catecholamines such as epinephrine/norepinephrine) released from
the adrenal medulla. This autonomic system of feedback and control mediates a variety of
cardiovascular reflexes (e.g. the baroreceptor reflex) which are important in the short-term
maintenance of adequate blood pressure through regulation of vascular tone, heart beat and
myocardial contractility. NOTE: The details of these cardiovascular reflexes and integration
will be covered in a later lecture.

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David G. Beiser, MD, MS

Autonomic Regulation

Cell & Organ Physiology: Cardiovascular

Clinical Correlation: Blockade of this centrally-mediated basal sympathetic tone can occur
(e.g. following a cervical spinal cord injury) can produce marked hypotension.

--- DO NOT MEMORIZE THIS TABLE Its just here for reference -Table 22-1. EFFECTS OF SYMPATHETIC AND PARASYMPATHETIC PATHWAYS ON
THE CARDIOVASCULAR SYSTEM
EFFECTOR
RESPONSE

ANATOMIC
PATHWAY

NEUROTRANSMITTER
RELEASED AT
EFFECTOR

RECEPTOR

Tachycardia

Sympathetic

Norepinephrine

1 on cardiac pacemaker

Bradycardia

Parasympathetic

Acetylcholine

Increase cardiac
contractility

Sympathetic

Norepinephrine

M2 on cardiac pacemaker
1 on cardiac myocyte

Decrease cardiac
contractility

Parasympathetic

Acetylcholine

M2 on cardiac myocyte
Presynaptic M2 receptor
on noradrenergic neuron

Vasoconstriction in
most blood vessels
(e.g., skin)
Vasoconstriction some
blood vessels

Sympathetic

Norepinephrine

1 on VSMC

Sympathetic

Norepinephrine

2 on VSMC

Vasodilation in most
blood vessels (e.g.,
muscle)
Vasodilation in erectile
blood vessels

Adrenal medulla

Epinephrine

2 on VSMC

Parasympathetic

Acetylcholine

Presynaptic M2 receptor
on noradrenergic neurons

Acetylcholine

M3 on endothelial cell

NO
VIP

NO receptor (i.e., GC)

inside VSMC
VIP receptor on VSMC

Parasympathetic

Acetylcholine

M3 receptor on gland cell

Sympathetic

Acetylcholine

Presynaptic M2 receptor
on noradrenergic neurons

NANC

Receptor on VSMC

Vasodilation in blood
vessels of salivary
gland
Vasodilation in blood
vessels of muscle in
"fight or flight" response

AC, adenylyl cyclase; cAMP, cyclic adenosine, monophosphate; GC, guanylyl cyclase;
GIRK, G-protein-activated/inwardly rectifying K+ channel; NANC, non-adrenergic/noncholinergic; NO, nitric oxide; NOS, nitric oxide synthase; PLC, phospholipase C; VIP,
vasoactive intestinal peptide; VSMC, vascular smooth-muscle cell.

- 11 -

Jason Poston, MD

Cell & Organ Physiology: CV physiology

SPECIAL CIRCULATIONS (PART I)

Recommended reading
Levy & Pappano:
Chapter 11: Coronary circulation
Chapter 12: Special circulations
KEY CONCEPTS
Aortic blood pressure is the driving pressure for coronary blood flow.
Coronary blood flow is influenced by physical factors including mechanical compression
during systole and autoregulation.
Coronary blood flow increases in response to metabolic demand.
The pulmonary circulation is a low-resistance circuit that is highly recruitable. Pulmonary
blood flow has three distinct flow patterns (zones of West).
The most important regulator of pulmonary vascular tone is hypoxia, which causes smooth
muscle constriction and is an important mechanism for matching ventilation with perfusion.
In the next two lectures we will consider the unique properties of a number of special
circulations. We will focus on those circulations that are not covered in detail elsewhere in the
course.
CORONARY CIRCULATION
Overview
The entire blood supply to the myocardium comes from the right and left coronary arteries. In
general, the left coronary artery mostly supplies the left ventricle and atrium with blood while the
right coronary artery supplies the right ventricle and atrium. Both arteries originate at the root of
the aorta behind the cusps of the aortic valve. The left coronary artery branches into the left
anterior descending artery and the circumflex artery. Venous blood returns to the right atrium via
the coronary sinus or, to a lesser extent, via the anterior coronary veins. In addition, there are a
number of smaller vascular communications that exist between the smaller vessels and the
cardiac chambers, and between these vessels and various sinuses.

Figure 11-1. Anterior and posterior surfaces of the heart, illustrating the
location and distribution of the principal coronary vessels.

The aortic pressure is the driving pressure for coronary blood flow. In addition, there are a
number of physical, neurohormonal, and metabolic factors that regulate blood flow.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Physical factors regulating coronary blood flow

Autoregulation: Dr. Beiser discussed this concept in the peripheral circulation
lecture. The figure on the left below illustrates this phenomenon as it applies to
coronary blood flow.
Mechanical compression of the blood vessels during systole. The contracting
myocardium squeezes blood vessels coursing through it. Thus, blood flow is highest
during early diastole. See the figure on the right below.

Neural and neurohormonal factors regulating coronary blood flow

Overall, these factors play are thought to play a minor role in the regulation of coronary blood
flow.
Stimulation of sympathetic nerve fibers causes coronary artery vasoconstriction. In
addition, sympathetic stimulation increases the heart rate, limiting the amount of time the
heart spends in diastole. Both of these processes tend to reduce coronary blood flow.
Yet, sympathetic stimulation is associated with an overall increase in coronary blood
flow. Why? The reason is that sympathetic stimulation leads to an increase in heart rate
and contractility with a consequent increased in metabolic demand. This increased
metabolic demand dilates resistance vessels as discussed below, overcoming the
tendency toward reduced blood flow engendered by the processes above.
Alpha recepors (constrictors) and beta receptors (dilators) are found on the
coronary vessels, and the coronary resistance vessels participate in the baroreceptor
and chemoreceptor reflexes.
Vagal nervous stimulation causes mild coronary artery vasodilation.
Clinical correlation: Transplanted hearts are denervated due to sectioning of the postganglionic
nerves that innervate the heart. As a result, transplant recipients are unable to sense cardiac
pain due to loss of ventricular sympathetic afferents responsible for this sensation. In addition,
this denervation limits exercise capacity. Still, it is remarkable that this loss of sympathetic
innervation is tolerated as well as it is. Interestingly, in many cases the heart undergoes
sympathetic reinervation, although this process is usually slow and not complete.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Metabolic factors regulating coronary blood flow

Coronary blood flow increases in direct proportion to myocardial metabolic activity. If
oxygen supply is not sufficient to meet the oxygen demand of the myocardium, vasodilating
substances are released. The metabolic mediators of vasodilation are unclear but likely include
CO2, hypoxia, lactate, K+, prostaglandins, the opening of ATP-sensitive K+ channels, and
vasodilating substances such as adenosine and nitric oxide.

Coronary blood flow increases

in direct proportion to metabolic
demand.

Effects of diminished coronary blood flow

Myocardial ischemia occurs when there is inadequate delivery of oxygen to the tissue.
The endocardium is typically more severely affected than the epicardium. This condition
may affect the entire heart, as when the patient has a low blood pressure (say, from
hemorrhage) or a specific area of the heart. The latter may occur with coronary
atherosclerosis. In this condition, the diseased vessel may supply sufficient oxygen to
the tissue under resting conditions, but be unable to increase coronary blood flow in
response to increased metabolic demand, as occurs during exercise. Angina and
reduced cardiac function may result.
Myocardial infarction or necrosis occurs when myocardial ischemia is severe and/or
prolonged. Death of the tissue occurs.
Myocardial stunning refers to a temporary reduction in myocardial contractility due to
a brief period of severe ischemia followed by reperfusion.
Myocardial hibernation is a reduction in myocardial performance due to a
downregulation of metabolism in response to persistently decreased coronary blood
flow. Myocardial performance returns to normal once coronary blood flow is returned to
normal.
Coronary collateral vessels develop in response to gradual and persistent reductions
in blood flow. Shear stress caused by increased blood flow velocity at sites of narrowing
serves as the stimulus for angiogenesis.
Clinical correlation: A number of techniques have been developed to restore blood flow to the
heart in patients with coronary atherosclerosis. In coronary artery bypass graft surgery the
diseased vessel (or vessels) is surgically bypassed using an artery (internal mammary artery) or
vein (saphenous vein) harvested from another site. A technique referred to as angioplasty
involves the insertion of a balloon-tipped catheter into the diseased vessel. The obstructing
lesion is fractured and flattened as the balloon is inflated. Sometimes a stent is placed across
the diseased area to prevent future narrowing.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

THE PULMONARY CIRCULATION

Structure and function
The lungs blood supply arises from two distinct circulations: the bronchial circulation and the
pulmonary circulation. The bronchial circulation receives approximately 2% of the entire cardiac
output and supplies blood to the non-gas exchanging regions of the lung. Bronchial arteries
arise from the aorta and thus are under systemic pressure.
The principle role of the pulmonary circulation is essentially to permit a stream of blood to be
exposed to a stream of gas, resulting in the oxygenation of mixed venous blood. Form follows
function in the pulmonary circulation, as illustrated by the observation that the pulmonary
arteries and the airways lie in close proximity to each other. The main pulmonary artery
branches into lobar arteries that enter the lungs at the hila and branch into ever-smaller arteries
and arterioles until terminating in a dense network of capillaries that intercalate with the alveoli.
Oxygenated blood is collected by the pulmonary veins, which lie in the interlobular and
interlobar connective tissue septae, and eventually empty into the left atrium by way of four
lobar veins. In addition to permitting the oxygenation of blood, the pulmonary circulation
performs several additional vital functions, delivering substrates to the lung parenchyma,
activating and inactivating various vasoactive substances, filtering clot and microbes from the
blood, and serving as a reservoir of blood for the left heart.
Pulmonary blood flow
The pulmonary circulation functions as a high-flow, low-resistance circuit that accommodates
the entire cardiac output at a pressure 1/7th that of the systemic circulation. Why the difference
between the two circulations? Whereas high systemic pressures are necessary for supplying
blood to diverse sites at different flow rates, the pulmonary circulation is not required to adjust
its blood flow to suit the needs of a variety of different microcirculations. Low pulmonary artery
pressures also ensure that transudation of fluid from the capillary bed into the lung is minimized,
thereby preserving gas exchange.
Pulmonary vascular resistance (PVR) can be
calculated through the use of the following
relationship, which relates the resistance of a
circuit to the pressure differential across the
circuit and the flow rate of the liquid (Ohms law
analogy):
PLA

PPA

(Pa Pb) = I * R

where (Pa Pb) represents the pressure

difference across the circuit, I = the flow rate of
the liquid, and R = resistance to flow. This
relationship can also be remembered as it is
commonly written for electrical circuits, V = IR, with V = voltage, which is analogous to pressure.
The PVR can be calculated clinically through the use of a pulmonary artery catheter. This
long, slender catheter is typically inserted into a large central vein, such as the subclavian vein.
A small balloon on the tip of the catheter is inflated with air and the catheter tip is passed
sequentially through the right atrium, right ventricle, and pulmonary artery, its passage guided
by pulmonary blood flow like a boat on a stream. Eventually, the tip of the catheter wedges into
a small pulmonary artery:

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Leff AR, Schumacker PT. Respiratory Physiology: Basics and Applications.

Because the balloon effectively blocks further pulmonary arterial blood flow in the small vessel
within which it is lodged, the pressure transducer at the tip of the catheter measures the
pressure of the static column of blood that lies between the tip of the catheter and the left
atrium. This pressure is called the pulmonary capillary wedge pressure (PCWP), and usually
serves as a reasonably accurate approximation of left atrial pressure and, in the absence of
mitral valve disease, left ventricular end-diastolic pressure. The PCWP also reflects the outflow
pressure of the pulmonary circulation, and therefore can be used to calculate pulmonary
vascular resistance, utilizing two additional measurements obtained through this procedure, the
inflow pressure (mean pulmonary artery pressure, MPAP) and pulmonary blood flow (cardiac
output, as calculated using the thermodilution technique briefly discussed in our lecture on
the cardiac pump). By rearranging the general relationship shown above and inserting these
measured values, we can arrive at the formula used to calculate PVR:

(Pa Pb) = I * R
(MPAP PCWP) = CO * PVR

PVR= (MPAP PCWP)/CO*

*Multiplication by the constant 80 produces units in dyne x s x cm-5.
The distribution of blood flow
Because the pulmonary blood vessels are not made of iron but are flexible, the distribution of
blood flow is affected by gravity. Transmural pressure (the pressure inside the vessel minus the
pressure outside the vessel) increases with gravity from apex to base in an erect individual.
Blood vessels dilate in response to this increase in distending pressure. As a result, blood flow
to the base of the lung is greater than to the apex (see panel on the left below).

Blood flow per alveolus

according to region of lung
(bottom, middle, or top).

Jason Poston, MD

Cell & Organ Physiology: CV physiology

West zones. Pulmonary arteries are depicted on the left side of the
figure, while pulmonary veins are shown on the right. From top to
bottom are zones I, II, and III. Alveolar pressure is the same in all 3
zones. See text for details.
In contrast to the pressures in the pulmonary circulation, the alveolar pressure is essentially the
same from top to bottom. When alveolar and vascular pressures are considered together, it is
apparent that three zones of pulmonary blood flow exist. These are commonly referred to as
West zones, after the physiologist John West, who first described them.

In the bottommost zone (zone III), pulmonary capillary pressure exceeds alveolar
pressure. The driving gradient for flow is thus the pressure in the pulmonary artery minus
the pressure in the pulmonary vein.
In the middle zone (zone II), alveolar pressure lies between pulmonary arterial and
pulmonary venous pressures. Capillaries in this zone will flutter between the open and
closed states. The driving pressure for pulmonary blood flow in this zone is the
difference between the pulmonary arterial and the alveolar pressure.
In the topmost zone (zone I), alveolar pressure exceeds intravascular pressures.
Capillaries are not perfused in this region.

Regulation of pulmonary blood flow is both passive & active

Regulation of blood flow in the pulmonary circulation is both passive and active. An example of
passive regulation is provided by the response to exercise. During exercise, healthy young
individuals may increase their cardiac output up to four-fold. Despite this, pulmonary artery
pressure does not increase significantly. For this to be so, PVR must decrease. This occurs
through the distension and recruitment (e.g. opening) of small arterioles and capillaries. The
volume of blood contained in the lung may double during exercise, reflecting a significant
increase in the capacitance of the pulmonary blood vessels.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Hicks GH. Cardiopulmonary

anatomy and physiology.

The graphs below show how a small increase in pulmonary arterial pressure is associated with
a sizable reduction in PVR and increase in pulmonary blood flow via this mechanism:

Changes in lung volume also affect pulmonary vascular resistance. Pulmonary blood vessels
are very complaint. As a result, changes in transmural pressure cause them to be deformed
rather easily. Vessels that are surrounded by alveoliso-called alveolar vesselstend to be
crushed when you take a deep breath, as the expanding alveoli compress the vessels coursing
between them (see figures below). On the other hand, vessels that are not surrounded by
alveoliextra-alveolar vesselsdilate as you take a deep breath, as pleural pressure and the
pressure in the interstitial space surrounding these vessels becomes more negative, pulling
them open. These effects on pulmonary vascular resistance oppose each other. Total
resistance is lowest at functional residual capacity (FRC), or the lung volume present at the end
of a normal expiration (more on this in pulmonary physiology!).

Jason Poston, MD

Cell & Organ Physiology: CV physiology

TLC = total lung capacity (the volume of air in your lungs at the end of a maximal
inhalation). RV = residual volume (the volume of air left in your lungs after you have
exhaled completely). Total resistance is lowest at FRC = functional residual capacity (see
text).

Active regulation of PVR, achieved by the active contraction or relaxation of smooth muscle,
occurs in response to a number of diverse influences. The most important of these factors is the
alveolar oxygen tension. Alveolar hypoxia is a potent pulmonary artery vasoconstrictor. This
mechanism of hypoxic pulmonary vasoconstriction has been shown to be present in isolated
lung tissue, demonstrating that it requires neither systemic circulating mediators nor an intact
nervous system for its expression. The precise mechanism for sensing and effecting this
response is still unclear. It appears that hypoxia acts directly on pulmonary vascular smooth
muscle cells, probably by inhibiting K+ channels, leading to smooth muscle cell depolarization,
Ca2+ influx via voltage-gated Ca2+ channels, and smooth-muscle contraction. This mechanism is
critically important for matching ventilation with perfusion, serving to redirect blood flow away
from poorly ventilated areas to areas with higher oxygen tensions (more on this in pulmonary
physiology). Unfortunately, this mechanism can also lead to disease.
Can you think of situations or conditions in which hypoxic vasoconstriction may be harmful?
Why?

A number of other substances have been identified as important regulators of pulmonary

vascular tone. In fact, this resting tone appears to reflect a balance between vasodilating
substances like prostacyclin and nitric oxide, and vasoconstrictor substances such as
angiotensin II and endothelin-1. Next year I will have the opportunity to tell you more about the
clinical importance of these mediators in the treatment of a disease called primary pulmonary
hypertension.
Of note, while the pulmonary blood vessels are innervated by the autonomic nervous system it
does not appear that neural regulation of pulmonary vascular tone is very important clinically.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

SPECIAL CIRCULATIONS (PART II)

Recommended reading
Levy & Pappano:
Chapter 12: Special circulations
KEY CONCEPTS
The cutaneous circulation regulates body temperature and is chiefly regulated by the
sympathetic nervous system.
The skeletal muscle circulation plays an important role in regulating blood pressure via the
baroreceptor reflex. While at rest this circulation is chiefly under sympathetic control, during
exercise metabolic factors heavily influence local blood flow.
The brain governs its own blood flow, chiefly through metabolic mechanisms.
The splachnic circulation is a reservoir of blood that may be mobilized in response to stress,
as in exercise or hemorrhage.
The renal circulation helps defend cardiac output and mean arterial pressure, chiefly
through activation of the renin-angiontensin-aldosterone system in response to a decrease
in renal perfusion.
In this lecture we will pick up where we left off on our coverage of special circulations.
CUTANEOUS CIRCULATION
The primary function of the cutaneous circulation is to regulate core body temperature.
Mechanisms of heat loss:
o Convective. Determined by:
Skin-air temperature gradient
Cutaneous blood flow
o Evaporative. Determined by:
Rate of sweat production
Skin-air water vapor pressure gradient
There are two types of resistance vessels in the skin: arterioles and arteriovenous
(AV) anastomoses.
o Arterioles. Similar to arterioles elsewhere in the body in that they exhibit basal
tone and are controlled both by the sympathetic nervous system and local
regulatory factors. They exhibit autoregulation of blood flow and reactive
hyperemia. An example of the latter can be seen when there is an increase in
skin blood flow (causing the skin to be very red) after a blood pressure cuff is
deflated. Still, sympathetic control is the most important influence.
o AV anastamoses. Shunt blood from arterioles to venules and venous plexuses.
Found principally in so-called apical skin (the fingertips, palms of hands, soles
of feet, toes, lips, nose, and ears). Vessels are richly innervated by sympathetic
fibers. Different from cutaneous arterioles in that they do not exhibit basal tone,
are not under metabolic control, and do not exhibit autoregulation or reactive
hyperemia.
Cutaneous vessels respond both to changes in ambient temperature and to core body
temperature.
o Placing your hand in ice water causes vasoconstriction locally and also in the
other extremities, whether or not a blood pressure cuff is inflated on the arm. If
the circulation is intact, however (e.g. the cuff is deflated), part of the reflex

Jason Poston, MD

Cell & Organ Physiology: CV physiology

vasoconstriction is mediated by the return of cooled blood to the temperatureregulating center in the anterior hypothalamus.
o Cold-induced vasodilation occurs in response to prolonged cold exposure.
If body temperature increases, dilation of resistance vessels (arterioles and
arteriovenous anastamoses) leads to an increase in blood flow to the skin and
increased dissipation of heat. Conversely, a reduction in body temperature leads to
vasoconstriction, a decrease in blood flow to the skin, and heat conservation. It
appears that vasodilation in apical skin is achieved principally through a reduction in
sympathetic tone, while the vasodilation that occurs in nonapical skin is greater than
that achieved through withdrawal of sympathetic tone alone. This active vasodilation is
closely associated with sweating.
Sweat glands are innervated by cholinergic fibers of the sympathetic system.
Stimulation of these fibers causes not only sweat excretionand evaporative cooling
but also dilation of resistance vessels in the skin. This is probably due to the release of
bradykinin as well as other vasodilators.
Blushing. The skin vessels in the head, neck, and upper chest respond to input from
cortical centers. The actual physiology of blushinge.g. what causes the vessels to
dilateis not clear. To see how confusing this subject can be, sympathectomy is
occasionally offered to patients who suffer from severe blushing and/or hyperhidrosis
(excessive sweating).
The skin is a reservoir of blood that may be mobilized in resonse to stress (such as
hemorrhage).

Clinical correlation: Why are patients with heart disease counseled to avoid whirlpools?

Jason Poston, MD

Cell & Organ Physiology: CV physiology

SKELETAL MUSCLE CIRCULATION

The vascular bed in the skeletal muscle is very large. As such, the arterioles in this bed
contribute significantly to peripheral resistance, and regulation of skeletal muscle
vascular tone plays an important role in regulation of the blood pressure and the
baroreceptor reflex.

Participation of the skeletal muscle

vascular bed in the baroreceptor reflex.

Regulation of skeletal muscle arteriolar tone is dominated by the sympathetic nervous

system at rest. Stimulation of alpha receptors on vascular smooth muscle via
norepinephrine released from sympathetic adrenergic neurons leads to arteriolar
vasoconstriction. Epinephrine released from the adrenal gland or during exercise
stimulates beta receptors, leading to vasodilation.
During exercise, local blood flow increases in response to increased metabolic demand
and the release of adenosine, lactate, and K+. In fact, muscle blood flow may increase
20x the resting level during exercise!
Muscular contraction and one-way valves propel blood from the periphery to the heart.

The pumping action of skeletal muscle

promotes venous return.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

SOME THOUGHTS ON THE CEREBRAL, SPLACHNIC, AND RENAL CIRCULATIONS

You will cover these topics in more detail in your discussions of the brain, digestive system, and
kidney. However, there are a few big-picture points about each of these systems that are
worth discussing now, while we are considering the cardiovascular system as a whole.
CEREBRAL CIRCULATION
The brain is extremely intolerant of hypoxiamore so than any other tissue in the body.
The brain governs its own blood supply.
The volume of blood and extravascular fluid in the brain must be kept relatively constant.
Otherwise, the pressure within the craniuma rigid structurewould rise to dangerous
levels. Autoregulation is important in maintaining constant cerebral blood flow.
Cerebral blood flow is mostly controlled via metabolic factors, including CO2 (a
vasodilator), adenosine, and K+.

Local blood flow increases in response to increases in

neuronal activity and metabolic demand.

SPLACHNIC CIRCULATION
The splachnic circulation supplies the gastrointestinal tract, spleen, liver, and pancreas.
The mechanisms of blood flow regulation are complex and vary from organ to organ.
Food intake increases splanchnic blood flow from 30-100%.
The splachnic circulation is both a reservoir of blood and a site of adjustable resistance.
Sympathetic efferents of the enteric nervous system cause vasoconstriction of the
splachnic circulation and mobilization of blood to the central circulation in response to
exercise and hemorrhage.
Clinical correlation: Why shouldnt you exercise soon after eating?

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Local blood flow increases in response to increases in

neuronal activity and metabolic demand.

RENAL CIRCULATION
The renal circulation will be discussed in detail in renal physiology. For now, I only want you to
appreciate that a considerable amount of interaction exists between the cardiovascular system
and the kidneys. One example follows:
A decrease in mean arterial pressure and therefore renal perfusion pressure is sensed by
mechanoreceptors in the afferent arterioles of the kidney. This stimulus activates the reninangiotensin-aldosterone system, leading to a number of responses that attempt to restore
arterial pressure to normal. These responses include increased renal sodium reabsorption,
leading to an increase in blood volume. This increased blood volume leads directly to an
increase in mean arterial pressure and also to an increase in venous return, which increases
cardiac output through the Frank-Starling mechanism. This increase in cardiac output increases
mean arterial pressure and improves renal perfusion. Angiotensin II also constricts veins and
arterioles, increasing venous return and peripheral resistance, and thereby also increasing
mean arterial pressure.
To summarize:

Decreased renal perfusion (as in hemorrhage or dehydration) leads to activation of the

renin-angiotensin-aldosterone system.
The activation of this system leads to increased sodium reabsorption.
Angiotensin is released and acts as a vasoconstrictor.
These effects tend to restore cardiac output and mean arterial pressure towards normal.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

CARDIOVASCULAR INTEGRATION AND ADAPTATION

Recommended reading
Levy & Pappano:
Chapter 13: Interplay of central and peripheral factors that control the circulation
KEY CONCEPTS
! Hemorrhage evokes a number of compensatory and decompensatory responses.
! Inspiration lowers intrathoracic pressure, thereby increasing venous return.
! The anticipation of exercise increases sympathetic outflow.
! The metabolic demands of exercise are met through an increase in blood flow to exercising
muscles and by an increase in oxygen extraction by the muscles.
During this lecture we will consider how the various elements of the cardiovascular system work
together in a coordinated fashion. First well take a little time to review the cardiovascular
responses to hemorrhage discussed previously in your laboratory session. The remainder of the
lecture will cover exercise.
Good news! There is actually not a lot of new material in this lecture. It mostly ties together what
you already know.
HEMORRHAGE
You have already studied the major cardiovascular responses to hemorrhage in the laboratory
session. The figure below summarizes these responses, while the remainder of this section
describes these responses in a little more detail.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Hemorrhage evokes the following compensatory mechanisms: the baroreceptor reflex,

chemoreceptor reflexes, cerebral ischemic responses, reabsorption of tissue fluids, release of
endogenous vasoconstrictor substances, and renal conservation of salt and water. The major
elements of these mechanisms are considered below.
!

A reduction in mean arterial pressure and pulse pressure decreases the stimulation of the
carotid sinus and aortic arch baroreceptors, leading to vagal tone and sympathetic tone.
This results in an increase in heart rate and contractility. The increase in sympathetic tone
also causes venoconstriction, increasing Pms and increasing the driving pressure for
venous return (and thus increasing preload). Vasoconstriction of blood vessels in the skin,
liver, and lungs diverts blood flow from these organs to the general circulation, further
augmenting Pms, and to the brain and heart.
Chemoreceptors are stimulated by local tissue hypoxia due to inadequate blood flow,
increasing peripheral vasoconstriction. Hypoxia also stimulates respiration, aiding venous
return.
Venous return increases during
inspiration. Inspiration (in box) reduces
intrathoracic pressure (ITP, shown in
upper panel), reducing the pressure in
the right atrium (RAP) and other great
vessels in the thorax. This increases the
driving pressure for venous return (PmsRAP), increasing superior vena cava
flow (SVCF, lower panel) and thereby
cardiac preload. JVP = jugular venous
pressure; FAP = femoral arterial
pressure.

Cerebral ischemia from inadequate cerebral perfusion activates the sympathoadrenal

system, leading to a massive sympathetic discharge. With more severe hypotension,
however, the sympathetic system may become depressed while vagal centers are activated,
provoking bradycardia and worsening hypotension.
Reabsorption of tissue fluids occurs when arteriolar constriction and reduced venous
pressures reduce capillary hydrostatic pressures to the point where the net reabsorption of
interstitial fluid occurs (Starling forces again!). The body may autoinfuse approximately 1
liter per hour of interstitial fluid through this mechanism. The following figure depicts
changes in arterial blood pressure and plasma colloid osmotic pressure in response to
phlebotomy. The reduction in colloid osmotic pressure is due to hemodilution from
reabsorption of tissue fluid.

Changes in arterial blood pressure and

plasma colloid osmotic pressure in
response to phlebotomy.

Jason Poston, MD

!
!

Cell & Organ Physiology: CV physiology

Release of the endogenous vasoconstrictors epinephrine and norepinephrine from the

adrenal medulla, vasopressin from the posterior pituitary gland, and angiotensin II via
activation of the renin-angiotensin-aldosterone system.
Renal conservation of salt and water in response to reduced renal perfusion and a
consequent reduction in the glomerular filtration rate. This reduces renal reabsorption of salt
and water. In addition, the renin-angiotensin-aldosterone system is activated, with
aldosterone stimulating sodium reaborption.

Hemorrhage also activates a number of decompensatory mechanisms. These include:

!

Cardiac dysfunction may result from a reduction in coronary blood flow due to hypotension
(remember, the mean aortic pressure is the driving pressure for coronary blood flow).
Sympathetically mediated tachycardia also reduces coronary blood flow by reducing the
amount of time spent in diastole. These reductions in coronary blood flow occur at the same
time that metabolic demand is increased due to an increase in (a) heart rate, (b) contractility,
and (c) afterload (from increased peripheral resistance). Myocardial ischemia may result,
reducing cardiac function and causing further reductions in the arterial pressure. This may
lead to further reductions in coronary blood flow, invoking a positive feedback loop (in this
case, a downward spiral) that, uninterrupted, leads to death.

Clinical correlation: Older patients with preexisting coronary artery disease (and a decreased
ability to increase myocardial blood flow) are more likely than younger patients to suffer a
myocardial infarction during the course of a gastrointestinal hemorrhage.
Bonus: which part of the heart is most likely to suffer this infarct? Why?

!
!

Acidosis caused by tissue hypoxia leads to anaerobic metabolism and a lactic acidosis.
The effects of acidosis on the cardiovascular system are controversial, but it overall reduces
cardiac function. It also reduces the sensitivity of the heart and resistance vessels to the
effects of catecholamines.
Central nervous system depression may result from several reductions in cerebral
perfusion, as discussed previously.
Alterations in blood clotting (hypercoagulability initially, followed by hypocoagulability)
and depression of the reticuloendothelial system may also occur. The latter results in
decreased phagocytosis of endotoxins released by the normal bacterial flora of the intestinal
tract. These endotoxins cause severe vasodilation by inducing arteriolar smooth muscle
dilation. We will not consider these mechanisms further.

Whether or not a patient survives hemorrhage depends on the severity of the hemorrhage, the
strength of the compensatory mechanisms relative to the decompensatory mechanisms, and
the presence of medical comorbidities. For instance, younger patients generally have stronger
compensatory mechanisms than older patients.
Clinical correlation: Younger patients may lose an extraordinary amount of blood before their
blood pressure falls. This is due to the fact that their hearts are usually healthy and their
compensatory systems are robust. Yet, such a patient may actually be in shock, with critically
reduced blood flow to the gut, kidney, and other vascular beds. The astute clinician will not be

Jason Poston, MD

Cell & Organ Physiology: CV physiology

deceived by the relatively normal blood pressure and will diagnose shock by way of other signs:
cold, clammy extremities (due to intense vasoconstriction), tachycardia, a reduced pulse
pressure (indicating a reduced stroke volume), and tachypnea (due to activation of the
chemoreceptor reflexes from tissue hypoxia).
EXERCISE
The oxygen consumed by the bodyVO2may increase 60-fold with exercise. This
dramatic increase in metabolic activity requires a significant increase in blood flow to exercising
muscles in order to supply oxygen and nutrients and eliminate carbon dioxide and other waste
products. The major cardiovascular responses are summarized below.
!

Central command refers to a set of cardiovascular responses initiated when an increase in

physical activity is anticipated. These responses are initiated by the cerebral cortex and
result in an increase in sympathetic outflow to the heart and blood vessels and a decrease
in parasympathetic outflow to the heart.

Sympathetic activation increases cardiac contractility and heart rate while also increasing
arteriolar resistance in the skin, kidneys, and splachnic bed, thereby diverting blood flow to
exercising muscle. (Later, as core body temperature rises, blood flow to the skin increases
in order to dissipate heat). Coronary blood flow and skeletal muscle blood flow increase in
proportion to metabolic demand through the release of vasoactive metabolites as discussed
previously. Skeletal muscle dilation decreases peripheral resistance and therefore left
ventricular afterload, decreasing myocardial work and increasing stroke volume.

Interestingly, a given increase in oxygen consumption requires a somewhat lesser increase

in muscle blood flow due to an increase in oxygen extraction in the tissues. This is
facilitated by enhanced unloading of oxygen due to a leftward shift of the oxyhemoglobin
dissociation curve as blood courses through skeletal muscle characterized by a reduced pH
and increased temperature.

Chemoreceptors respond to changes in ambient pH, pCO2, and pO2, regulating

respiratory responses (and to a lesser extent cardiovascular responses), increasing the
depth (and later in exercise, the rate) of respiration. This will be discussed in more detail in
pulmonary physiology. Stimulation of these receptors also increases sympathetic tone.

Actively contracting muscle stimulates intramuscular mechanoreceptors and local

chemoreceptors that send afferent fibers to the central nervous system, which increases
sympathetic neural outflow.

Venous return is aided by the respiratory and skeletal muscle pumps. An increase in
the rate and depth of respiration promotes venous return through a reduction in intrathoracic
pressure (vide supra), while skeletal muscle contraction and one-way venous valves propel
blood back to the heart.

Why does the cardiac output increase during exercise?

The cardiac output may increase 6-fold during exercise. Remember the determinants of cardiac
output:

CO = SV x HR
4

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Both the stroke volume and heart rate are increased during exercise. In fact, the increase in
heart rate (say, from 60 to 180 in a young person) is considerably greater than the increase in
stroke volume (say, from 80 to 100). It is therefore tempting to conclude that an increase in
heart rate is the principal mechanism for the increase in cardiac output. This is an
oversimplification, however. The evidence for this is as follows:
!

Increasing the heart rate from 60 to 180 by electrical stimulation does not increase the
cardiac output in a resting animal. Thus, stroke volume decreases as the heart rate
increases and there is less time for filling. The animals cardiac output is therefore likely
chiefly controlled by the systemic vessels (which determine preload), which are
unaffected by pacing the heart.
Dogs in whom the hearts autonomic innervation has been ablated still experience an
increase in cardiac output during exercise, chiefly through an increase in stroke volume
(although the heart rate does increase somewhat because of its response to circulating
catecholamines). Give that dog a beta-blocker (a beta-adrenergic receptor blocking
agent), however, and exercise performance is impaired, probably because it prevents
catecholamine-induced increases in heart rate and contractility.
Patients taking beta-blockers have reduced exercise capacity, but not so much as one
may think, so long as they have preserved cardiac function.

Thus, an increase in heart rate may contribute to an increase in cardiac output, but it is not the
principle factor as it may appear from a simple analysis of the CO equation above.
Why can most of you run farther than I can?
Training is associated with an increase in the maximum VO2 the individual can obtain, reflecting
an increase in the capacity to perform sustained exercise. Training results in a lower resting
heart rate, a greater stroke volume, and a lower peripheral resistance. Sympathetic tone is
reduced, and parasympathetic tone is enhanced. Physical training also results in improved
oxygen extraction in the muscles, which also show an increase in capillary density and the
number of mitochondria. While all these phenomena are well known, the precise determinants
of exercise limitation are rather poorly understood.

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Cardiovascular responses to exercise

that involve the skeletal muscle.

Make notes here

Jason Poston, MD

Cell & Organ Physiology: CV physiology

Cardiovascular responses to
exercise. A global view.

REFERENCE PARAMETERS & CALCULATIONS

CARDIOVASCULAR PHYSIOLOGY
Cell & Organ Physiology
Systolic blood pressure (SBP)

100-140 mmHg

Diastolic blood pressure (DBP)

60-90 mmHg

Pulse pressure (PP=SBP-DBP)

30-50 mmHg

Mean arterial pressure (MAP)

DBP + 1/3(PP)

Heart rate (HR)

60-90 bpm

Body surface area (BSA)

1.6-1.9 m2

Stroke volume (SV)

50-100 mL

Stroke index (SI)

SV/BSA = 35-50 mL/m2

Right atrial pressure (~ central venous pressure) (Pra, CVP)

2-8 mmHg

Mean systemic pressure (Pms)

10-15 mmHg

Resistance to venous return (Rvr)

1-2 mmHg/L/min

Pulmonary systolic pressure

16-24 mmHg

Pulmonary diastolic pressure

5-12 mmHg

Pulmonary pulse pressure

8-15 mmHg

Mean pulmonary artery pressure (MPAP)

9-16 mmHg

Mean pulmonary capillary wedge pressure (PCWP)

5-12 mmHg

Cardiac output (CO = SV x HR)

4-6 L/min

Cardiac index (CI = CO/BSA)

2.5-3 L/min/m2

Systemic vascular resistance (SVR)

SVR = (MAP Pra)/CO

10-15 mmHg/L/min
(900-1200 dyne*s/cm5)

Pulmonary vascular resistance

PVR = (MPAP PCWP)/CO

1.5-2.5 mmHg/L/min
(120-200 dyne*s/cm5)

Venous return (VR)

VR = (Pms Pra)/Rvr

4-6 L/min

Lecture Notes
Module 3
Pulmonary Physiology
Hall, Naureckas, & Sattar

Med Bio 303

Cell and Organ Physiology
Respiratory Statics
January 27-28, 2014
In the beginning, life was easy (from the standpoint of cellular respiration). In single cells, entry
of oxygen into the cell and the exit of carbon dioxide occur through simple diffusion. Cells
consume oxygen using aerobic metabolism and produce carbon dioxide. Oxygen tension
decreases intracellularly, creating a diffusion gradient with respect to the surrounding
environment; oxygen enters the cell as a result of this gradient. As carbon dioxide builds up
within the cell, this creates a gradient in the opposite direction, with CO2 leaving the cell again
through simple diffusion. (See figure 1)

O2

O2

CO2

Figure 2 to the right is a highly

simplified schematic representation of
the lung. Ventilation moves oxygen
into the alveoli and carbon dioxide out
(this movement is generated by the
muscles of the diaphragm and chest
wall; more on this later). Oxygen
diffuses through the alveoli into the
blood circulating in the pulmonary
capillary. The circulation delivers this
oxygen to the peripheral tissues. This
same circulation removes carbon
dioxide from the peripheral tissues,
which then diffuses back into the

As organisms become more complex and

energetic, these gradients quickly become
exhausted due to local depletion of oxygen
and accumulation of carbon dioxide in the
area immediately around the cell.
Thus, an essential function of the
cardiovascular and pulmonary systems is to
maintain these gradients to allow cellular
respiration to continue in a highly active
multi-cellular organism. Many of the
adaptations that allow mammals to be so
successful, such as the four-chamber heart
and red cells lacking nuclei, developed to
make this process more efficient.
Figure 1

CO2

Figure 2

alveoli. The bulk flow of air in and out of the lungs to maintain gradients at the alveolar level
requires air movement and can best be understood from the standpoint of the statics and
dynamics of the lung. The study of statics refers to the forces acting on a body at rest. In the case
of the lung, this refers to those forces determining lung volumes.
Measurement of Lung Volumes
As the famous Scottish physicist Lord Kelvin stated, When you can measure what you are
speaking about, and express it in numbers, you know something about it; but when you cannot
measure it, when you cannot express it in numbers, your knowledge is of a meager and
unsatisfactory kind... The beginning of such knowledge in respiratory physiology - the ability
to measure lung volumes in a consistent fashion - began with the water seal spirometer, first
invented by John Hutchinson in 1844. This device collects expired air between two cylinders
using water to seal the space in between. The volume of air moving into and out of the
spirometer was initially recorded on a rotating cylinder. In modern spirometers this data is
collected electronically using a mouthpiece that measures flow rather than volume.

Figure 3
Figure 3 above demonstrates a spirometry tracing. It would be worthwhile to study this figure as
these volumes and capacities will be referred to repeatedly in the following lectures (and are easy
targets for exam questions). In this graph time is plotted on the x-axis. Volume is plotted on the
y-axis; in this example volume inspired by the subject is positive and exhaled volume negative.
The volume that enters and exits the subject during quiet breathing is known as the tidal volume
(TV). In normal tidal breathing inhalation is active and exhalation is passive. At the end of
passive exhalation the lung reaches a value known as the functional residual capacity. A capacity
is made up of two or more volumes, in this case the expiratory reserve volume and the residual
volume. The expiratory reserve volume (ERV) is the amount of air that can be exhaled from the
end of a normal tidal volume until no further air can be expired despite the subjects greatest
2

effort. The amount of air remaining in the lungs at this point is referred to as the residual volume
(RV). Inspiratory reserve volume is the volume of air that can be inhaled in addition to a normal
tidal inspiration, i.e. once a normal inhalation is made; one continues to inhale until the lungs are
filled. This additional volume is the IRV.
In a vital capacity maneuver the subject inhales maximally from FRC (i.e. from the state at the
end of a normal exhalation) and the lungs become fully inflated. The volume of air contained
within the lungs at this point is the total lung capacity (TLC). The patient then exhales to RV
(i.e. exhales as much as possible). The total volume of air between these two values is the vital
capacity (VC = ERV + TV + IRV). Note that the VC is a dependent value, because any process
that alters TLC or RV (including inadequate effort during the maneuver) will alter the VC.
Hutchinson demonstrated that lung volumes were proportional to height. It was later shown that
these volumes also varied with age, with increasing values until early adulthood, followed by an
inexorable decline thereafter. By measuring lung volumes on a large number of individuals,
regression equations can be use to determine a predicted value for any given a subjects age,
height and gender. The actual volumes for the subject can be divided by this predicted value to
yield a percent predicted. One fortunate coincidence of pulmonary function testing is that two
standard deviations on either side of the mean, the normal range, correspond to roughly 80 to
120% of the predicted value.
The problem with the use of spirometry to determine lung volumes becomes self evident when
one considers the RV as that volume which remains in the lung at the end of maximal exhalation.
With spirometry alone one can directly measure the VC and the ERV, but not TLC, FRC or RV.
Two methods are commonly used to measure the amount of air within the lung without requiring
it to exit the lung. The first technique relies on inert gas dilution. This technique uses the
principle of conservation of mass. A known concentration of an inert gas such as helium is
inhaled into the lung. The air constituting the TLC then dilutes this gas. The exhaled
concentration of gas can then be measured and TLC calculated.
C1V1 = C2V2 is the general form of the equation. Where C is concentration and V is volume.
[He]1IV = [He]2TLC is the form of the equation where [He] is the concentration of helium
gas.
Solving for TLC: TLC= IV([He]1/[He]2), where IV = inhaled volume of gas = vital capacity
This method assumes that the helium gas distributes quickly and mixes completely with the air
contained within the lung. These conditions are violated in individuals with severe obstructive
diseases (e.g. COPD). Therefore TLC tends to be underestimated in subjects suffering from
these conditions.
A second method of measurement utilizes a plethysmograph, or body box, to measure the FRC
directly using Plethysmography. To accomplish this, the subject is sealed within a closed
container, usually made of transparent plastic to minimize claustrophobia, and pants against a

closed shutter, thereby compressing the air within the lung slightly. The pressure is then
measured both at the mouthpiece and within the box. Because the box is a closed system, the
amount by which the subjects lungs (and hence chest wall) expand to accommodate the inspired
air will lower the volume of the box not occupied by the subject by the same amount, thereby
increasing the pressure within the box (remember the ideal gas law!). Plethysmography will be
demonstrated more fully during your workshop demonstration in the hospital.
By Boyles Law: P1V1 = P2V2; Where V1 is FRC and V2 = FRC + V (the change in volume with
panting this value can be determined by the change in pressure within the box)
FRCPatm = (FRC + V) (Patm + P) where P = Change in pressure at the mouthpiece
FRCPatm = FRCPatm +FRCP+ Patm V + VP
VP is very small and can be neglected making it easy to solve for FRC
FRC = - Patm V/P
Once FRC is known the remainder of the lung volumes can be obtained in combination with
spirometry using simple arithmetic.
Determinants of Lung Volumes
Lung volumes are determined by the mechanical properties of the lung, the chest wall, and by
respiratory muscle strength. In order to best understand how these different components of the
respiratory system interact, we can start with a simple model of the lung as an elastic sphere.
The pressure within the lung is the alveolar pressure represented as PA. The pressure on the
outside of the lung is the intrapleural pressure PPl. The difference in pressure between the inside
of the lung and the outside of the lung (PA PPl) is known as the trans-pulmonary pressure. It is
this trans-pulmonary pressure that provides the distending pressure for the lung. Countering this
distending pressure is the elastic recoil pressure of the lung. This pressure, which increases with
volume (think of a rubber bands recoil force increasing as it is stretched out more and more), is
created by the elastic elements of the lung. This force is additive to the intrapleural pressure
such that PA = Pel + PPl. In a static
situation where the lung is held motionless
at any lung volume the transpulmonary
pressure (Ptp) will be equal to the elastic
recoil pressure:
PA = Pel + PPl
PPl = PA Pel
Ptp = PA PPl = PA (PA Pel)

PA

Pel

Ptp

Ptp = Pel

PPl
4

Figure 4

At FRC, the natural resting point of the lung, The Pel is equal to about 5 cm of water. (A cm of
water is the amount of pressure is takes to raise a column of water within a manometer one cm)
As the alveolar pressure will be zero, assuming an open glottis, the pleural pressure, using the
first equation above, must be -5cm of water, which is what is usually observed in normal lungs.
One of the important properties of the lung is lung compliance. Compliance is the relationship
between the volumes and pressures within the respiratory system and is given by the formula:
C =V/P. Lungs are said to be compliant when a small change in pressure results in a large
change in volume. Stiff non-compliant lungs demonstrate only a small change in volume for a
given pressure.
Compliance is also dependent on the amount of lung available. Figure 5 demonstrates the effect
of successively removing lung by surgical resection and its effect on lung compliance. The same
effect can be seen when individual alveoli are lost to atelectasis (collapse) or flooding with
edema fluid.

Figure 5
Of note, compliance also has a large impact on the work of breathing. As you remember from
college physics, Work = Force x Distance. As pressure is expressed as F/cm2 and Volume is

expressed in cm3. The product of P x V, that is the change in volume induced by a change in
pressure, is expressed in units of work F x cm and is equal to the amount of work required to
effect that change in volume.
When discussing the recoil properties of the lung we have used the analogy of a rubber band
implying that stretch of elastic proteins within the walls of the alveoli and airways accounts
entirely for PEL. In reality, the majority of the elastic recoil pressure in the intact lung is due to
surface tension, the inevitable consequence of being land mammals and the requirement for gas
exchange across an air liquid interface. The effects of an air liquid interface can be seen in
figure 6 which depicts the pressure volume curve for the lung when inflated with air or with
saline. The x-axis depicts pressure as the independent variable and volume is on the y-axis.
Two important differences can be note between these two graphs. The first is that it takes
significantly less pressure to inflate a saline filled lung than an air filled lung. The second is that
the airway filled lung demonstrates significant hysteresis- that is that it requires higher pressures
to inflate the lung to a given pressure than is required to maintain the lung at a given volume
once it is achieved. Both of these effects can be explained by the presence of surface tension and
the substance that has evolved to counteract surface tension: surfactant.

Figure 6.
In order to understand how surface tension is created we need to think in molecular terms.
Figure 7 demonstrates two separate atoms both with a nucleus and electrons. The electrons in
the atom will be of course tightly associated with the nucleus. The nucleus of each atom will
also be attracted to the electrons of the neighboring atom. This will cause the two atoms to
approach each other until the repulsive force of the electrons prevents the two nuclei from
coming any closer. This force is known as the Van der Waals force and the optimal distance that
results in the lowest energy state is known as the Van der Waals radius. This is the force that
causes most matter together rather than gravity which is very weak at small scales. Water, which
makes up a substantial portion of the surface lining fluid of the alveoli, is dipolar by virtue of the
fact that electrons are more strongly attracted to the oxygen nucleus within the molecule than the
hydrogen nuclei resulting in the oxygen being slightly negatively charged with respect to the
6

hydrogen atoms. This imbalance in electron distribution results in a relatively strong form of
electrostatic attraction between molecules called hydrogen bonding.
Consider a glass of water. A water molecule situated in the center of the glass is subject to the
forces of hydrogen bonding to all of the water molecules surrounding it. Because these forces
are uniform in all directions, the net force on the water molecule will add up to zero. At the
surface of the water, however, the forces acting on any given molecule are asymmetrical due to
the presence of an air-liquid interface. The forces of the molecules on the surface of the glass
line up to result in a tension pulling inward, tension being simply a force per unit length.
If you take the water molecules from the surface of the glass and form them into a sphere, you
have created a bubble. Bubbles are spherical in shape as this shape results in the smallest surface
area for a given volume. A bubble remains stable due to the fact that as surface tension of the
water molecules reduces the surface area, the air trapped within the bubble becomes compressed
until the pressure within the bubble is in equilibrium with the surface tension. The relationship
between the radius of a sphere and the pressure required to maintain that radius for a given
surface tension is:
P =2T/r where P is pressure within the bubble, T is the wall tension and r is the radius.
Note that as the radius of the bubble decreases, the pressure required to maintain the sphere at a
given radius increases in an inverse relationship. In a closed sphere equilibrium is achieved as
the volume within the sphere decreases inversely to the third power of the radius and the
resultant compression of the air contained within the bubble quickly yields the necessary
pressure.
Now consider what happens when a hole is poked in the side of the bubble. In this circumstance
the air within the bubble leaks out and the system quickly becomes unstable as the pressure
required to maintain the radius can no longer be maintained. In fact the bubble will continue to
get smaller as the pressure required increases as the bubble shrinks. A bubble with a hole in it is
an exact analogy of an alveolus as there needs to be an opening in the wall of the alveolus for
ventilation to occur. Alveoli are inherently unstable.
The reason why we are able to breathe air and exchange oxygen and carbon dioxide across an air
liquid interface is the presence of surfactant. Surfactant had the property of having a variable
surface tension. It is made up of a number of components but the largest single component is
phosphatidylcholine a molecule with a hydrophilic head and hydrophobic tails. The hydrophilic
heads dissolve in the surface lining fluid of the alveoli and float on the surface by virtue of the
hydrophobic component of the molecules. The charge on the hydrophobic component of the
molecule is such that the molecules of phosphatidylcholine repel each other the more closely
they are compacted together stabilizing the alveolus. The net effect is an overall reduction in
surface tension. The surface tension of water is approximately 80 dyne-cm whereas the
equilibrium surface tension of surfactant is close to 25 dyne-cm.
The importance of surfactant can be demonstrated by the condition known as respiratory distress
syndrome. In this syndrome infants who are born prematurely have not yet developed surfactant

and are unable to open their alveoli in order to breath. In the era before mechanical ventilation
was available to provide an external pressure to force open the alveoli, this condition was
uniformly fatal. Artificial surfactants were developed in the 1980s and have markedly reduced
respiratory complications in pre-term infants.
While we have been dealing with a relatively simplified model of the isolated lung, in reality
(and thankfully) lungs are contained within the thorax coupled to the chest wall by negative
pressure within the pleural space. To understand the mechanical interaction between the lung
and the chest wall it is instructive to consider each component separately. One property of lung
mechanics is that the same result is obtained whether you apply a pressure internally by pushing
air into the airways with a syringe or by exerting a negative pressure around to lungs. This
allows a pressure vs. volume curve for the lung to be created by inflating the lung to a series of
volumes and measuring the pressure required.

Lung
TLC

RV
- Pressure (cm H2O) +
Figure 7
The overall theme for the lungs is that lungs want to get smaller. This is consistent with the
simplified elastic sphere model discussed above. Of interest is what happens when the
transpulmonary pressure becomes large or negative. When the transpulmonary pressure
decreases below zero, the lung volume does not decrease further. This occurs because the small
airways of the lung are tethered open by outward pull from inflated lung parenchyma. As the
lung deflates during exhalation, the pull on these small airways is progressively less, and
eventually they close, trapping some gas in the alveoli. This effect is exaggerated with age,
especially with obstructive airways diseases, resulting in gas trapping at quite large lung
volumes. With higher pressures, the lung becomes increasingly stiffer with a greater amount of
pressure required for any change in volume. It is this stiffness at higher lung volumes that
mainly determines the total lung capacity.
A similar pressure/volume curve can be created for the chest wall. In this case the theme is that
the chest wall wants to get big. This is observed in the case of a pneumothorax, where air
inadvertently enters the pleural space. Not only does the lung collapse inward, but the chest wall
will recoil outwards as evidenced by an increase in the space between ribs on a CXR. The lung
is very compliant (big change in volume for a small change in pressure) at large lung volumes

but much stiffer and less compliant at low lung volumes. In the absence of the airway closure
mentioned above, the mechanical properties of the chest wall tend to determine the residual
Chest Wall
TLC

RV
- Pressure (cm H2O) +

volume.
Figure 8

Figure 8
The pressure volume relationship can be determined by summing the pressures for the lung and
the chest wall at any given volume. This is shown by the yellow line in the diagram above. Note
that at FRC these pressures add up to zero consistent with its role as the natural resting point of
the lung; that is, the point at which the outward recoil of the chest wall is matched by the inward
recoil of the lung. The balance of forces between the chest wall and the lung therefore
determines the lung volumes. In cases where the lung compliance is reduced (stiffer, more
elastic lungs) the lung will win the tug of war between itself and the chest wall and the FRC and
other lung volumes will be smaller (See B above, showing fibrosis causing lower lung
compliance). In situations where the lung compliance is increased such as emphysema (See B
above), lung volumes are increased as the chest wall wins the battle.

Left to its own devices, the lungs would settle at FRC and remain there forever if it were not for
the respiratory muscles. The musculature of the respiratory system is hugely overpowered with
respect to what is required to achieve TLC. In terms of pressure, it takes approximately -60 cm
of inspirational pressure to move to the far end of the pressure volume curve above. Most
individuals can create pressures on the order of -200 cm of water. Similarly, significant
weakness in the muscles of exhalation needs to occur before RV is significantly decreased.
When this does occur, residual volume rises and total lung capacity decreases resulting in
marked decreases in the vital capacity that is caught in-between.

Figure 9
The lung model represented above is of course highly simplified in a number of ways, the most
obvious being the regional differences in ventilation due to gravity. To understand how gravity
might influence the mechanical properties of the lung, it is helpful to consider a Slinky TM, a toy
popular in the latter half of the 20th century consisting of a stainless steel spring which acts as a
good stand-in for the elastic properties of the lung. If you hold a Slinky from one end and let the
other end hit the floor, the weight of the lower parts of the spring will result in progressively
larger amount of stretch as you move up the spring. If the spring is stretched further the percent
change between each coil will be much greater at the base of the spring where it is less stretched
at baseline than at the top of the spring. In the same way, the apex of the lung will be more
inflated at FRC due to gravitational effects than the base of the lung. For this reason, during
inspiration, a larger amount of ventilation will go to the bases of the lungs than the apex. The
implications of this heterogeneity of ventilation will be discussed in the section on
Ventilation/Perfusion relationships.

10

Med Bio 30300

Cell and Organ Physiology
Respiratory Dynamics
January 28, 2015
The figure below is the simplified schematic representation of the lung we discussed during the
lecture on the static properties of the lung. Ventilation moves oxygen into the alveoli and carbon
dioxide out. Oxygen diffuses from the alveoli to the blood, and the circulation delivers this
oxygen to the peripheral tissues. This same circulation removes carbon dioxide from the
peripheral tissues that then diffuses back into the alveoli to be exhaled. The bulk flow of air in
and out of the lungs to maintain gradients at the alveolar level requires air movement and can
best be understood from the standpoint of fluid dynamics.

Figure 1

Through the course of the next two lectures we will discuss the forces acting on air to move it in
and out of the lungs and how these may be altered in disease. Changes that increase the amount
of work required to create this air movement may be perceived by patients as shortness of breath,
hence understanding of these processes will allow you to better understand the basis of
pulmonary diseases you will be called upon to treat.
Air movement in the atmosphere, such as wind, is created by differences in air pressure with air
molecules moving from areas of high pressure to areas of low pressure. Within the lungs this

.
V=

movement needs to be constrained by some structure to be distributed to the enormous surface

area of the alveoli (more about that in the diffusion lecture).

(P1-P2) r4
8l

P1

P1

P2

P2

Figure 2
As simple way to study this problem is to consider the pressure required to push a fluid (liquid or
gas) through a tube or airway. One of the first physiologists to consider this problem was Jean
Poiseulle, a French nineteenth century physician who studied the flow of blood through vessels
using a model of rigid tubes. Through a series of experimental observations he was able to
identify a relationship between the diameter of a tube, its length, the viscosity of a fluid and the
pressure required to move a given fluid through a tube at a given velocity. This relationship is
known as Poiseulles law:

Where V = Flow (first derivative of volume with respect to time), P = pressure, r = tube radius,
l=tube length and = viscosity of inspired air.
This equation works well as long as a number of conditions are met. The fluid has to be
Newtonian, meaning that the viscosity does not change with flow. The tubes have to be noncollapsible and flow needs to be laminar. While this model is fairly simple, it turns out that at
least one of these conditions turns out to be untrue in almost any airway you consider.
The pressure required to move air through a tube is critically dependent on the flow regimen.
The most efficient (that is, requiring the lowest pressure for a given flow) flow profile is laminar
flow. The pressure drop along a tube or in this profile is completely due to frictional energy loss
as one layer of fluid slides along the next. In the diagram below, the speed of flow along the
airway is greatest in the center and drops off until it reaches zero at the airway wall. The flow is
greatest at the center due to the fact that each layer as you move towards the center of the pipe is
sliding against neighboring layers with increasing velocities.

Figure 3 - Laminar Flow

This is similar to the flow observed in a large river where the current will me much greater at the
center of the river than along the bank. A graph of flow velocity versus distance from the center
will be parabolic in shape.

Laminar Flow
0 mph
2 mph

4 mph

2 mph

0 mph

Figure 4

As flow rates increase, flow becomes chaotic and achieves turbulent flow. In this case the
pressure required to move air through the tube at a given velocity is increased as compared to
laminar flow due to the energy required to change direction of the air molecules as they swirl
around. Remember for physics that a change in direction requires acceleration and hence
increased force (or pressure: force per unit area) to achieve this acceleration.

Figure 5

Turbulent flow

Re = D u

The tendency for flow to be laminar or turbulent can be predicted using the Reynolds number:

Where D= tube diameter, u = average velocity, = fluid density and = viscosity. A Reynolds
number of > 2000 is generally associated with turbulent flow. This equation can be used to
demonstrate that flow in the trachea is likely to be turbulent.

For the trachea:

U= 150 cm/second
= 0.0012 g/cm3
=1.83x10-4 g/sec*cm
D= 3 cm
Re = 2950

As most airways are small, and flows are relatively low, the majority of flow in the lungs is
laminar except in the large bronchi. An easy way to determine whether or not flow is laminar is
to use your stethoscope: if you can hear breath sounds, the flow is not laminar. Most breath
sounds are created by what is known as transitional flow where turbulent eddies are created at
branch points where airways divide:

Figure 6

While we are modeling a single airway in the above examples, in reality, the lung is comprised
of millions of airways each with their own airways resistance (Raw = P/ V). Counter-

intuitively, resistance is greatest in the large airways and least at the peripheral airways. While
the trachea is the largest airway, there is only one trachea per customer, while there are millions
of smaller airways giving a much greater surface area as demonstrated below (remember how
resistance works in parallel circuits this is the same principle at work here):

Mouth

Alveoli
Terminal
Bronchi

Segmental
Bronchi
Trachea
Cross-sectional
Area

Figure 7

What are the consequences of airways resistance on the work of breathing? A simple model of
these effects can be seen on the following page. In this model a piston is used to mimic the
effects of the diaphragm and chest wall on pleural pressure. Ppl is equal to the intrapleural
pressure, which is negative in most instances. Alveolar pressure Palv is the pressure within the
gas exchange units at the end of the airways and the transpulmonary pressure Ptp is the difference
between these two. Transpulmonary pressure is equal to the elastic recoil (Pel) pressure in the
lecture on lung statics.

Expiration

Inspiration
0.5
0.4
0.3
Volume
0.2
(liters)
0.1
FRC = 0
Pleural
Pressure
(cm H2O)

Expiratory
Flow
(liters/sec)
Alveolar
Pressure
(cm H2O)

-6
-7

At FRC

Patm = 0
D

Ptp = 5

-8
-9

+0.5

Palv=0

Ppl=-5
C

-0.5
+1

-1

Lung Volume = 3000 ml

B
time

Figure 8a
Expiration

Inspiration
0.5
0.4
0.3
Volume
0.2
(liters)
0.1
FRC = 0
Pleural
Pressure
(cm H2O)

Expiratory
Flow
(liters/sec)
Alveolar
Pressure
(cm H2O)

-6
-7

Start of Inspiration

Patm = 0
D

Ptp = 5

-8
-9

+0.5

Ppl=-6
C

-0.5
+1

Palv=-1

-1

Lung Volume = 3000 ml

B
time

Figure 2b

At rest, Palv and Patm will be equivalent because flow = 0. At point A on figure 8a the lung is at
FRC and the inward elastic recoil pressure is balance by the negative pleural pressure pulling the
lung toward the chest wall. Remaining at the same point on the diagram, a respiratory effort is
now initiated (Figure 8b). The pleural pressure now becomes slightly more negative. As the
lung volume hasnt changed the elastic recoil pressure remains the same therefore alveolar
pressure decreases by an amount equivalent to the decrease in the pleural pressure.

Expiration

Inspiration

Pleural
Pressure
(cm H2O)

0.5
0.4
Volume 0.3
0.2
(liters)
0.1
FRC = 0

During Inspiration

Patm = 0
D

-6
-7

Ptp = 7

-8
-9

Palv=-1

Expiratory
A
Flow
(liters/sec) -0.5
+1

-1

Patm = 0

+1

time

Palv= 0

Ppl=-9
C

-1

Ptp = 9

-8
-9

Alveolar
Pressure
(cm H2O)

Lung Volume = 3300 ml

+0.5
Expiratory
A
Flow
(liters/sec) -0.5

End Inspiration

-6
-7

Pleural
Pressure
(cm H2O)

Ppl=-8

+0.5

Alveolar
Pressure
(cm H2O)

Expiration

Inspiration

0.5
0.4
Volume 0.3
0.2
(liters)
0.1
FRC = 0

Lung Volume = 3500 ml

B
time

Figure 8c

In the next panel (Figure 8c), points B and B on the graph represent mid inspiration. As the
lung volume has increased, so has the transpulmonary or elastic recoil pressure. The difference
between B and B in the intrapleural pressure represents the difference in intrapleural pressure
created by airways resistance. Note that this is equivalent to the difference between the
atmospheric and alveolar pressures. At point C on the diagram the lung is at end inspiration. As
the lung now has 500ml of additional volume the transpulmonary pressure has now increased to
9. As flow has stopped, there is again no difference between the atmospheric and alveolar
pressures.
Expiration

Inspiration
0.5
0.4
Volume 0.3
0.2
(liters)
0.1
FRC = 0
Pleural
Pressure
(cm H2O)

-6
-7

Patm = 0
Ptp = 7

-8
-9

+0.5
Expiratory
A
Flow
(liters/sec) -0.5
Alveolar
Pressure
(cm H2O)

+1

Patm = 0
D

Ptp = 5
B

-8

+0.5
Expiratory
A
Flow
(liters/sec) -0.5

-6
-7

At FRC

Alveolar
Pressure
(cm H2O)

Lung Volume = 3300 ml

B
time

+1

Ppl=-5
C

-1

Palv=0

-9

Ppl=-6

-1

Pleural
Pressure
(cm H2O)

Palv= 1

C
C

Expiration

Inspiration
0.5
0.4
Volume 0.3
0.2
(liters)
0.1
FRC = 0

During Exhalation

Lung Volume = 3000 ml

B
time

Figure 8d

This next panel (left, Figure 8d)) represents mid-expiration. As inspiratory effort ceases
(expiration in tidal breathing is passive) pleural pressure become less negative. As
transpulmonary pressure remains increased at this higher volume, this results in a positive
alveolar pressure. The final panel at end expiration completes the cycle. While this may appear
esoteric, the ability to differentiate the cause of elevated airways pressure, whether due to
abnormal lung compliance or increased airways resistance is of great use when treating patients
in the intensive care unit.

Cm H2O
90

Cm H2O
90

PR

1.2

l/s

1.2

l/s

Pc

-0.8

-0.8

Figure 9

Pressures and flows can be directly measure when a patient is intubated in the intensive care unit.
An endotracheal tube is inserted into the trachea and a balloon is inflated to seal off the space
between the tube and the trachea. Pressure and flow are measured at the end of this tube. The
figure at the upper right represents pressure (upper panels) and Flow (lower panels) curves from
patients with obstructive airways disease (left panels) and restrictive lung disease (right panels).
The x-axis in each graph is time. These graphs demonstrate what is known as an inspiratory
pause hold maneuver. This test takes advantage of the fact that in the absence of flow the
pressure at one end of the tube is the same as on the other end. At the end of inspiration just
before flow stops the pressure at the airway opening is the sum of pressure losses down the tube
and airways due to resistance as well as the pressure required to inflate the lung. When flow is
stopped the pressure drop due to airways resistance is removed and only that pressure required to
hold the lung in an inflated state remains. On the left, showing obstructive disease, there is a
minimal plateau, as most of the peak pressure was due to airways resistance. On the right the
pressure remains high during an inspiratory hold, as the lung is restricted and requires increased
pressures to hold the lung at this volume (low compliance). (By the way, these pressures would
be truly frightening if you actually observed them on an intubated patient and would require
immediate action to prevent lung injury.)
This maneuver helps distinguish between two of the main categories of abnormal lung
physiology: restrictive lung diseases, which are those that result in increase work of breathing
due to decreased lung compliance, and obstructive lung disease, those diseases that result in
reduced air flow. Examples of restrictive lung disease include Interstitial Pulmonary Fibrosis
(IPF), sarcoidosis, obesity and chest wall deformities such as scoliosis. Obstructive diseases
include asthma, emphysema and chronic bronchitis. Some diseases such as sarcoidosis can
manifest both obstructive and restrictive physiology.
We have spent a great deal of discussion on airways resistance (Raw). As mentioned above, the
majority of airway resistance is concentrated in the upper airways. As demonstrated in the
diagram below, resistances in parallel result is a reduced overall resistance (1/2+1/2+1/2+1/2=2
RT=1/2) whereas resistances in series are additive (2+2+2+2=8= RT). The resistance of the
airways can therefore be modeled as a combination of parallel and serial resistances.

Trachea

R1

R2

R3

R4

Mainstem
Bronchi

Lobar
Bronchi

Segmental
Bronchi

RT=R1+R2+R3+R4

R1
R2
R3

1/RT = 1/R1+ 1/R2 + 1/R3+ 1/R4

R4

PM

Resistance (cm H2O/liter/sec)

PB
Shutter Closed:
Mouth Pressure = Alveolar Pressure
Alveolar pressure correlated with
box pressure

.08

VM

.06

Respiratory
Zone

Conducting
Zone

.04

PB

Shutter Open:
Air flow measure at mouth
Alveolar pressure inferred from
Box pressure

.02

10

15

20

R=Pressure/Flow

Airway Generation

Figure 10

Airways resistance can be directly measured in the PFT lab. The patient pants against a closed
shutter in an enclosed box. As the shutter is closed the pressure measures at the mouth are the
same as the alveolar pressure due to the fact that flow during this phase of the measurement is
zero. This allows a standard curve of box-pressure versus alveolar-pressure to be created.
Then when the shutter is opened the patient then pants again and the amount of flow can be
measured to calculate resistance:

Raw=

(PM/PB) PM
=
. <2
(VM/PB) VM

Figure 11

It is important to note that the airways resistance in normal lung is extremely low: less than 2cm
H2O/L/sec. It is also important to note that this measurement is made at very low flows and does
not measure change due to dynamic obstruction seen in diseases such as emphysema. Airway
resistance is also usually measured at functional residual capacity, but can be measured at any
lung volume. It is important to note though that the value may change at differing lung values
due to differing airway diameters created by changes in the interparenchymal tethering forces at
differing volumes. These forces in the lung, the interconnectedness of the lung, become more
important when talking about the factors that limit airflow during a forced expiratory maneuver.

Figure 12

V
(l/sec)

RV

Volume (liters)
TLC

Figure 13

Figure 12 represents the various lung volumes.

The amount of air that can be exhaled from the lung between the Total Lung Capacity (TLC) and
the Residual Volume (RV) is the Vital Capacity. When measured as part of a forced expiratory
maneuver, this measurement is referred to as the forced vital capacity. Another way of
representing spirometric data is by means of a flow volume loop. This is a same data shown on
the previous slide with volume as the X axis and flow as the Y axis. Note that there is no time
axis. This maneuver is performed with the patient coached to perform at maximum effort. Note
also that the flows obtained are linearly dependent on volume with the greatest flows occurring
10

at TLC at the beginning of the forced expiratory maneuver and the flows dropping off to zero at
residual volume (RV).
This dependence between lung volume and
maximal airflow is reinforced in the diagram
to the left. If maximal expiratory maneuvers
are made starting at various percentages of
vital capacity, the maximal flow at the start
of expiration corresponds to the same
velocity at that point of expiration in a flow
volume curve initiated at 100% of vital
capacity. Also note that the amount of flow
at any percentage of vital capacity increases
with increasing effort but then plateaus at a
given flow above which increases in effort
results in no additional increases in flow.
This raises the question of what limits
maximal air flow during forced expiration.

75

50

25

Figure 3

The diagram at the upper left is a crude drawing of a waterfall. This is useful analogy for the
flow-limiting segment of the airway. Just as the level of water at the base of the waterfall does
not effect on the flow of water up to the waterfall nor does any downstream obstruction, airway
characteristics downstream of the flow-limiting segment of airways will not affect airflow. In a
forced expiration, the initial flow-limiting segment is in the most proximal airways beginning
with the trachea. As lung volume decreases as the patient expires, the flow-limiting segment
moves to smaller and smaller airways.

11

A = Luminal Area

.
V

A
Ptot
Plat

Pel(v)
Psfr

Palv

Ptm
Ppl
Ppl = Pleural Pressure
Palv = Alveolar Pressure
Pel = Elastic Recoil
Plat = Side stream Pressure
Ptot = Total Pressure

Ptm = Transmural Pressure

Figure 4

The diagram above summarizes the pressures acting on a given segment of airway. A number of
pressures have already been discussed including the alveolar pressure Palv and the elastic recoil
pressure, Pel. Another pressure diagrammed above is the pressure due to frictional resistance,
essentially what is measured by the Raw determination in the PFT lab. There are two other
important pressures that we have yet to discuss: the side stream pressure, the Plat, and the
transmural pressure or Ptm which is the difference between Plat and the pleural pressure, Ppl.
These pressures are important, as they are what determine the luminal area of the airway as
demonstrated in the diagram at the upper left. This graph represents the relationship between
transmural pressure and cross sectional area in a floppy tube. Think of a very thin walled piece of
Tygon tubing. Values to the right of the y axis represent positive transmural pressures leading to
small but noticeable increases in the cross sectional area of an inflated airway. Values to the left
represent negative trans-mural pressures leading to various degrees of airways collapse.
Alveoli

Mouth

Terminal
Bronchi

D = 3cm

D = 2.1cm

D = 3cm

Segmental
Bronchi
Trachea
140 cm/sec

280 cm/sec

Cross-sectional
Area

140 cm/sec

Pressure =
Potential
Energy

Kinetic Energy = u2
slow

fast

Figure 5

What would possibly lead to a negative transmural pressure when a large positive alveolar
pressure is being created upstream during a forced expiratory maneuver? If you remember back
to your organic chemistry lab in college, there was a device attached to the faucets in the lab that
would create a vacuum that could be used in a number of experiments. Forcing a fluid through
an area of reduced cross sectional area creates this drop in pressure. As the same amount of fluid
has to cross through a smaller area, the velocity must increase (unfortunately this does not apply
to cars on the Dan Ryan during construction). As velocity increases the kinetic energy in the

12

Figure 18

system increases, and in order to maintain conservation of energy, the other form of energy
(potential energy) must decrease, leading to a drop in pressure
This observed pressure drop is known as the Bernoulli principle. If you will note the diagram of
the cross sectional area of the lung from earlier in the handout you will notice that there is a
tremendous degree of narrowing occurring between the alveoli and the trachea creating this very
% VC
effect during a forced
expiration. In fact the majority of the pressure drop along the airway
during a forced expiration is due to this convective, accelerative effect rather than the frictional
effects described by Poiseulle.
Figure
6
To add to the complexity of the
picture,
this drop in pressure due to the Bernoulli
Effect causes the airways (which after all
are floppy, not rigid, tubes) to collapse
during maximal air flow. This tendency of
the airways to collapse is countered by
inter-parenchymal tethering forces and by
the presence of cartilage in the larger
airways. These forces are created by the
interconnection of airways with each other
through alveolar septa. Diseases such as
emphysema result in decreased airflow not
only by decreasing elastic recoil but by
reducing these tethering forces.
These tethering forces and other structures such as cartilage within the upper airways manifest
themselves by altering the relationship between the transmural pressure and airway cross
sectional area.

A
Bronchi

Trachea

75

50

25

0
Ptm

Again demonstrating the relationship between the transmural pressure on the x axis and the cross
sectional area on the y axis we see that the relationship is much different for the trachea (which is
re-enforced with cartilage) than for smaller bronchi which demonstrate a greater change in area
with respect to pressure. The rigid tubes studied by Poiseulle would be represented as a
horizontal line, as the area would not change at all with transmural pressure. The diagram on the
upper left demonstrates what happens when a smaller airway (or a larger airway behaving like a
13

smaller airway due to excessive narrowing or collapsibility) becomes the flow-limiting segment
early in the forced expiratory maneuver. This effect leads to the characteristic scooping seen on
the flow volume loop with obstructive airways disease.

14

Med Bio 30300

Cell and Organ Physiology
Ventilation and Diffusion
January 29, 2015
In the previous lecture we discussed the physics of the movement of air through the
airways. In the current lecture we will discuss how this air movement alters the
composition of air within the alveoli, thereby determining arterial PCO2. We will also
discuss diffusion of gas across a membrane and discuss why some gasses equilibrate
more quickly than others. We will also discuss the physics of gas exchange in the
systemic capillaries.
Rib orientation determines thoracic (lung) volume

Figure 1

We had earlier described a simplistic model of the lung using a piston to represent the
diaphragm. This acts to create a negative pressure within the pleural space that in turn
draws air into the lung. The minute volume - the amount of air entering and leaving the
lung each minute - is equal to the tidal volume of each breath multiplied by the number of
breaths per minute. In reality the motive power for respiration is a bit more complex. In
addition to the diaphragm, the volume of the chest cavity is altered by the orientation of
the ribs. The muscles of the neck and the intercostal muscle act to elevate the ribs in a
more horizontal direction, thereby increasing the anterior-posterior dimensions of the
lung. This component of respiration is especially prominent during heavy exercise or in a
patient who is laboring to breath with heavy use of the accessory muscles of respiration.
An understanding of the mechanics of the chest wall also helps account for the increased
work of breathing associated with chest wall deformity. In addition to altering chest wall
compliance, these disorders can also make breathing less efficient by altering the normal
positioning of the ribs during inspiration and expiration.

Figure 2

Lung Ventilation
Minute Ventilation = TV x Frequency
= 500 ml x 15 per min = 7,500 ml/min

Conducting
Airways
150 ml

Anatomical dead space ventilation:

150 ml x 15 per min = 2,250 ml/min
Alveolar
Gas
3,000 ml

Alveolar ventilation:
350 ml x 15 per min = 5,250 ml/min

Tidal volume = 500 ml

15 breaths/min
Figure 3

The diagrams above give the vital statistics of total ventilation and anatomical dead
space ventilation. The total minute ventilation (MV or VE for Expired Ventilation) is
equal to the volume taken in with each tidal breath multiplied by the number of breaths
per minute. Not all of the ventilation is effective in participating in CO2 elimination. The
first 150ml that is inhaled into the alveoli consists of air inhaled from the conducting
airways that represents used air from the previous breath. This dead space ventilation
does not effectively contribute to alveolar ventilation. Out of a total minute ventilation of
7500 ml/minute, only 5250 represents alveolar ventilation.

The table to the left

demonstrates the
components of air. As
Dry Ambient Air
Inspired Air Alveolar gas
noted in the diagram
Gas
Fraction
Gas tensions
Gas tension
Gas Tension
ambient air is the dry air
Nitrogen
.7809
593.5
556.8
566
Oxygen
.2093
159.1
149.2
100
around us in the
Carbon dioxide .0003
0.23
0.21
40
Argon
.0095
7.2
6.8
6.9
atmosphere. Inspired air
Water
0
0
47
47
represents the
Total
1.00
760
760
760
composition of air after
Ambient gas: Pga s = PB * dry gas fraction
it has been humidified to
Warm, humidified gas: Pga s = (PB-47) * dry gas fraction
100% saturation with
water. This has to occur
to prevent the drying of
Ambient Air
the alveolar membranes.
Inspired Air
This usually occurs in
Alveolar Gas
the nose and upper
airway but sometimes
will also occur in the lower airways. Even with very cold dry air with rapid ventilation,
air is completely humidified before it reaches the alveoli.

GAS PARTIAL PRESSURES

When discussing the components of a gas, the concept of partial pressure is often used.
This would be the pressure that a single component gas would exert if it were removed
from the gas mixture and placed in an equivalent volume. A partial pressure of a gas can
be calculated by multiplying the barometric pressure of a gas mixture (in this case air) by
the fraction of the gas mixture that is made up by that particular gas. As an example for
oxygen: at sea level barometric pressure (PB) is 760 mmHg (where a mmHg is the
pressure required to raise a column of mercury by one mm). The fraction of oxygen in
the atmosphere is 0.2093. Therefore the partial pressure of Oxygen (PO2) is 7600.2093
= 159.1. When calculating the partial pressure in fully humidified inspired air, the
contribution of water vapor to the partial pressure needs to be subtracted. At 37 C the
vapor pressure of water is 47 mmHg. Thus the calculated value for the partial pressure
inspired oxygen (PiO2) at sea level is FiO2(PB-PH2O) = 0.2093(760-47)=149.2.

Inspired Air:
PiO2 = FiO2( Patm PH2O)
PiO2 = 0.21(760-47)

Conducting
Airways

Alveolar Gas:
PAO2 = PiO2 PCO2/RER

Alveolar
Gas

CO2

O2

Figure 4

This next diagram demonstrates the calculations for partial pressures of oxygen at various
points throughout the airway. The alveolar partial oxygen pressure (PAO2) is equal to the
inspired partial pressure of oxygen minus the partial pressure of the oxygen that has left
the alveolus. This can be estimated by knowing the PACO2, the partial pressure of carbon
dioxide in the alveolus, which fortunately is almost equivalent to the partial pressure of
carbon dioxide in the bloodstream, the PaCO2. The latter can be measured directly via an
arterial puncture performed in the radial artery. The amount of O2 leaving the alveolus
and the PACO2 are related to each other by a value called the respiratory exchange ratio
(RER). This is usually approximately 0.8 but can vary with diet. Note the standard
notation for subscripts of PA for alveolar partial pressures and Pa for arterial partial
pressures. Note also the bias of pulmonary physiologists reserving the capital letter for
the alveoli!

.
VCO2 = ml CO2 delivered into alveolar gas each minute
.
VCO2 = ml CO2 exhaled by the lung each minute
.
.
VCO2 = VA X FACO2

VI

VE

VD

VA
Q
Figure 5

While breathing is tidal and circulation through the pulmonary vasculature is pulsetile, it
is sometimes useful to think in terms of a continuous flow model. In this construct the
tidal breathing is averaged into a continuous value, as is the blood flow Q (this is the
same a cardiac output). The VCO2 is equivalent to the amount of CO2 produced by the
body each minute and at steady state is equivalent to the amount of CO2 expired by the
lung each minute. This expired VCO2 is of course equivalent to the alveolar ventilation
(VA) multiplied by the fraction of the alveolar gas that is carbon dioxide (FACO2). As
noted above, not all of ventilation is effective: a certain amount the dead space
ventilation is wasted. The alveolar ventilation is thus the total ventilation VE minus the
dead space ventilation VD.

Physiologic Dead Space

PETCO2 = 20

PACO2 = 40

VD
P CO
= 1.0 E 2
VT
PACO2

PACO2 = 0

Figure 6

Dead space can be either anatomic (as in the earlier slide) or physiologic. A pulmonary
embolus is an example of a cause of physiologic dead space. In the example above a
large blood clot occludes the left pulmonary artery. This lung is ventilated but does not
exchange CO2 or oxygen with the blood stream. The total minute ventilation will need to
double to maintain a normal PaCO2. Thus the CO2 measured at end expiration (which
corresponds to alveolar gas) will be the average of the value found in the alveoli of each
lung.
5

The fraction of dead space can be calculated using the above equation. The fraction of
total ventilation that is wasted on dead space is equal to: one minus the end expiratory
CO2 at the mouth divided by the PACO2 of the alveoli that are participating in gas
exchange with the alveolar vessels. Fortunately this is the same as the arterial CO2, the
PCO2 that can be directly measured via arterial puncture. For the previous example, the
end tidal (ET) expired CO2 is measured as 20, the arterial PaCO2 is 40, thus Vd/Vt= 1
20/40 =.5 giving a dead space fraction of 0.5 or 50%

80

VCO2 = 750 ml/min

(Mild Exercise)

60
40
20

VCO2 = 250 ml/min

(Rest)

Hyper

Alveolar PCO2 (torr)

100

Hypoventilation

Alveolar Ventilation Controls PCO2

0
5
20
10
15
Alveolar Ventilation l/min

25

Figure 7

This graph of PCO2 versus Alveolar ventilation demonstrates how Alveolar ventilation
alters the PCO2. When the production of CO2 increases, e.g. with exercise, the amount of
ventilation required must increase to maintain normal PACO2.When ventilation increases
enough to drop the PACO2 below normal, this is called hyperventilation. When ventilation
is insufficient to allow for a normal PACO2, this is defined as hypoventilation.
The movement of air into the alveoli is of no use if it cannot diffuse into the bloodstream
to be carried to the peripheral tissues. We need to discuss how gasses cross the alveolar
membrane and enter the bloodstream.

Ficks Law of Diffusion of Gasses

Vgas = (P)

A.D
T

Diffusivity = D

Gas Diffusion
Ml/min

D is Proportional
To Solubility and
To 1/(MW)0.5
Thickness T

Figure 8

This diagram outlines the parameters that are important in the diffusion of gas across a
membrane. Diffusion is proportional to the pressure gradient across the membrane and
the area of the membrane (A) available for diffusion. The flow is also proportional to a
parameter called diffusivity that is related to solubility of the gas and the inverse of the
square root of its molecular weight. Diffusion is inversely proportional membrane
thickness. The lung is optimized to allow diffusion with an alveolar surface area
equivalent to the size of a tennis court and a membrane thickness made up only of a
single endothelial cell and a single epithelial cell.

Higher Solubility

Dissolved Gas Content (ml/dl)

Ether

4
3

Lower Solubility

2
N2O

O2

N2
He

0
20

40

60

80

100

Gas Partial Pressure mmHg

Figure 9

The solubility of a gas is the volume of a gas (at standard temperature and pressure) that
will dissolve into a liquid or a membrane for given partial pressures. The slope of the
line for each gas is proportional to its solubility. Ether, an old fashioned anesthetic agent
is highly soluble whereas helium is not very soluble. This makes it very useful for the
gas dilution determinations of TLC. It is also very useful for deep sea diving, as very
little helium will dissolve at depth, preventing the formation of bubbles in the
bloodstream as a diver ascends.

Alveolar PHe = 300 mmHg

Distance Along Capillary

Distance Along Capillary

PCO in blood element

Pether in blood element

PHe in blood element

0.0005

150

Mixed
Venous
Blood

Blood Element O
2

100

0.1

.25

.5

End
Capillary
Blood
Alveolar Pco2 = 40 torr
Alveolar Po2 = 100 torr

Blood Element

Blood Element
0.001

End
Capillary
Blood
Alveolar Pco = 0.1 mmHg

Alveolar Pether = 0.001 mmHg

Blood Element
300

Mixed
Venous
Blood

End
Capillary
Blood

.75

Time Along Capillary (sec)

46

CO2
40

40
0

.25

.5

.75

Pco2 in blood element

Mixed
Venous
Blood

PO2 in blood element

End
Capillary
Blood

Mixed
Venous
Blood

O2 and CO2 Equilibrate at

moderate rates

Carbon Monoxide Equilibrates

Very Slowly (Diffusion Limited)

High Solubility Gas

Low Solubility Gas

Time Along Capillary (sec)

The time required to reach equilibration is the same

Figure 10

As long as a gas is inert (that is, it does not react with the blood in the alveolar
capillaries) the equilibration time, that is, how long it take the gas in the alveolus to come
into equilibrium with the blood, will be the same regardless of solubility. A poorly
soluble gas such as helium will diffuse slowly across a membrane but by the same token,
it will take only a small amount of this gas to fully saturate an element of blood traveling
through the capillary. In a highly soluble gas, a large quantity of gas will be required to
8

reach equilibrium but as this gas diffuses quickly, it will also reach equilibrium with the
blood before it exits the capillary. Both of these gases are said to be perfusion limited, as
the amount of gas exiting the alveolus is dependent on how much blood is flowing
through the capillary, and will not be increased by enhanced diffusion.
In contrast, carbon monoxide is diffusion limited. That is, it equilibrates so slowly that
the blood element traversing the capillary is nowhere near saturated, and the amount of
carbon monoxide being delivered to the peripheral tissues is dependent on diffusion.
Carbon dioxide and oxygen both interact strongly with blood and hence have
equilibration rates that are slower than those of inert gasses but nevertheless are still
perfusion limited under normal conditions.

Carbon Monoxide exhibits

Very high solubility

Oxygen and CO2 Exhibit

Moderate solubility in Blood

O2 CO2 and CO all exhibit

Low solubility in the blood gas
membrane

Figure 11

The reason why these gasses equilibrate more slowly is that they are are relatively
insoluble in the blood-gas membrane but moderately soluble, in the case of oxygen and
carbon dioxide, and highly soluble, in the case of carbon monoxide, in blood. This
means that a large quantity of the gas will have to diffuse across to reach equilibrium but
that diffusion will occur slowly due the low membrane solubility. This can be expressed
mathematically but boils down to the same thing as shown below:

Gases equilibrate across the blood-gas membrane at a rate

determined by the solubility in the membrane relative to the
solubility in blood:

t
solubility in membrane
Pgas (t ) = Pfinal (1 e )
solubility in blood
Helium: Low solubility in membrane, low solubility in blood
- Fast equilibration
Ether: High solubility in membrane, high solubility in blood
-Fast equilibration
Carbon monoxide: Low solubility in membrane, enormous
solubility in blood
-Slow equilibration
Oxygen and CO2: Somewhere in between
Diffusion Limitation at Maximum Exercise
Mixed
Venous
Blood

End
Capillary
Blood

Alveolar Po2 = 100 torr

PO2 in blood element

Blood Element

O2

100

40
0

.25

.5

.75

Time Along Capillary (sec)

Figure 12

The one case in which oxygen delivery is diffusion limited is in a highly trained athlete
such as Lance Armstrong during maximal exercise. Such athletes are so cardiovascularly
fit that they can move an element of blood through the capillary at such a rate that
equilibration does not occur. This effect is exaggerated at high altitude.

10

Exchange of O2 and CO2 along a systemic capillary

Tissue Cylinder

Blood
Flow
O2 CO2 O2 CO2

Figure 14

O2 CO2

Arterial
End

O2 CO2

Venous
End

Figure 13

Figure 13 shows a tissue cylinder demonstrating the unloading of oxygen and uptake of
carbon dioxide from the peripheral tissue. In instances of low flow or hypoxemia, tissues
at the venous end will be disproportionately
affected.
Diffusion can be directly measured by using
small, non-hazardous, quantities of inhaled
carbon monoxide. As was shown earlier, this
gas is diffusion limited, making calculations
simpler. The test actually measures the
diffusion of gas across the alveolar membrane
through the plasma and the binding of the gas
to hemoglobin (that is the quantity of Theta
shown above in the diagram). For this reason,
the diffusing capacity test described in the
following slides is dependent on hemoglobin
concentration.

11

Example of CO Diffusing Capacity

Carbon Monoxide Diffusing Capacity Test
From Ficks Law

Vgas = (P)

A D
T

Vgas = (P) DL
Therefore

But for CO uptake, P2=0, so

diffusing capacity for CO is

DLCO =

DLCO =

Patient inhales 0.3% CO, holds breath 10 seconds, then

exhales. During the breath-hold, the lungs take up 0.67 ml
of CO (i.e. 4.0 ml/min). The average alveolar PCO during
breath-hold was 0.1 mmHg.

DLCO =

VCO
( P1 P2 )

VCO
PACO

VCO
PACO

ml
min
=
= 40 ml / min/ mmHg
0.1mmHg
4.0

DLCO

The area, diffusivity and thickness variables are replaced by a quantity called the
diffusing capacity DL. This is another value that we routinely measure in the pulmonary
function laboratory. The avid binding of carbon monoxide to hemoglobin maintains a
partial pressure of 0 in the bloodstream, simplifying the equations above.
The slide above right is an example of how this test would be performed on an actual
patient. The thickness of the alveolar membrane does not change much (those processes
that markedly thicken alveolar membranes also tend to wipe out vessels). What this test
actually measures clinically is the surface area of the lung that is participating in gas
exchange with the capillaries. Diseases that wipe out capillaries such as emphysema or
idiopathic pulmonary fibrosis will cause a decrease in the diffusing capacity or DLCO.

12

Med Bio 30300

Cell and Organ Physiology
CO2 and Oxygen Transport
February 2, 2015
In the last lecture we discussed ventilation and diffusion. The next challenge of the
cardio-respiratory system is to transport oxygen in the bloodstream to peripheral tissues
and to bring carbon dioxide back to the lung for removal (see schematic Fig. 1).
.
.
VO2
VCO2
Mixed
Venous
CvO2

Arterial
CaO2

.
VO2

.
VCO2

Systemic Tissue
Figure 1

Ficks Relationship for O2 Transport:

Systemic Oxygen Delivery = QT CaO2
Oxygen Return = QT CvO2
Oxygen consumption (VO2) is the difference between delivered and
returned Oxygen: VO2 = QT (CaO2 - CvO2)
The equation at the bottom is the one that most commonly comes to mind when Ficks
name is mentioned. It proves useful when assessing the adequacy of oxygen delivery in
an individual in the Intensive care unit. Delivery of oxygen to the systemic tissues is
equal to the amount of oxygen in a deciliter of blood (CaO2) multiplied by how much
blood flows through the lung and out to the peripheral tissues (Cardiac Output or Qt).
Blood returning from the peripheral tissues isnt devoid of oxygen. In fact, under normal
conditions only 25% of the oxygen content is usually extracted. The amount of oxygen
returning from the peripheral tissue is equal to the CvO2 - or venous content - multiplied

by cardiac output. The amount of oxygen consumed, the VO2, is the difference between
the two.
Definition: Gas Partial Pressures
Gas Species

Percent in Dry Air

Dry Gas Fraction

Partial Pressure
In dry ambient air

Partial Pressure in
inspired air
(saturated with
H2O at body
temperature)

Nitrogen

78.09

0.7809

593.5

556.8

Oxygen

20.93

0.2093

159.1

149.2

Carbon
Dioxide

0.03

0.0003

0.23

0.21

Argon etc.

0.95

0.0095

7.2

7.0

Water

0.0

0.0

0.0

47

Total

100%

1.0

760

760

Partial Pressure = Gas Fraction X Total Barometric Pressure

At sea level, total barometric pressure = 760 mmHg
Water vapor pressure at 37 = 47 mmHg

PO2 =760(.21)
= 160 mmHg

PBar =PO2 = 160 mmHg

PO2 = 160 mmHg

PO2 = 160 mmHg

Figure 2

The table in Figure 2 above demonstrates the components of air. Ambient air is the dry
air around us in the atmosphere. Inspired air represents the composition of air after it has
been humidified to 100% saturation with water. This has to occur to prevent the drying
of the alveolar membranes. This usually occurs in the nose and upper airway but
sometimes will also occur in the lower airways. Even with very cold dry air with rapid
ventilation, air is completely humidified before it reaches the alveoli.
A partial pressure of a gas can be calculated by multiplying the barometric pressure of a
gas mixture (in this case air) by the fraction of the gas mixture that is made up by that
particular gas. As an example for oxygen (Fig. 2 above): at sea level barometric pressure
(PB) is 760 mmHg (where one mmHg is the pressure required to raise a column of
mercury by one mm). The fraction of oxygen in the atmosphere is 0.2093. Therefore the
partial pressure of Oxygen (PO2) is 7600.2093 = 159.1. When calculating the partial
pressure in fully humidified inspired air, the contribution of water vapor to the partial
pressure needs to be subtracted. At 37 C the vapor pressure of water is 47 mmHg. Thus
the calculated value for the partial pressure inspired oxygen (PiO2) at sea level is FiO2
(PB-PH2O) = 0.2093 (760-47)=149.2.
The above equations describe the partial pressures of oxygen in air; but what does it
mean to speak of a partial pressure of a gas in a liquid? The easiest way to think of this
concept is that the partial pressure of a gas in liquid is the concentration of gas that is
dissolved in a liquid in equilibrium with this gas in the gas phase at a given partial
pressure. In the example above, a liquid is equilibrated with a large volume of gas at
160mmHg.
Oxygen is carried in the blood in two forms:
1. Dissolved in the water and lipid of blood
Dissolved O2 content = PO2 0.003 (the solubility factor)
If PO2 = 100 mmHg, dissolved O2 content = 0.3 ml/dl
2. Bound to the hemoglobin (Hgb) molecule

O2.

Each Hgb can bind up to 4 O2 molecules; 1g of Hgb can bind up to 1.39 ml

Hemoglobin-bound content depends on the concentration of hemoglobin,
and the percentage of its binding sites that are carrying O2 molecules
If [Hgb] = 14 g/dl and O2 Saturation = 97% when PO2 = 100 mmHg
then Hgbbound content = 1.39 ml O2/g Hgb14 g/dl 0.97 = 18.88 ml/dl

Plasma by itself is a very poor carrier of oxygen, as demonstrated by the relative content
of oxygen in plasma compared to the content of oxygen bound to hemoglobin, as
demonstrated in the equations above.
CaO2 (ml/dl) = 1.39 [Hgb](g/dl) %Sat + PO2 0.003

Dissolved Oxygen Content (ml/dl)

This is an equation you should know. The first part of the equation expresses the amount
of oxygen bound to hemoglobin; the second, the amount of oxygen dissolved in plasma.
Generally the term denoting the dissolved oxygen is small and can be neglected. When
the concentration of hemoglobin is very low, however, this term becomes more
important.

20
15
10
Dissolved Oxygen
5
0
20 40
60
80 100
Oxygen Partial Pressure (mmHg)

Figure 3

The graph in Figure 3 above demonstrates the poor solubility of oxygen in water.

O2 binds reversibly at each of the 4 heme

groups on hemoglobin molecules
02Heme

02Heme

02Heme

The adult
hemoglobin (Hb
A) has two
chains and
two chains,
each carrying a
porphyrin heme
group

O2

02Heme

Figure 4

The four chains in hemoglobin (two alpha and two beta) interact: as each heme molecule
binds oxygen, it influences the binding constant of the other molecules for oxygen.
Mutations involving single amino acid substitutions can produce profound changes in the
O2 binding characteristics of the red cell. Sickle Cell disease results from a single amino
acid substitution that causes the hemoglobin to precipitate out in deoxygenated
environments.

Figure 5

Sickle Cell Disease

Normal

Definitions: O2 Content, Partial Pressure and O2 saturation:

O2 content represents the volume of O2 (ml) carried per 100 ml blood (dl).
Gases diffuse from areas of higher partial pressure to lower partial pressure.
O2 saturation represents the percentage of heme binding sites that are
occupied by O2 molecules

When CO binds to a heme group on Hb, it alters

the affinity of O2 for the remaining heme sites

100

Oxygen +Hemoglobin 14 g/dl

80
60
Carbon Monoxide +
Hemoglobin

40

Oxygen +
Hemoglobin

100

Oxygen+Hemoglobin
With 50% carboxyhemoglobin

15

10

Oxygen +Hemoglobin 7 g/dl

20

40
60
80
100
Oxygen Partial Pressure (mmHg)
20

0
20 40
60
80 100
Oxygen Partial Pressure mmHg

Hemoglobin Saturation (%)

20

Oxygen Content (ml/dl)

Hemoglobin Saturation (%)

Carbon monoxide competes with O2 for binding

at heme sites

Oxygen +Hemoglobin
(7 or 14 g/dl)

80

Oxygen+Hemoglobin
With 50% carboxyhemoglobin

60
40

20

20
40
60
80
100
Oxygen Partial Pressure (mmHg)

Note the difference in definition between O 2 content (ml/dl)

and hemoglobin saturation (%)

Figure 6

These graphs in Figure 6 demonstrate why carbon monoxide is bad for you and why that
bag of charcoal on your deck advises against grilling indoors. Carbon monoxide binds
much more avidly to hemoglobin than oxygen, competitively inhibiting the binding of
oxygen. Even when not occupying all the heme sites, carbon monoxide adversely affects
the binding of oxygen to the unoccupied sites, lowering oxygen content in the blood.

Hemoglobin Saturation (%)

The affinity of hemoglobin for O2 changes rapidly

under physiological conditions
100
80
60
40

Temperature
PCO2
2,3-DPG
pH

Temperature
PCO2
2,3-DPG
pH

20
0
20 40
60
80 100
Oxygen Partial Pressure (mmHg)

Figure 7

A variety of compensatory mechanisms shift the oxyhemoglobin saturation curve in

response to changing conditions. For example, high carbon dioxide levels in the
peripheral tissues and reduced pH favor the unloading of oxygen. This is known as the
Bohr Effect, named after Neils Bohrs father.

Carbon dioxide is carried by blood in three forms:

1. Dissolved in blood
Dissolved CO2 content increases in proportion to PCO2

2. Reversibly bound to Hgb at the N terminus of the a and B chains

of hemoglobin, forming carbamino compounds:

Hgb N

+ CO2 = Hgb H N

COO-

+ H+

3. As bicarbonate ions:

CO2 + H2O = H2CO3 = H+ + HCO3-

Blood CO2 Content(mg/dl)

As with oxygen, carbon dioxide is poorly soluble in plasma. However, binding to the
N-terminus of hemoglobin chains to form carbamino compounds, and the formation
of bicarbonate ions, allows a great deal more carbon dioxide to be carried in the
bloodstream than oxygen (compare Fig. 8 below and figures 3 and 6 above)

50
40
30
20
10
0

Total CO2 Content

A red blood cell passes through a systemic capillary

Plasma Bicarbonate Component

Component
carbonate
Red Cell Bi
Component
Carbamino
rbon Dioxide
Dissolv ed Ca

40
60
20
30
50
70
CO2 Partial Pressure (mmHg)

80

Figure 8

The red blood cell, in addition to carrying oxygen, helps facilitate the transport of carbon
dioxide in the blood as demonstrated in the schematic above. Carbonic anhydrase
contained within the red cell catalyzes the conversion of carbon dioxide into bicarbonate
anions. The accompanying graph represents the various compartments containing CO2 as
a function of partial pressure. Plasma bicarbonate takes up the lions share, though recall
that the red cell facilitates its formation.
Venous blood is able to contain a larger quantity of carbon dioxide for any given partial
pressure (See Fig. 9 below). This is due to the fact that the unloading of oxygen favors
the binding of carbon dioxide to the n-terminus of the hemoglobin chains. This effect is
6

known as the Haldane effect. Note that this is the complimentary of the Bohr Effect on
the oxyhemoglobin curve shown in an earlier slide, where the low carbon dioxide levels
in the lungs facilitate the binding of oxygen.

Venous

Blood CO2 Content (ml/dl)

54
53

Arterial

52
51
50
49
48
47
46
40
60
20
30
50
CO2 Partial Pressure (mmHg)

70

80

Figure 9

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Ventilation

Perfusion

The convective movement

of air that exchanges gases
between the atmosphere
and the alveoli

The convective movement

of blood that carries the
dissolved gases to and from
the lung

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Ideal (one compartment) Lung Model

This diagram represents an ideal single alveolus model. Mixed venous blood with low oxygen
enters the pulmonary arterioles & continues into alveolar capillaries, the blood equilibrates with
alveolar oxygen. In upcoming slides we will discuss the content of the oxygen inspired and the
content of the air in this alveolar space and how it can be estimated using arterial CO2. In this
ideal model, the arterial oxygen exiting the lung is the same as alveolar oxygen.
The lung consists of a large number of parallel alveolar units in association with pulmonary
capillaries, and in health ventilation and perfusion are well matched, as shown graphically
below. The ratio of ventilation (V) to perfusion (Q) in L/min can be considered to be roughly 1
(V/Q = 1) with most lung units clustered around this ideal alveolus condition. As we shall see,
in disease V/Q relationships may diverge greatly, with alveolar units with little or no ventilation
yet still perfused (low V/Q) or units with ventilation but no perfusion (high V/Q). In fact, V/Q
relationships in patients are sometimes assessed by V/Q scanning radiologically (see figure
below)

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Volume & Efficiency of Ventilation

Minute Ventilation
= Tidal volume X respiratory frequency
= 0.5 Liter X 12 breaths / minute

= 6 Liters / minute

The volume of air inspired and exhaled per minute is an important factor in assessing the
efficiency of a patients ventilation and is referred to as the minute ventilation. It is a major
determinant of the muscle work invested in breathing.

Total Ventilation is the sum of

dead space ventilation and
alveolar ventilation

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Since a portion of each tidal volume occupies a portion of the pulmonary system where gas
exchange does not occurincluding the upper airway and tracheanot all of minute
ventilation is utilized for gas exchange. This portion of the respiratory system constitutes
anatomic dead space. Alveolar units that do not receive perfusion (what might cause a large
number of alveolar units to suddenly be deprived of blood flow?) or abnormalities of the lung
such as emphysematous blebs constitute another form of dead space.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Estimating Dead Space by Fowlers

approach

This is a slide that measures anatomic dead space by the Fowler technique. The air that exists in
the anatomical dead space after inhalation has the same content of the inspired air (because no
exchange with blood has occurred). The Fowler technique capitalizes on that concept. In this
technique the patient inspires 100% O2, this air enters the respiratory system, most of it gets to
the alveoli, but the last portion of the breath (about 150mL in an adult) remains in the mouth
(or nose), trachea and conducting bronchi, this area is the anatomic dead space. The pure
oxygen introduced to the alveoli mixes with the nitrogen containing air from the previous
breath. The patient then exhales and the first portion of gas that comes out is 100% oxygen
because that is the gas that was left in the dead space (the parts of the respiratory tract that
do not exchange O2 and CO2). Nitrogen is detected as exhalation continues, with the
concentration rising to a plateau (see figure below).
By the way, If the patient takes a really big deep breath (greater than tidal volume), the
conducting airways would dilate and the volume of air would be larger and overestimate
anatomic dead space during quiet breathing.
What decreases dead space measured in this way? During breath holding, eventually, the
oxygen in the conducting airways would diffuse / mix with the air in the alveoli spaces , with
earlier appearance of nitrogen in the exhaled gas, and dead space would be underestimated
Exhaling vigorously causes turbulence in the larger airways, further blurring the boundary
between dead space and alveolar gas.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

The content of air as it exits the lung. The point at which nitrogen increases represents the
volume of air from the anatomical dead space. The greater the mixing between conducting
airways and gas exchanging air spaces (alveoli), the more spread out is the S-shaped transition
in the above figure.
An important point here is that in order to measure alveolar air, one must sample end-
expiratory gas. This principle is important with regard to capnographythe measurement of
exhaled carbon dioxide, which is used clinically as a surrogate measure of arterial CO2 level and
the adequacy of ventilation.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Dead space by Bohrs Method

(CO2)

This slide shows Bohrs method of measuring dead space. Bohrs method is more
comprehensive in assessing dead space because it can detect the physiologic dead space, that
is, the parts of the lung substance itself that does not participate in gas exchange (this is
functional dead space). The functional dead space consists of alveoli (or destroyed alveolar
units such as are seen in emphysema) that are ventilated but not perfused by capillary blood
This method utilizes CO2 detection. PCO2 in the alveolar gas is virtually the same as the PCO2
of the arterial blood (~40mmHg), this is in contrast, of course to room air, which has almost no
CO2.

The patient takes in a normal breath (tidal volume ~ 500mL) of room air. The initial portion
enters the lung and exchanges gas in the alveoli, resulting in a PCO2 of 40mmHg. The last part
of the breath (~150mL) that remains in the dead space or conducting airways (trachea,
conducting bronchi) has a PCO2 of 0 because there are no alveoli there to exchange gas. When
the patient exhales, the first air that exits the airway is the CO2 free gas that had filled the
conducting airways (mouth, trachea, conducting bronchi), followed by the CO2 containing
alveolar air. If there is deadspace within the lungs (that is if there are alveoli that are
ventilated but not perfused by capillaries), the exhaled CO2 will be diluted by dead space air.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago
Using a CO2 probe to measure the partial pressure of carbon dioxide in expired gas, one can
calculate the dead space.
Methods of Measuring Dead Space

Fowler versus Bohr

Fowler method
Anatomical dead
space

Bohr method
Physiologic dead
space

In healthy individuals, anatomical and

physiologic dead spaces are identical

Fowler the volume of conducting airways from the mouth and nose up to the point where
nitrogen in the alveolar gas rapidly dilutes inspired 100% O2.
Bohr the fraction of each breath not receiving CO2 from the pulmonary circulation and
therefore not engaging in gas exchange. Bohrs method of measuring dead space INCLUDES
ALVEOLAR dead space

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

In order to determine what percent of each breath represents dead space, the Bohr equation
shown above can be used.
PECO2 is the PCO2 in the mixed-expired air and can be measured by with a capnography.
Capnographs have many uses in clinical medicine. One is to determine whether an intubation
has been successful. Why would such a device be useful for this purpose?
PACO2 is assumed to be equivalent to PaCO2 and can be obtained from the arterial blood gas.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Bohr equation calculates the

percent of dead space

VD
VE

40 28
40

= 30%

The dead space percent of total expired air is proportional to alveolar CO2 minus total (mixed)
exhaled CO2, divided by alveolar CO2.
Inserting the values of 40 for PACO2 and the normal value for exhaled CO2 which is 28 you can
see the dead space fraction of total ventilation is 30%. Typically dead space fraction is between
20-35% in healthy individuals but can be much higher in patients with pulmonary disease.
During panting RR is very high, but tidal volume is very low, thus most of the tidal volume is
dead space ventilation. If tidal volume is lower than dead space, then in principle there is no
ventilation at all.
Consider snorkeling if the snorkeling tube has a volume of 350mL and this is added to the
normal 150mL of normal dead space, then if the swimmer is taking breaths of 500mL tidal
volume, this volume would not be enough to produce any alveolar ventilation.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Alveolar Ventilation

From a physiological standpoint, the dead space does not contribute to ventilation, thus we really
want to know what the alveolar ventilation is

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Alveolar Ventilation Principles

The body produces CO2 by oxidative
metabolism at a rate of ~200mL / minute
PCO2 stays relatively constant (+/- 4mmHg)

In a steady state, CO2 production equals the rate at which CO2 enters the alveoli and the
rate at which CO2 is exhaled

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

An important concepts in respiratory physiology is that Alveolar PCO2 is inversely proportional

to alveolar ventilation
That is: if CO2 production is fixed and ventilation (VA) doubles then PACO2 will half
Conversely: if ventilation is 50% or halved, then PACO2 will double
Keep in mind that arterial PCO2 is virtually the same as alveolar PCO2
The constant 0.863 takes into account that PACO2 is proportional to the mole fraction of CO2 in
alveolar air but also accounts for the different conditions for measuring the parameters.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Figure 31-4

The blue curve illustrates this relationship: the points on the blue curve demonstrate increasing
amounts of alveolar ventilation. In this figure the amount of CO2 produced stays constant. The
middle point shows that at an alveolar ventilation of 4.2 liters per minute, the alveolar P CO2
(and therefore the arterial PCO2) is 40mm Hg. The point to the right and slightly below shows
what happens when a person increases their minute ventilation or alveolar ventilation to 8.4 L
per minute (hyperventilation), this would decrease the arterial PCO2 to (20 mm Hg). The
acid-base consequence of this reduction in carbon dioxide would be alkalosis, and the process
driving the alkalosis is respiratory, thus the disturbance would be considered an acute respiratory
alkalosis.
The point to the left and above is a case of hypoventilation, here the ventilation is halved, leaving
more CO2 in the lungs, causing a higher arterial CO2. The acid-base consequence here is an
acidosis driven by a primary respiratory process, and hence a respiratory acidosis.
**The inverse relationship applies to oxygen and alveolar ventilation and this is demonstrated by
the orange curve. With increasing alveolar ventilation (increasing to infinite levels) the alveolar
PO2 would eventually equal the PO2 of inspired air which is about 149 mm Hg. Lets now look
at how the these gases influence PAO2.this is shown by the alveolar gas equation

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Alveolar Gas Equation

PAO2 = PIO2- PACO2/R
FIO2 (Pbaro PH2O)
760 mm Hg at Sea Level

47 mm Hg at 37C

The PIO2 includes the fraction of dry air (FIO2) multiplied by the barometric pressure, and the
vapor pressure of water at 37C
At 37 degrees Celsius (98.6 degrees Farenheit) the partial pressure of H2O is 47 mm Hg.
The remaining partial pressure is that for CO2.
R = 0.8 because the exchange rate for 8 CO2 is 10 O2.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

This equation assumes that all alveolar units are ventilated exactly the same.
Sea Level: PAO2 = 0.21 * (713) 50 = ~100
At 7,000 feet: PAO2 = 0.21* (586-47)-50 = ~63
Aircrafts are typically pressurized to about 7,000 ft

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

This figure demonstrates the relative lack of capillaries in diseased lung compared to normal
lung and also how thick the membrane is between the alveolus and the capillary. One can see
how a PAO2 that is adequate in normal lung would not be high enough in Idiopathic Pulmonary
Fibrosis.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago
At the Mount Everest Summit: PAO2 = 0.21* (253 47) 40/0.8 = -6.74!
But these guys look alive, why?

With increased ventilation, the PCO2 decreases (because PCO2 is inversely proportional to
ventilation!) Note how the PO2 increases with increased ventilation (which results in decreased
PCO2 which changes the equation).

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

In this case the patient is breathing 30% oxygen

Ventilation is greater at the base of the lungs

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

In reality, alveolar ventilation is not homogenous throughout the lung. It is greater at the bases
and overall, it decreases toward the apices of the lungs.

ss

First, review intrapleural pressure at rest

Patm = 0
At rest, intrapleural
pressure is -5 cm H20
(relative to atmosphere)
This is the result
of opposing forces:
the lungs tendency
to collapse and
The chest wall
tendency to expand

-5

Transmural pressure
across
the lungs at rest
is +5 (alveolar pressure
minus intrapleural
pressure,
that is: 0 (-5)
This keeps the alveoli
open

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago
ss

During inhalation, the diaphragm contracts which causes the chest cavity to increase in volume.
Boyles law states that Pressure X Volume is constant at a given temperature. Thus as the
volume increases the pressure decreases and so the the intrapleural pressure becomes more
negative (which results in the transpleural pressure becoming more positive), and the alveolus
now has a transient negative pressure relative to the atmosphere. There is now a gradient from
positive to negative from the atmosphere to the alveolus resulting in the movement of gas or air
into the alveoli. As gas or air flows into the alveoli, the pressure increases and ultimately equals
the atmosphere again and the airflow stops.
With the volume of air that has been inhaled, the pressure inside the alveoli will increase, partly
because of the natural tendency of the lungs to recoil, and also because the respiratory muscles
relax and are no longer creating as negative a pleural pressure. Now the chest cavity becomes
smaller as gas is exhaled, since the pressure in the alveoli is now positive relative to the
atmospheric pressure and there is a gradient from alveolus to the atmosphere. The air or gas
flows out of the alveoli and into the atmosphere, following the gradient. At the end of
exhalation, once the gradient from alveoli to the atmosphere is once again zero (figure A),
airflow cease and at this point the volume left in the lungs is the Functional Residual Capacity or
FRC

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

The reason that lungs are not uniformly ventilated to the same extent is because the intrapleural
pressure differs over different regions of the lung. At the base of the lung the intrapleural
pressure is ~-2.5 cm H2O (which keeps that section somewhat under-inflated) but at the apex of
the lung the pleural pressure ~-10 cmH2O (which keeps that section somewhat overinflated).
The curve on the right shows the pressure volume curve that is inherent to the lung. At a lower
volume the lung will expand more for a given pressure than if the alveoli started at a higher
volume. Thus with inspiration, the change in pleural pressure yields a higher change in volume
for the dependent regions of the lung. Ventilation is determined by the change in volume per unit
time, not the initial static volume

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Pulmonary Vasculature
Low pressure

Low resistance
High compliance
Influenced by tidal volume
Influenced by gravity
Recruitable
Fishman E K et al. Radiographics 2006;26:905-922

2006 by Radiological Society of North America

Until now, we have focused on the alveoli in ventilation and perfusion. The pulmonary
vasculature and its dynamic response to what is happening in alveoli also play a significant role
in ventilation and perfusion.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

This equation demonstrates the factors that govern pulmonary vascular resistance. The
resistance of the pulmonary circulation is only about 1/10 that of the systemic circulation. The
vasculature in the lungs has a high surface area which makes a large surface for gas exchange,
the blood vessels are shorter and wider than systemic blood vessels, and they are less muscular
than systemic blood vesselsall of these properties combine to produce a low pressure, low
resistance system.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

The resistance of the pulmonary vasculature also depends on the transmural pressure.
Transmural pressure is the difference between the in the vessel lumen and the surrounding
alveoli.
The pressure in the vessels also varies with the cardiac cycle, with each heart beat there is a
bolus or pulse of flow and pressure, how much pressure depends on where the vessel is
compared to the left atriumthe greater the distance above the left atrium, the lower the
pressure.
Focusing now on the alveoli, the pressure in these structures varies with the respiratory cycle.
During inspiration when the lung volume is high, the alveolar walls stretch and increase the
pressure on the surrounding vessels.

The pulmonary vascular bed is a low

pressure, high flow system

During exercise, the pulmonary vasculature receives about a 2-3 fold increase in cardiac output,
the system does this without increasing the pressure due to recruitment of vessels in parallel

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

The way that the pulmonary circulation can take on a 2-3 fold increase in cardiac output is by
utilizing or recruiting underused capillaries.
The left panel shows the resting state in which not all vessels are fully filled with blood, other
vessels may even be collapsed.
The middle panel shows how when there is an increase in perfusion pressure the vessels which
were opened but not quite fully perfused in the resting state are now widened, and the areas that
had been closed are now opened from the increased perfusion pressure.
The panel on the right shows all capillaries now recruited, dilated and conducting blood. There
is an increase in parallel capillary pathways and so the resistance has fallen.
If there is further increase in pressure in a vessel that is already open and conducting, the vessel
will respond by dilating thus avoiding a rise to resistance to flow.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Hypoxia causes increase in pulmonary vascular resistance -- specifically low PO2 in the alveolar
space causes increased resistance more effectively than low arterial oxygen content.
This hypoxic vasoconstriction occurs in isolated lung tissue . It is a means of matching blood
flow to oxygen rich alveolar units (by decreasing flow to hypoxic units).
Other environments which cause vasoconstriction are high PCO2 and low pH
On the other hand examples of pulmonary vasodilators are prostacyclin & nitric oxide. These
are sometimes used in the ICU when we are having trouble oxygenating a patient. Both can be
inhaled through the ventilator circuit and titrated according to the patients oxygen saturations.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Perfusion is greatest at the base of the lung

Perfusion is least at the apex of the lung

Ventilation perfusion ratios vary throughout the normal lung

Weve already learned that ventilation is not equal throughout the lung (ventilation is greatest at
the bases and decreases toward the apex). This figure demonstrates that perfusion, also, is
greatest at the base of the lung and decreases toward the apex of the lung. With exercise,
perfusion increases in ALL regions of the lung but MOST at the apex of the lung, so the
nonuniformity of perfusion is minimized during exercise.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Zone 1 ventilation
PA > Pa> PPV
Alveolar pressure is greater
than the pressure in arterial
or venous blood.
Exists in hemorrhage and in
positive pressure
ventilation (mechanical
ventilation)

A = Alveolar; a = arterial

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Zone 2 ventilation
Flow is determined
by the difference
between arterial
pressure and
alveolar pressure
Pa > PA > PV
A = Alveolar; a = arterial

arterial pressure is greater than alveolar pressure which is greater than venous pressure
Blood flow is determined by the differences between pulmonary arterial and alveolar pressures.
Moving downward in this zone, the hydrostatic pressures in the arteriole, capillary and venule all
rise in parallel.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Zone 3 Ventilation
Both arteriolar and venous
pressures are greater than
alveolar pressures.

Pa > PV > PA

A = Alveolar; a = arterial

Zone 3 ventilation prevails in the middle to lower lung , both arteriolar and venous pressures are
greater than alveolar pressures. Moving downward in Zone 3, the hydrostatic pressures in the
arteriole, capillary, and venule all continue to rise this increasing pressure of the alveolar vessel
causes dilation leading to a decrease in resistance and overall an increase in perfusion.

Taking a step back, recognize that these lung zones are physiological, not anatomical, the
boundaries between these zones are not fixed or sharp. For example, during exercise
cardiac output increases causing a relative increase in arterial pressure the result is that
the zones move upward. During positive pressure ventilation (on mechanical ventilation)
zone 1 comes into play.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Another figure depicting the 3 zones of blood distribution of the lung (Costanzo, Physiology)

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Lung zones change with position

and with body habitus

Greys Anatomy, ABC

For a patient lying on their back, zone 3 shifts from the mid /lower lung to the posterior
dependent regions, and zone 2 is anterior. For a morbidly obese patient, the pleural pressure is
not as negative, increasing the % of zone 3 ventilation

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

The normal value for V/Q = 0.8

That is alveolar ventilation (L/min) is
usually 80% of pulmonary blood flow
(L/min)

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

ss

Effect of regional differences in ventilation / perfusion (V/Q) in the lung on PCO2 and PO2

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Another way to demonstrate this is by the figure in your textbook which shows the various
ventilation to perfusion ratios that exist in the lung beginning with the mixed venous blood
coming from the pulmonary artery (with have a V/Q = 0) on the left side of the graph and a V/Q
(perfused but not ventilated) ratio of infinity in the trachea shown at the right side of the graph.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Ventilation Perfusion Ratios

Shunt

Pulmonary
Embolism

Pure
Dead
Space

We have reviewed the physiologic variation of perfusion within the normal lung.
This is a diagram from the Schumaker and Leff textbook that demonstrates the various
ventilation perfusion ratios. The far left alveolus shows a ventilation perfusion ratio of 0 (Shunt)
and moving toward the far right alveolus which shows an infinite ventilation perfusion ratio
(dead space). In the normal lung, there is very little dead space and no shunt. In a patient with
pulmonary disease, however, these extremes of V/Q will be a dominate theme in the clinical
course of their disease.
Next we will focus on these two extremes of ventilation / perfusion mismatching.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

In a pulmonary embolism, a pulmonary artery becomes obstructed with a clot, preventing

perfusion to the affected alveoli. The alveoli are ventilated but not perfused.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Pulmonary Embolism

Lots of ventilation
No perfusion
Aveolar gas = inspired air
Perfusion of other lung

V/Q
PAO2
PACO2
PaO2
PaCO2

This is the model of dead space ventilation:

1) with loss of perfusion and continued ventilation, alveolar gas becomes that of inspired air
(PO2 = 149, PCO2 = 0)
The lung responds by:
a) bronchiolar constriction
b) type II alveolar pneumocytes stop making surfactant leading to closure of the alveoli
2) the blood is diverted to the perfused area of the lung causing increased perfusion in the other
areas of the lung relative to the ventilation.thus V/Q ratio decreases in these areas.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

SHUNT

Shunt is the opposite extreme of dead space along the V/Q mismatch spectrum. In this
circumstance, alveoli are filled with pus, blood, or water. There is no air in these alveoli and
thus no oxygen in the alveoli to diffuse into the blood. Thus the MIXED VENOUS blood
coming from the right heart flowing past these alveoli flows through the lung without being
oxygenated and returns to the left side of the heart to mix with the blood that has been
oxygenated from other healthier parts of the lung. The result is a PO2 that is lower than normal
in the systemic circulation.
EXAMPLES of shunt are: pulmonary edema, pneumonia, obstructed airway (but only transiently
until hypoxic vasoconstriction establishes improved VQ relationship)
As a result: airflow is diverted to the normal parts of the lung, where this increase in airflow
now causes a relative higher V/Q ratio
* the vascular smooth muscle in the arteries of the shunted part of the lung sense a decrease of
PO2, an increase of PCO2, and a lower pH and respond by constricting a process referred to as
hypoxic vasoconstriction. Hypoxic vasocontriction leads to the diversion of blood away from
the unventilated lung. Whether or not the vasoconstriction of these arteries causes overall
increase in pulmonary vascular resistance depends on the size of the shunt, for example if the

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago
area of affected lung is <20% the effect is minimal. If the area is global, as in the context of high
altitude, the overall resistance may be double.

Shunt may look like this on a CXR

Causes of shunt: Pneumonia, Alveolar Hemorrhage, Pulmonary edema, Atelectasis

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

PAO2 = 0.21 (760 47) PACO2/R)

= ~100

= SO2 100%

75 + 100/2 = 87.5
SO2 = ~88%
= SO2 75%

This diagram represents what happens to oxygenation when shunt occurs: the alveoli fills with a
substance (fluid, pus, blood or tumor), the saturation in the end capillary (EC) is the same
saturation in the pre-capillary blood because no ventilation has occurred. Using the
oxyhemoglobin saturation curve, the PO2 can be converted to saturation. This low saturated
blood mixes with 100% saturated blood producing a decreased saturation (in this case 87.5%)
returning to the left heart and out to the systemic circulation.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

SHUNT is refractory to high FIO2

PAO2 = 1 (760 47) PACO2/R)
= ~663
PAO2 = 663
PO2 = 663
SO2 = 100%

75 + 100/2 = 87.5
SO2 = ~88%
= SO2 75%

This is an example of administering 100% oxygen to a patient with a shunt. Unfortunately, no

matter how high the pressure of oxygen is in the alveoli and blood vessel, the hemoglobin
cannot be saturated more than 100%. T he blood leaving the shunted area has the same
saturation of mixed venous blood (because no ventilation occurred, so it was as if the blood
isnt even in the lung at all). The blood leaving the ventilated alveoli has a saturation of 100%,
the mixture of the blood coming from each of these units is called venous admixture and will
always have a saturation less than 100%. This inability to raise the patients oxygen even
with supplemental oxygen is a defining feature of shunt.

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Critically ill patients have a low mixed venous

oxygen due to high oxygen extraction
PAO2 = 1 (760 47) PACO2/R)
= ~663
PAO2 = 663
PO2 = 663
SO2 = 100%

PVO2 = 27

PO2 = 27

50 + 100/2 = 75
SO2 = 75%

= SO2 50%

Critically ill patients have lower than normal mixed venous oxygen saturations because of an
increase in oxygen extraction. The venous blood coming into to alveoli is lower than in a normal
healthy state. This exacerbates the problems of venous admixture. In these cases attempts are
made to decrease the high metabolism that is extracting the higher amounts of oxygen from the
circulating blood. Examples of therapeutic options are: putting a patient on mechanical
ventilation to rest the respiratory muscles, or a cooling blanket for a febrile patient. At the same
time it is important to make sure oxygen content is maximal. As you know oxygen content is
hemoglobin and cardiac output (CaO2 = 1.39 X Hgb X %saturation + PaO2 X 0.003), thus
ensuring the patient is not anemic is important in the treatment of shunt and patients with heart
failure may require medicines to increase cardiac output.
FACT: You become hypoxic by perfusing nonventilated alveoli

Cell and Organ Physiology 2014- MEDC 30403

Ventilation-Perfusion Relations I & II
Jesse Hall, MD
Professor of Medicine
Section of Pulmonary and Critical Care Medicine
University of Chicago

Summary
Dead space is about 30% of total ventilation and can
be estimated by using the Bohr equation

Alveolar PCO2 is INVERSELY proportional to alveolar

ventilation
PAO2 = FIO2 (713 mmHg) - PACO2 / 0.8

The pulmonary vasculature is a low pressure, low

resistance, and recruitable system
Ventilation Perfusion is heterogeneous throughout
the lung
Hypoxemia that is refractory to supplemental oxygen
is suggestive of shunt

Med Bio 30300

Cell and Organ Physiology
Control of Ventilation
February 3, 2015
We have spent the last several lectures discussing the physiology of respiration.
Ventilation is controlled by the central nervous system, with both voluntary and
involuntary input. In this lecture we will discuss the ventilatory centers of the brain and
how central and peripheral O2 and CO2 sensors are integrated to regulate ventilation.
There are a number of demands placed on the control of ventilation. Baseline ventilation
needs to be maintained, but the degree of ventilation also needs to be increased in
response to increased metabolic demand or exercise. The respiratory system also
provides the rapid component of the bodys response to alterations in acid base
homeostasis. The central nervous system also responds to airway irritation and
atelectasis (the collapse of part or all of a lung) with coughing, sighs and yawns. Speech
requires the ability for all of this control to be overridden by the upper cortical areas to
allow phonation.

Figure 1

The schematic in Figure 1 depicted above depicts mechanisms of respiratory control.

In the simplest of models, a

central pattern generator
transmits a signal to the
muscles of respiration via
spinal motor neurons. These
have their motor nuclei in the
region of C3-C5. The fact that
injuries to this level result in an
inability to maintain respiration
has been know since the time
of Galen, who observed that
gladiators with wounds to this
area would no longer make
respiratory efforts, as opposed Figure 2
to those with transections below this point.
The location of the central pattern generator has been localized to the medulla in the
brainstem.

Innervation of the Muscles of Respiration

Muscles

Nerve

Location of the Cell

Body of MN

Primary Muscles of Inspiration

Diaphragm

Phrenic Nerve

Ventral Horn C3-C5

External Intercostals

Intercostal Nerve

Thoracic Ventral Horn

Secondary Muscles of Inspiration

Larynx and Pharynx

Vagus CN X and
Glossopharnyngeal IX

Nucleus ambiguus

Tongue

Hypoglossal XII

Hypoglossal Nucleus

Sternocleidomastoid and Spinal Accessory XI

Trapezius

Spinal Accessory
Nucleus C1-C5

Nares

Facial Nucleus

Facial Nerve VII

Secondary Muscles of Expiration

Internal Intercostals

Intercostal Nerve

Thoracic Ventral Horn

Abdominal Muscles

Spinal Nerves

Lumbar Ventral Horn

Figure 3

The table in Figure 3 above lists the innervations of the muscles of respiration. The
primary muscles of respiration (diaphragm and external intercostals) are used during
quiet inspiration. There are no primary muscles of expiration (as in quiet tidal breathing),
as expiration is passive. The secondary muscles of inspiration can be divided into two
groups: (1) those that further assist in changing the conformation of the rib cage, such as
the sternocleidomastoid muscles, and (2) those that help hold the upper airway open
during inspiration, such as the nares and the laryngeal and pharyngeal muscles. The lack
of activity in these last two groups during the deeper levels of sleep is though to be a

contributor to sleep apnea. The secondary muscles of expiration assist in forcing air out
of the lungs during active expiration.

Figure 4

Figure 4 above demonstrates the effects of sectioning the brain and spinal cord at various
levels. If the cord is transected above C3-5 there is no phrenic nerve output, but output to
the hypoglossal nerve continues, indicating that the central pattern generator is still
active. If a transection occurs above the medulla, activity continues both in the phrenic
and hypoglosal nerves.

Pre-motor nerve activity during normal quiet breathing

Figure 5: Nerve activity measured

from the inspiratory pre-motor
neuron during inspiration and
expiration. The x axis represents
time and the y axis represents the
firing rate of motor neurons in the
central pattern generator measured
electrically from single fibers.
Figure 5

The activity of central pattern generation, and hence the level of ventilation, can be
influenced by both central and peripheral chemoreceptors. The central receptor is most
sensitive to the pCO2, whereas the peripheral chemoreceptors respond to hypoxemia, pH,
and pCO2.
Forebrain

Brainstem
Central
Chemoreceptor

Central
Pattern

Sensory
Integration

Generator
Spinal Cord

CN X

Respiratory
Muscles

CN IX

Peripheral
Chemoreceptor

PCO2
pH
PO2

Stretch
Receptors

Figure 6

Further input occurs from stretch receptors: proprioceptors that sense muscle activity and
position, as well as J receptors within the lung that respond to lung stiffness and
atelectasis. The upper levels of the brain can modulate the effects of the brainstem or can
directly activate the muscles of respiration via the spinal nerves. This allows you to
override your normal respiratory pattern during speech or other activities.

Decreases in arterial PO2 stimulate ventilation through peripheral chemoreceptors

Figure 7

The peripheral chemoreceptors are located primarily in the carotid sinus and to a lesser
extent in the arch of the aorta. The carotid body is an organ that has a very high rate of
oxygen consumption. Thus, when the PaO2 level falls in the carotid (an important site to
monitor) the rapid O2 consumption within this organ will cause a quick response in
respiration.
Increases in PaCO2 stimulate ventilation via peripheral and central chemoreceptors

Peripheral Chemoreceptors respond to both Oxygen and CO2

PaO2 = 37

50

60

PaO2 = 47

Minute Ventilation

Minute Ventilation

50
40
PCO2 = 49

30
20

PCO2 = 44

PaO2 = 110

40

30

20

10

10
PCO2 = 36

0
20

40

60

80
Arterial PO2

100

120

140

20

30
40
Arterial PCO2

50

Figure 8

The left diagram in Figure 8 demonstrates how the degree of response to hypoxemia will
be markedly altered by PCO2 levels. This diagram demonstrates why its a bad idea to
hyperventilate prior to diving. At low PCO2 values the respiratory drive to breath is
lessened in response to hypoxemia to the point that unconsciousness may ensue.
Conversely, oxygen levels as shown at the upper right will affect the response of
ventilation to various levels of carbon dioxide. Each curve represents the response of
ventilation to various levels of PaCO2 while holding PaO2 at a constant level.

Central chemoreceptors respond to changes in the composition

of cerebrospinal fluid PCO2 and pH

Henderson-Hasselbach equation applies to blood or to CSF

Regulated by renal reabsorption
of bicarbonate. Normally 24 mM.

pH = pK '+ log

Normally 6.1

pH = 6.1 + log

[ HCO3 ]
[ H 2CO3 ]

Varies with PCO2.

Calculate as 0.03 x PCO2
Normally 0.03 x 40 = 1.2

24
= 7.4
1.2

Figure 9

As CO2 crosses easily through the blood-brain barrier, it will alter CSF pH and increase
ventilation. Hydrogen ions pass poorly across the blood-brain barrier, thus peripheral pH
will minimally impact the central chemoreceptors. This results in a differential response
in these central receptors between respiratory and metabolic acidosis.
pH and PCO2 are directly linked through the Henderson-Hasselbach equation. The
concept of acid-base regulation will be covered in more detail in the renal section of this
course. Suffice it to know for now that altering the pCO2 by increasing or decreasing
ventilation can allow the body to rapidly respond to alterations in pH.
Plasma bicarbonate is regulated by kidneys

Ventilatory response to CO2 is the increase in ventilation

produced by an increase in arterial PCO2

When increased, pH rises -- metabolic alkalosis

When decreased, pH falls metabolic acidosis

PCO2 is regulated by alveolar ventilation

When PCO2 rises, pH falls respiratory acidosis
When PCO2 falls, pH rises respiratory alkalosis

Minute Ventilation

[ HCO3 ]
pH = pK '+ log
[ H 2CO3 ]

50

40

30

20

10

0
20

30
40
Arterial PCO2

50

60

Figure 10

The two components of this equation can be manipulated independently by the lungs and
the kidneys, respectively. When PCO2 rises in the plasma this increases the amount of
H2CO3 with the blood, leading to respiratory acidosis, and when PCO2 drops, the opposite
effect occurs, resulting in a respiratory alkalosis. The level of bicarbonate ion (HCO3-) is
in turn regulated by the kidney. Elevations in the levels of this anion result in metabolic
alkalosis and a decrease in acidosis.
The degree of change in minute ventilation to an increase in PCO2 is known as the
ventilatory response. An example of a change in ventilatory response is shown in the
graph in Figure 10. The curve on the right represents a decreased ventilatory response. A

decreased ventilatory response can lead to chronic respiratory acidosis in the settings of
impaired ventilation such as COPD.
Abnormal Breathing Patterns
Cheynne-Stokes breathing

Apneuistic breathing

Figure 11

Alterations in respiratory control in certain disease states can result in altered respiratory
patterns that can be observed clinically. The graphs above describe Cheynne Stokes
respiration and apneuistic breathing. This is an abnormal ventilatory response where the
response to CO2 leads to alternating episodes of hyperventilation and apnea. This can be
seen in the setting of CHF, brain injury, or during sleep at high altitude. Apneuistic
breathing can be seen in brain injury (pons) or with heavy narcotic use. This respiratory
pattern is characterized by deep prolonged inspiration interspersed with brief expirations.

Med Bio 30300

Cell and Organ Physiology
Physiology of Exercise
February 3, 2015
This final section combines principles discussed in prior lectures on both pulmonary and
cardiovascular physiology. It highlights the reason for the immense reserves available in both
these systems. The mammalian cardiopulmonary system is optimized to deliver oxygen to
muscles to a degree exceeded only by birds. Figure 1 below demonstrates a previously presented
(over)simplified model.
.
.
Cardio-Respiratory System: Simplified
Model
VO2

VCO2

Mixed
Venous
CaO 2

Arterial
CaO2

Systemic Tissue (Muscle)

.
VO2

Figure 1

.
VCO2

In this model, tidal ventilation maintains

a diffusion gradient for oxygen and
carbon dioxide. Oxygen in taken up by
the pulmonary circulation at the same
time as carbon dioxide is removed.
Oxygen is then delivered by the
cardiovascular system (the heart is
conspicuous in its absence in this
diagram) by means of the peripheral
circulation. Oxygen is then taken up
along with energy producing substrates
by the systemic tissues in order to
produce ATP. ATP is then utilized to
drive cellular processes including actinmyosin cross bridge cycling.

The cardiopulmonary system needs to respond to requirements for oxygen delivery over a 12
fold range, while at the same time eliminating the escalating amounts of CO2 produced by
respiration in order to maintain a normal serum pH (Recall that PCO2 is the rapid-response
component of acid/base regulation). Figure 2 below demonstrates the responses of the various
components of the supply chain of oxygen delivery required to meet these goals.

VO2

Pulmonary
Circulation

Systemic
Circulation

QO2

QO2

Lungs
VCO2
Response:

QCO2
TV
RR

Recruitment

Heart/
Blood
HR
SV

QCO2
Arteriolar
Dilation

Muscle/
Mitochondria
RQ
Aerobic/
Anaerobic
Metabolism

Figure 2 Bioenergetics of Muscle

In a break from the usual lung centered view of this group of lectures, well consider the far end
of this diagram first, namely the bioenergetics of skeletal muscle. Skeletal muscle contracts as a
result of actin/myosin cross-bridge formation, which derives its energy from the hydrolysis of
ATP. In skeletal muscle this energy is stored in the form of creatine phosphate that can be
converted back to ATP by means of creatine phosphokinase (CPK). ATP can be produced
aerobically either from fats (such as palmitate) or carbohydrates (such as glucose) or
anaerobically from carbohydrates. Protein, while utilized during starvation states, is not usually
metabolized for energy production either at rest or with exercise. The energy equations for fats
and carbohydrates are demonstrated schematically below:

RQ = 0.71

23 O2 + C16H32O2 = 16 CO2 + 16 H2O+ 130 ATP ~P:O2 = 5.65

RQ = 1.0

6 O2 + C6H12O6 = 6 CO2 + 6 H2O+ 36 ATP

~P:O2 = 6

RQ = ?

0 O2 + C6H12O6 = 2 C3H6O3 + 2 ATP ~P:O2 =

Figure 3: Aerobic metabolism of fat (top), aerobic metabolism of carbohydrates (middle), anaerobic
metabolism of carbohydrates (bottom)

Note that as one moves down the diagram from aerobic metabolism of fat to anaerobic
metabolism of carbohydrates, a number of tradeoffs occur. Fats are most highly energy dense,
producing the most energy per gram of substrate, but require the most oxygen per high-energy
phosphate bond formed. Fat also produces the least carbon dioxide for the amount of oxygen
consumed, resulting the lowest respiratory quotient, R, a concept we discussed in the lecture on
ventilation-perfusion relationships. Anaerobic metabolism is the least efficient mechanism of
ATP production per gram of substrate, but has the virtue of requiring no oxygen at all. Oxygen
delivery is the primary limiting factor in maximal exercise. Therefore the cellular level response
to the demands of exercise includes increased oxygen extraction and an alteration in the energy
substrates utilized. This involves a transition from fat metabolism + carbohydrate metabolism
with mild exercise towards primarily carbohydrate metabolism (mostly glucose and glycogen)
with heavy exercise. With maximal exercise, anaerobic metabolism also appears while aerobic
metabolism of carbohydrates continues. Because glucose stores are limited, this reduced reliance
on fat metabolism imposes a limitation on exercise as glucose stores are depleted; the infamous
wall faced by marathon runners at approximately mile 20.
While it makes no sense to talk about a respiratory quotient with anaerobic metabolism (as no
oxygen is involved), there is CO2 production in the absence of oxygen consumption as the
hydrogen ions created by lactic acid combine with sodium bicarbonate. Furthermore, the
additional acid load as bicarbonate is consumed results in a greater ventilation requirement in
order to maintain a normal pH.

CH3CHOHCOO- H+ + NaHCO3
Lactic Acid

Sodium
Bicarbonate

H2CO3

CH3CHOHCOONa + H2CO3
Sodium Lactate

Carbonic
Acid

H2O + CO2

Figure 4

Overall, as skeletal muscle metabolism converts from aerobic fat metabolism to anaerobic
metabolism, there is a reduced oxygen requirement for each ATP produced, with the resulting
increased demand on ventilation, with more CO2 produced relative to oxygen consumed.
Substrate utilization is not uniform across all muscle types, as each muscle fiber type is adapted
for a specific form of exercise. These differences are highlighted in Figure 5 below:

Characteristics

Type I
Type IIA
Slow oxidation Fast oxidation

Type IIB
Fast glycolytic

Color

Red

Red

White

Myoglobin content

High

High

Low

Triglyceride content

High

Moderate

Low

Glycogen content
Oxidation potential
(mitochondrial content;
oxidative enzyme potential;
capillary density)
Fiber diameter
Contractile behavior (time to
peak tension following
activation)

No appreciable differences

High

High

Low

Moderate

Small

Large

Slow

Fast

Fast

Figure 5: Muscle Types

Slow oxidative (or slow twitch) fibers develop active tension less quickly than other fiber
types and are better suited for oxidative metabolism than are fast twitch fibers, which in turn
have higher glycolytic capacity. For this reason, slow twitch fibers are more suited for activities
requiring endurance. On the other hand, the ability to slam-dunk is facilitated by an adequate
supply of fast twitch fibers.
Cardiovascular Response to Exercise
Because oxygen uptake in normal individuals is perfusion limited, the delivery of oxygen by the
cardiovascular system is the limiting factor for maximal exercise in the absence of disease. The
cardiovascular system can respond to the demands of exercise both by increasing cardiac output
and by means of the peripheral circulation. As the cardiac output is the product of stroke volume
multiplied by heart rate, the normal cardiac response to exercise involves both. In a non-athlete,
heart rate can triple with exercise from approximately 70 up to 210 beats per minute, depending
on age. Stroke volume is increased somewhat during exercise, mainly through the action of
increasing venous return and through the response of the peripheral circulation mediated by
circulating chatechols.
With cardiovascular training, stroke volume at all heart rates increases and the heart rate required
to deliver a given cardiac output at any level of exercise decreases. This explains the low resting
heart rate seen in performance athletes. These same athletes similarly have markedly elevated
maximal oxygen delivery at maximal heart rate, which explains their phenomenal exercise
capacity. It is this acquired cardiac conditioning that is responsible for improved athletic
performance with training (for aerobic pursuits).

Dynamic control of the cardiovascular system is mediated through the autonomic nervous system
with a decrease in parasympathetic activity to the heart and an increase in sympathetic activity.
A slight increase in heart rate can be seen even before the start of exercise, due to conscious
anticipation. As exercise begins, circulating catecholamines such as epinephrine further augment
heart rate and mobilize glucose from glycogen stores. Sympathetically mediated
vasoconstriction results in increased venous return, augmented physically by the action of
muscle contraction on the veins.
Another effect of the autonomic system, in addition to local vasodilatation of arterioles mediated
by nitric oxide, is to redistribute blood flow away from the viscera and towards the skeletal
muscles. The magnitude of this effect is illustrated by the fact that, at rest, only 15-20% of the
cardiac out put goes to the skeletal muscle (approximately 1 liter/min), whereas during maximal
exercise 80% of a markedly increase cardiac output is distributed to the skeletal muscles (on the
range of 15 liters/min or greater). In addition to arteriolar dilation, this process is driven by
increases in blood pressure that may increase to 210 mmHg. As stroke volume is also increased,
an elevation in the arterial pulse pressure (the difference between the systolic and diastolic
pressure) is also seen.

Figure 6

Respiratory Response to Exercise:

As we have noted in this series of lectures, the lung uses only a small portion of its ventilatory
capacity to meet basal metabolic demands. For this reason, individuals with significant amounts
of obstruction, restriction, and/or ventilation/perfusion abnormalities may have minimal
symptoms at rest. However, during exercise, minor abnormalities in ventilation/perfusion
relationships or more significant abnormalities in lung mechanics may become exercise limiting.
In clinical practice, you may find, however, that patients will tend to subconsciously limit their
activity in response and still remain somewhat asymptomatic in the face of fairly significant
disease.
In normal individuals, pH, PaCO2 and PaO2 remain relatively constant over a wide range of
aerobic exercise. As oxygen consumption increases, carbon dioxide increases as well, resulting
in an increased requirement for greater alveolar ventilation in order to maintain the same PaCO2
and prevent acidosis. This is demonstrated in the left panel of Figure 6 below. The arrow on the

80

30
40

50

VA
(l/min) 40

PaCO2

1.0
0.85

}
R

0.7
VCO 2
(l/min)

VCO2 (l/min)

VO2 (l/min)

left end of the x-axis represents basal CO2 production, approximately 0.2 l/min. CO2 production
can increase ten fold to 2 l/min with only moderate exercise. As substrate utilization shifts
during exercise, and with the advent of anaerobic exercise, the requirement for CO2 elimination
increases further. The figure above right demonstrates the relationship between VO2, R and
alveolar ventilation (VCO2). The arrow on the left end of the x-axis represents basal VO2
production, approximately 0.25 l/min.
In patients with abnormal lung mechanics, such increases in the alveolar ventilation may not be
possible, resulting in an increase in PaCO2 with concurrent acidosis.
The maximal ventilation that can be sustained for one minute is the maximal ventilatory capacity
(MCV) or maximum minute volume (MMV). This value can be estimated by multiplying the
amount of air that can be exhaled in 1 second (FEV1) by a maximal respiratory rate of 40. The
level of ventilation that can be sustained is usually 50-60% of this maximal value.
Figure 7

Alveolar Arterial P02

As oxygen requirements increase with

exercise, oxygen extraction by muscle
cells from capillary blood will increase.
This will result in a decrease in the
80
partial pressure of oxygen in the mixed
70
venous blood returning to the lungs from
the peripheral tissues. With the mild
60
levels of ventilation/perfusion
50
inhomogeneity seen in normal lungs, this
does not result in a worsening of the A-a
40
gradient during exercise, as recruitment
30
of capillaries increases perfusion at the
same time that ventilation increases. In
20
situations such as asthma or interstitial
10
lung disease where the
ventilation/perfusion (V/Q)
inhomogeneity is increased, exercise
50
45
25
20
40
35
30
results in an increase in the A-a gradient,
as demonstrated in Figure 7. The open
Mixed Venous PO2
circles just above the x-axis represent the
response of the A-a gradient with a
normal V/Q distribution. The data
represented by the open triangles represents an individual with significantly increase V/Q
inhomogeneity. It is clear from this graph that desaturation does not occur in normal exercise,
even with extreme exertion, whereas exercise will exaggerate deoxygenation in individuals with
abnormal ventilation/perfusion relationships at baseline.

Cardiopulmonary Exercise Testing

Figure 8

The diagram above demonstrates one technique of assessing exercise performance in the
pulmonary function laboratory using graded exercise. The patient is seated on a bicycle
ergometer. The patient breathes through a scuba mouthpiece where airflow and the
concentrations of inhaled and exhaled oxygen and carbon dioxide are measured. Airflow can be
integrated to yield volume, and in concert with the oxygen and carbon dioxide measurements,
can be used to calculate VO2 and VCO2. The patient is instructed to pedal at a fixed rate against
an increasing amount of resistance. This results in an increasing power output (work/time) in a
stepwise fashion with approximately 1-second increments. While true steady state is not
achieved with a one-minute interval, this allows an assessment of exercise at a series of levels
from rest up to and including maximal exercise, where maximal exercise corresponds to the
highest VO2 achieved during the test.

VE
Isocapnic
Buffering

60
VCO2

Anaerobic
Threshold

2500

VO2
(ml/min) 2000

VO2

VCO2
1000
(ml/min)

40

VE
L/min

20
10

500
200
50

50

30

1500

VE/VC02
VE/VO2

70

VE/VCO2
VE/VO2

30
1.7

0.7
175

Workload
(Watts)

-3 -2 -1

9 10 11

Time (Minutes)

Figure 9 above represents an idealized exercise study in a normal individual. Note that oxygen
consumption (VO2) increases linearly in parallel with power output (watts). Heart rate (not
shown) also increases linearly with workload until the maximum heart rate is achieved. The
respiratory exchange ratio, R, increases towards 1. As lactate production due to anaerobic
metabolism increases and exceeds the bloods buffering capacity, the pH begins to fall, marking
the onset of anaerobic metabolism. Note that VO2 continues to increase, even after the onset of
anaerobic metabolism, until maximum exercise is achieved. In order to respond to this excess
CO2 production created by the buffering effect of bicarbonate, minute ventilation (VE) increases
beyond the amount required to keep up with increasing VO2, resulting in an increase in the
VE/VO2 ratio. Initially the increase in VE parallels the VCO2 curve, resulting in a steady, VE/VCO2
ratio, the so-called isocapnic buffering phase. As the pH continues to fall, chemoreceptors are
increasingly stimulated, resulting in a further respiratory response to the acidosis. At this point
the VE and VCO2 curves begin to diverge resulting in an increase in the VE /VCO2 ratio.

The figure to the

left depicts an actual
exercise tests.
While there is a
greater amount of
noise in these
tracings due to
breath to breath
variation, the
overall trends
described above can
still be observed,
including the linear
increase of VO2 to
its maximum value.

Figure 9

10