Original Article

TITLE: CARDIOVAGAL AND VASOSYMPATHETIC BAROREFLEX LATENCIES

MEASURED DURING ACTIVE STANDING IN NORMAL SUBJECTS

Authors: 1Estaol Bruno, Delgado Guillermo R, Malamud Kessler Caroline,

Macas Gallardo Julio, 2Fossion Ruben, Rivera Ana Leonor, Frank A.lejandro

Affiliations: 1From the Clinical Neurophysiology Laboratory, Department of

Neurology and Psychiatry of the National Institute of Medical Sciences and

Nutrition Salvador Zubirn, 2Institute of Complexity Sciences.

Corresponding Address: Bruno Estaol, M.D.

National Institute of Medical Sciences and Nutrition Salvador Zubiran, Vasco de

Quiroga 15, Tlalpan, Mexico City, 10700.

Tels. 55-55683450

E-mail: bestanol@hotmail.com
Abstract

Introduction

Cardiovagal and vasosympathetic latencies were measured during the immediate fall of

blood pressure (BP) that is seen during active standing (AS). The fall during AS is profound

and after its nadir is followed by a gradual recovery. The heart rate (HR) increases to a peak

and gradually decreases. The BP stabilizes in about 20-25 s and the HR between 25-30 s.

Subjects and methods

We studied 29 healthy control subjects during AS. The subjects were recumbent for 6

minutes and then were asked to sit up and immediately assume the upright position. The

upright position was maintained during 5 minutes. The BP and interbeat intervals (IBI) were

continuously monitored using the non invasive finger pressure Finapres device during the

entire maneuver.

Results

There was an initial peak of rise of systolic blood pressure of 22 mmHg followed by an

abrupt fall of 25-40 mmHg that gradually recovered. The cardiovagal reflex was measured

from the trough of the SBP and the initial rise of recovery of the IBI and was found to be 2.8

with CI between 0.81-3.63 s . The vasosympathetic vasoconstrictive latency was measured

from the basal BP (immediate SBP before standing) to the trough or nadir of the fall of BP

and was found to be 7 1.8 s.

Discussion

There is a complex sequence of physiological events during AS. The immediate profound

fall of BP is seen only during AS and is not seen during passive tilt. The relationship between

the changes of BP and HR are clearly seen during active standing, and this allowed us to

measure the cardiovagal and vasosympathetic vasoconstrictive latencies. We obtained

slightly longer cardiovagal latencies than those reported previously. This may be due to the
previous profound fall of BP before its rise and was slightly different in each subject. The

vasosympathetic vasoconstrictive latencies were very consistent at 7 s with a time constant

of 4.2 s. Vasosympathetic vasoconstrictive latencies have been difficult to measure

previously. These data may be useful to study patients with different disorders such as

neurally mediated syncope, orthostatic hypotension and POTS.

Key words: active standing (AS), fall of SBP, cardiovagal latency, vasosympathetic latency.

Running title: Cardiovagal and cardiosympathetic latencies during active standing

Introduction

Blood pressure autoregulation is a fundamental mechanism that corrects the

perturbations of BP that occur during the activities of daily life (1,2) On a short term

basis is performed by a complex negative feedback mechanism termed the

baroreceptor reflex (13). The baroreflex has at least two afferent entries: 1) the

high pressure, and 2) the low pressure baroreceptors, and at least three effector

arms: 1) the cardiovagal reflex; 2) the cardiosympathetic reflex, and 3) the

vasosympathetic or vascular reflex. It has a central integration network located at

the nucleus tractus solitarii, the nucleus ambiguous, the ventrolateral medulla and

the intermediolateral column of the spinal cord (3,4). It is a polysynaptic reflex that

(is) activates under the (influences) effects of several supranuclear influences

mostly from the hypothalamus, the limbic system and the insular cortex (2,5,6). The

supranuclear modulation is poorly understood but is mainly related to perturbations

of BP given by central mechanisms or central commands and (is) are associated to

emotions, cognitive activities and voluntary muscle contractions (1,5,6). The

purpose of (the) this reflex, which is altered by the multiple internal and external

disturbances, to which it is constantly exposed, is to stabilize the BP (from) the

multiple internal and external disturbances to which is constantly exposed (1). The

two main external disturbances are the gravitational stress and the respiratory

movements, both, induce well known hemodynamic changes (3,7,8). (Se puede

poner el grfico que realizamos)

Active standing (AS) induces an immediate fall of BP with subsequent recovery, that

has three phases: 1) an initial peak that is characterized by a parallel rise of BP and
HR that is induced when the person is changing the position from supine to sitting;

2) a fall of BP with an associated tachychardia (9,10) ; the tachycardia has been

ascribed to reflex withdrawal of vagal influences and the entrance of

cardiosympathetic activity (9,10); the fall of BP has been attributed to the pooling of

blood in the abdomen and lower extremities due to the action of the gravitational

acceleration vector, although a reflex inhibition due to activation of the

cardiopulmonary reflexes or arterial baroreflex vasosympathetic inhibition by the

previous rise of BP, has also been suggested (7,11,12); the drop of BP is followed

by a recovery phase, and finally 3) a second rise of BP that ends in a second peak

that appears to be a sympathetic overcompensation or overshoot similar to that

seen in the fourth phase of the Valsalva maneuver (7,9,1115). (Figure 1)

We attemped to measure the latencies of the three effector arms of the reflex as we

considered AS an excellent physiological window to measure these latencies, as

the fiducial or sample points can be very well defined, and because the immediate

profound fall of BP when assuming the upright position is solely seen during AS and

is not observed with passive tilt (7,8,11,12,15). The baroreflex vasosympathetic

inhibitory component, following the initial BP peak, induces mainly vasodilation and

is partly responsible of for the fall of BP (8,15). In any event the abrupt fall of BP

successively activates the cardiosympathetic and the vasoympathetic reflexes, and

during the gradual increase of the recovery phase of BP, the cardiovagal reflex is

activated. The latencies and duration of these influences can thus, be clearly

defined.

SUBJECTS, MATERIAL AND METHODS

Study Population. We enrolled twenty eight healthy subjects, aged 19 to 35 years

of age, without a history of diabetes, hypertension, cardiac or neurological diseases,

or history of syncope; subjects were nonsmokers and were on no medications. They

all had, as part of the previous evaluation, BP measurements in supine, sitting and

standing positions. BP measurement was performed using standard

sphygmomanometry. In all subjects, BP was 120/80 mmHg or less. The BP

measurements were done by two subjects that were blind to each other findings.

Blood sugar levels were below 95 mgs/dl, and the body mass index was below 26.

They also underwent a neurological examination and had normal pupils, normal

myotatic reflexes and no Romberg sign. The study was approved by the Ethical

Committee of the National Institute of Medical Sciences and Nutrition and an

informed written consent was obtained from all participants.

Protocol. All evaluations were performed in the morning. Participants were

instructed to avoid alcohol, caffeinated beverages and over-the-counter medications

after 22:00 on the night before the evaluation. Finger arterial pressure (FAP) was

non-invasively and continuously (beat-to-beat) monitored using the volume-clamp

method by Pez and the Physiocal (physiological calibration) criteria by

Wesseling.12 SBP, DBP and mean BP (MBP) were then reconstructed from FAP;

and heart rate (HR) was meanwhile computed as the inverse of the interbeat interval

(Finometer PRO, Finapres Medical Systems, Amsterdam). Measurements were

made at supine rest before AS (5 min), and during AS. Hemodynamic parameters

were extracted with BeatScope for Windows (v.1.1a, Finapres Medical Systems).

Description of the maneuver. The subjects stayed resting in a supine position

breathing normally for 10 minutes and thereafter they were asked to sit and stand

up immediately after they sat up. We recorded the beat to beat changes in basal
SBP and HR while supine, during the time the subject moved from supine to the

sitting position, and during the period of active standing. We also recorded the SBP

and HR for five minutes after the subject stood up.

Data Analysis and Statistics. The investigation was focused on SBP and HR

changes in the initial hemodynamic response to AS and was carried out utilizing

BeatScope software. Supine values of SBP and HR were calculated as the

corresponding arithmetic means of the 5 min supine rest, and afterwards SBP

response was determined at the time of the initial peak of SBPa (tSBPa), time at valley

or trough of the fall of SBPb (tSBPb), and at the SBP overshoot (tSBPos). The selection

of sample points was prompted by the results of previous studies (79,1113,16).

Statistical analysis was performed with STATISTICA for Windows (v.5.1). Prior to

group analyses, individual data were tested for normality (Shapiro-Wilk test). The

calculation of latencies was performed by either using Student's t-test or Mann-

Whitney U test. A p-value below 0.05 (p < 0.05) was considered significant. All

results are expressed as mean SD or median (interquartile range).

RESULTS

1. AS is a relatively simple method to measure cardiovagal latencies during a

step stimulus? It can be measured directly from the point of the onset of

recovery of SBP to the time of the first increase of the IBI. In normal subjects

it had a mean latency of 2.8 s with C.I. between 0.81-3.63 s. The latencies

did not have a normal distribution but the measurements were precise as the

onset of the recovery of the SBP was clearly seen in all subjects and the

onset of the lengthening of the IBI was also well defined (Figure 2).
2. The vasosympathetic latency was measured from the first peak of the SBP

to the valley or trough of the fall of the BP. We found similar latencies to those

reported by Wieling with a mean of 7 1.8 s (7,8). (Figure 3)

3. The fall of the SBP was measured from the basal SBP, while the subject was

supine, to the trough or valley and was 29.6 15 mmHg. This is more

pronounced than that found by Wieling that had a mean of 20 mmHg (7,8).

When we made the calculations from the first peak to the trough it was 52.3

16.5 mmHg. We carefully repeated the calculations and found both of them

were o to be accurate.

4. The time of recovery recovery time of the SBP was measured from the point

of onset of the ascending arm (which indicated the onset of recovery) to the

second peak of the SBP. The measured time was 9.6 s with C.I. between

7.8-11.4 s.

5. We attempted to measure the latency of the cardiosympathetic reflex but

could not find reliable fiducial points. The initial shortening of the IBI at the

onset of the fall of SBP could be attributed to withdrawal of vagal influences

and it was difficult or impossible to recognize the point where the sympathetic

influences began. We also attempted to measure the cardiosympathetic

latency from the onset of the fall from the second peak, to the onset of

tachycardia but could not find clear fiducial points.

DISCUSSION

AS is probably one of the simplest maneuver to calculate cardiovagal

latencies as they can be measured directly from the time of the onset of
 recovery of SBP to the time of the initial lengthening of the IBI (Figure 2). AS

is one of the routine maneuvers that are performed in the autonomic

laboratory and therefore most researchers can do this calculation easily. We

found cardiovagal latencies longer than those reported with other methods8.

One of the reasons may be the very profound fall of SBP of approximately

30 mmHg and the slight magnitude of the initial recovery of the SBP after this

profound fall. Therefore, the stimulus (SBP) may take longer to act. It may

also reflect the dynamic nature of the cardiovagal reflexes having a slight

time difference under different conditions (17). The intersubject variability is

also compatible with a polysynaptic reflex that is constantly modulated by

supranuclear influences. Polysynaptic reflexes have variable latencies in

general. The variability of latencies may also be related to the timing of

respiratory movement (3,17).

The vasosympathetic reflex had latencies similar to those reported previously

by others with a mean of 7 s (7,15). The vasosympathetic or vascular latency

is most likely the longest of the three effector arms of the baroreceptor reflex

(1). This is to be expected as it has a long central processing time at various

successive sites including the nucleus solitarii, the ventrolateral medulla ,the

intermediolateral columns of the spinal cord, the slow conduction velocities

of the C fibers that innervate resistant blood vessels, the slow release of

noradrenaline at the neuroeffector junction, and the proper time constant of

the arteriolar constriction (1).

The time course of the response of the resistant blood vessels, which are a widely

distributed and rather large system, also has to be taken into account. The duration
of the vasosympathetic response (time of recovery of SBP) to the second peak was

found to be 9.6 s with a C.I. between 7.8-11.4 s. This indicates that the duration of

the vasosympathetic response has a mean of 10 s during in which there is gradual

increasing vasoconstriction until the complete recovery of the basal SBP. The time

constant (TC) of the recovery is thus ~6 s. This is also compatible with the

anatomophysiological characteristics of the central and peripheral sympathetic

networks that innervate the resistant blood vessels. The vasosympathetic latency

and duration are both important characteristics in the understanding and the

evaluation of the autoregulation of BP. The cardiovagal response has been

evaluated thoroughly through the different types of baroreflex sensitivity indices

(BRS) but the vasosympathetic response has been more elusive because its

measurement is done indirectly through the changes of BP, as the peripheral

resistance is difficult to measure with direct means (5,8). Hence, the measurement

of its latency and duration, during active standing, are feasible and also relatively

easy to perform.

The measure of the latency and duration of the vasosympathetic response are both

important in the evaluation of different pathologies that produce orthostatic

hypotension (4,7,14,1824). The work of Wieling that has characterized various

types of initial or immediate orthostatic hypotension using AS as a research tool

has been very important in focusing attention to this relatively simple maneuver

(7,8). We think that not only the amount of the fall of SBP during active standing is

of fundamental importance, but also: 1) the time of duration of the fall, and, 2) the

time of recovery after the initial physiological orthostatic hypotension are of interest

for the understanding and evaluation of the latency and duration of the arterial

baroreflex vasoconstricting response.

The small initial peak, observed during the time of position change from supine to

sitting, is most likely induced by the contraction of the abdominal and limb muscles

during the time from sitting to the recumbent position (712). At the point of

increased venous return to the right heart cavities and the pulmonary circulation

there may be activation of the low pressure cardiopulmonary receptors. The parallel

tachycardia seems to be due to reflex vagal withdrawal (10). The activation of the

low pressure pulmonary receptors and the increase of BP immediately before the

fall may enhance the fall of SBP at the time of standing by activation of arterial

baroreceptors (7,11,12).

REFERENCES:

1. Karemaker JM, Wesseling KH. Variability in cardiovascular control: the

baroreflex reconsidered. Cardiovascular engineering (Dordrecht,

Netherlands) [Internet]. 2008 Mar [cited 2013 Feb 8];8(1):239. Available

from: http://www.ncbi.nlm.nih.gov/pubmed/18041583

2. Van de Vooren H, Gademan MGJ, Swenne CA, TenVoorde BJ, Schalij MJ,

Van der Wall EE. Baroreflex sensitivity, blood pressure buffering, and

resonance: what are the links? Computer simulation of healthy subjects and

heart failure patients. Journal of applied physiology (Bethesda, Md.: 1985)

[Internet]. 2007 Apr [cited 2013 Feb 5];102(4):134856. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/17185500

3. Eckberg DL. The human respiratory gate. The Journal of physiology

[Internet]. 2003 Apr 15 [cited 2012 Nov 1];548(Pt 2):33952. Available from:
 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2342859&tool=p

mcentrez&rendertype=abstract

4. Gulli G, Cooper VL, Claydon VE, Hainsworth R. Prolonged latency in the

baroreflex mediated vascular resistance response in subjects with postural

related syncope. Clinical autonomic research: official journal of the Clinical

Autonomic Research Society [Internet]. 2005 Jun [cited 2013 Jan

6];15(3):20712. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/15944870

5. La Rovere MT, Pinna GD, Raczak G. Baroreflex sensitivity: measurement

and clinical implications. Annals of noninvasive electrocardiology: the official

journal of the International Society for Holter and Noninvasive

Electrocardiology, Inc [Internet]. 2008 Apr;13(2):191207. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/18426445

6. Vaschillo EG, Vaschillo B, Buckman JF, Pandina RJ, Bates ME.

Measurement of vascular tone and stroke volume baroreflex gain.

Psychophysiology [Internet]. 2012 Feb [cited 2013 Feb 2];49(2):1937.

Available from:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3366428&tool=p

mcentrez&rendertype=abstract

7. Wieling W, Krediet CTP, Van Dijk N, Linzer M, Tschakovsky ME. Initial

orthostatic hypotension: review of a forgotten condition. Clinical science

(London, England: 1979) [Internet]. 2007 Feb [cited 2012 Dec

 8];112(3):15765. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/17199559

8. Wieling W, Dambrink JH, Borst C. Cardiovascular effects of arising

suddenly. The New England journal of medicine [Internet]. 1984 May 3 [cited

2013 Feb 8];310(18):1189. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/6709016

9. Borst C, Van Brederode JF, Wieling W, Van Montfrans GA, Dunning AJ.

Mechanisms of initial blood pressure response to postural change. Clinical

science (London, England: 1979) [Internet]. 1984 Sep [cited 2013 Feb

8];67(3):3217. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/6467836

10. Borst C, Wieling W, Van Brederode JF, Hond A, De Rijk LG, Dunning AJ.

Mechanisms of initial heart rate response to postural change. The American

journal of physiology [Internet]. 1982 Nov [cited 2013 Feb 8];243(5):H676

81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7137360

11. Sprangers RL, Veerman DP, Karemaker JM, Wieling W. Initial circulatory

responses to changes in posture: influence of the angle and speed of tilt.

Clinical physiology (Oxford, England) [Internet]. 1991 May [cited 2013 Feb

8];11(3):21120. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/1893679

12. Sprangers RL, Wesseling KH, Imholz AL, Imholz BP, Wieling W. Initial blood

pressure fall on stand up and exercise explained by changes in total

peripheral resistance. Journal of applied physiology (Bethesda, Md.: 1985)

 [Internet]. 1991 Feb [cited 2013 Feb 10];70(2):52330. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/2022542

13. Borst C, Wieling W, Brederode JFMVAN. Mechanisms of initial to postural

change heart rate response. 1982;16.

14. Guelen I, Westerhof BE, Van Der Sar GL, Van Montfrans GA, Kiemeneij F,

Wesseling KH, et al. Finometer, finger pressure measurements with the

possibility to reconstruct brachial pressure. Blood pressure monitoring

[Internet]. 2003 Feb [cited 2013 Feb 8];8(1):2730. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/12604933

15. Imholz BP, Settels JJ, Van der Meiracker AH, Wesseling KH, Wieling W.

Non-invasive continuous finger blood pressure measurement during

orthostatic stress compared to intra-arterial pressure. Cardiovascular

research [Internet]. 1990 Mar [cited 2013 Feb 8];24(3):21421. Available

from: http://www.ncbi.nlm.nih.gov/pubmed/2346955

16. Borst C, Karemaker JM. Time delays in the human baroreceptor reflex.

Journal of the autonomic nervous system [Internet]. 1983 Nov;9(2-3):399

409. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6663021

17. Keyl C, Schneider A, Dambacher M, Bernardi L, Fisher JP, Kim A, et al.

Time delay of vagally mediated cardiac baroreflex response varies with

autonomic cardiovascular control Time delay of vagally mediated cardiac

baroreflex response varies with autonomic cardiovascular control.

2011;2839.
18. Gulli G, Claydon VE, Cooper VL, Hainsworth R. R-R interval-blood pressure

interaction in subjects with different tolerances to orthostatic stress.

Experimental physiology [Internet]. 2005 May [cited 2012 Dec

18];90(3):36775. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/15665146

19. Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman M,

Dodaballapur SK. Are current recommendations to diagnose orthostatic

hypotension in Parkinsons disease satisfactory? Movement disorders:

official journal of the Movement Disorder Society [Internet]. 2009 Sep 15

[cited 2013 Feb 10];24(12):174751. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/19562759

20. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of

idiopathic Parkinsons disease: a clinico-pathological study of 100 cases.

Journal of neurology, neurosurgery, and psychiatry [Internet]. 1992 Mar

[cited 2013 Jan 31];55(3):1814. Available from:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1014720&tool=p

mcentrez&rendertype=abstract

21. Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari M. EFNS

guidelines on the diagnosis and management of orthostatic hypotension.

European journal of neurology: the official journal of the European

Federation of Neurological Societies [Internet]. 2006 Sep [cited 2013 Feb

7];13(9):9306. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/16930356
22. Freeman R, Wieling W, Axelrod FB, Benditt DG, Benarroch E, Biaggioni I, et

al. Consensus statement on the definition of orthostatic hypotension,

neurally mediated syncope and the postural tachycardia syndrome. Clinical

autonomic research: official journal of the Clinical Autonomic Research

Society [Internet]. 2011 Apr 26 [cited 2012 Oct 26];21(2):6972. Available

from: http://www.ncbi.nlm.nih.gov/pubmed/21393070

23. Andersen EB, Boesen F. Sympathetic vasoconstrictor reflexes in

Parkinsons disease with autonomic dysfunction. Clinical autonomic

research: official journal of the Clinical Autonomic Research Society

[Internet]. 1997 Feb [cited 2013 Feb 8];7(1):511. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/9074823

24. Fisher JP, Kim A, Young CN, Ogoh S, Raven PB, Secher NH, et al.

Influence of ageing on carotid baroreflex peak response latency in humans.

The Journal of physiology [Internet]. 2009 Nov 15 [cited 2013 Jan 29];587(Pt

22):542739. Available from:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2793874&tool=p

mcentrez&rendertype=abstract
CAPTIONS FOR FIGURES

1. Healthy subject 30 years old. Two positive peaks of BP are seen during

active standing. The first peak is observed when the subject changes

position from supine to sitting position. The negative peak is the valley

of the fall of the BP at the moment of standing. The second positive

peak is seen at the end of the recovery of the BP while the subject is

still standing.

2. Measurement of cardiovagal latencies: time from the valley of the fall of

SBP immediately after standing to the onset of the lengthening of the

IBI. The two fiducial points were clearly observed in all subjects.

3. Measurement of the vasosympathetic latency: time from the onset of

the fall of the BP from the first peak to the valle. The two points were

clearly observed in all subjects.

4. Measurement of the duration of the vasosympathetic response: time

from the valley of the fall of SBP to the highest point of the second peak

of SBP.
Figure 1
Figure 2
Figure 3
Figure 4

Cambios posturales
respiracin
contraccin muscular
Red de integracin central

Perturbaciones
externas

Control neural:
Sistema simptico Barorreflejo Reflejo cardiosimptico PAS2
Sistema parasimptico
PAS1

Receptores locales de presin arterial Reflejo vasosimptico

Alta presin

Baja presin

Figura 1 Flujograma del control de la presin arterial: la PAS1 indica la PAS inicial, PAS2 se reere a la PAS
posterior al control del barorreejo y PASnal se reere a la PAS nal posterior al mecanismo de
retroalimentacin.