Oral Arginine

Supplements: Should
we or shouldn’t we
Jill Kanaley, PhD
Dept of Exercise Science
Syracuse University
 Outline
z Background facts
z Pathways
z Effect on GH release
z Effect on blood flow
z Effect on metabolism
z Conclusions
 Arginine facts
z L-arginine (2 amino-5-
guanidinovaleric acid) – basic
semi- essential amino acid

z Several metabolic functions

including:
transport
processing and excretion of
nitrogen
urea synthesis
substrate for the synthesis of
creatine and nitric oxide

z Hormonal release
 L-arginine hormone
secretagogue EPI/NE
Insulin
glucagon prolactin GH

↓ in hepatic glucose output

 Facts
z 5.4 g of l-arginine is absorbed each day in adults who
eat the average American diet

z Each gram of dietary protein supplies about 54 mg

of L-arginine

z So 70 kg man eating about 50 g of protein/day

consumes about 2.7 g of arginine per day

z Only 5% of urea production is derived from plasma

arginine – reflects low uptake of arginine by the liver
 Creatine NG,NG-dimethylarginine
CO2 Pathways
agmatine
L-Arginine
Urea
fumerate

Ornithine
NO
aspartate NH3

putrescine
L-citrulline

L-arginine is a precursor to NO
 Arginase inhibitor
(L-NMMA)

Ornithine
STIMULUS
Arginase
ARGININE activates

urea O2 Nitric Oxide

GTP Synthase
(eNOS)
guanylyl
+ ↑ Nitric
cyclase
oxide

cGMP

PDE5 ↑smooth muscle

relaxation
5’-GMP Viagra
Arginine and GH
 z Merimee et al. 1969
To test pituitary function
Minimum effective arginine load causing GH was 1/6
g/lb body weight in men

IV administration of
arginine is known to
result in large GH
responses – 40g dose

GH response to
arginine - can
attenuated or delayed
by a previous
stimulus for GH
release
Induce muscle growth by stimulating protein
synthesis
Ingestion of arginine in an attempt to stimulate
GH release → enhance protein synthesis

•?? What dose of oral arginine is needed to induce a

GH response?
Purpose:
z To determine the dose of oral arginine that
will give the highest GH response

z N=9 men; placebo, 5, 9, 13 g

Timing of induced GH response
15 Peak
concentration
GH ng/ml

10
Start of
GH rise

5
Arginine

0
0 30 60 90 120 150 180 210 240
Time (min)
 Effects of dose of oral arginine
750
Integrated GH concentrations

500
(min·mg/L)

250

0
Placebo 5 grams 9 grams 13 grams
Arginine (g)
*P<0.05 from other groups
z What is the combined effect of resistance
exercise and oral arginine on the GH
response?

z We hypothesized that resistance exercise and

arginine supplementation would cause an additive
effect on the GH response

Collier et al. 2006

 METHODS
N=8 (18-22 yr)
–Placebo
Blood –Arginine
sampling –Exercise
Subjects arrive, begins
–Arginine + Exercise
catheter inserted
(q 10 min)
Exercise
End
Supplement 3 sets, 10 rep
ingested 80% 1RM test
2 min rest

0700 0730 0800 0900 1000 1100 1130

Time (hrs)
Collier et al. 2006
 Resting GH Concentrations
8

6
GH (ng/ml)

0
Placebo Arginine Exercise Arg + Ex

Collier et al. 2006

 Placebo
Arginine
Exercise Exercise
15
Arginine+Exercise

10
GH (µg/L)

Arginine
or Placebo

0
0 30 60 90 120 150 180 210 240
Time (min)
 Area Under The Curve
750 †
GH iAUC (min· ng/ml)

500
†
*

250

0
Placebo Arginine Exercise Ex + Arg

† p < 0.03 vs. placebo * p < 0.05 vs. exercise Collier et al. 2006
 Conclusion
z Supplemental oral arginine taken prior to exercise
may blunt the exercise GH response
Exercise
+
+
Arginine hypothalamus

GHRH
- + Somatostatin

-
pituitary

+
GH
Oral L-arginine ingestion has much less effect than L-
arginine infusion

Low bioavailability of ingested L-arginine –

metabolized in intestinal mucosa

or high doses of L-arginine with infusion

Fogelholm et al. 1993 – used weight lifters
z 4 day combined L-arginine, L-ornithine and
L-lysine supplementation (2 g/d – taken in 2
doses)
No effect of supplementation on serum
insulin or GH concentrations

z Suminski et al. 1997 - found no effect of

arginine on GH, even when combined with
resistance exercise.
What is the effect of aging on the GH
response and the effect of arginine
ingestion?
 Marcell et al. 1999
z compared the GH responsiveness to an
acute bout of resistance exercise and the
effect of oral arginine ingestion in young
vs. old individuals

z 20 young (~22 yr) and 8 older (68 yr)

z 3 conditions exercise only, arginine only (5
g arginine), and arginine+exercise
 GH responses to arginine and exercise in
young and older individuals

young
1200 *
old
GH - AUC (ng/ml)

1000
800
600

400
200
0
basal exercise arginine arginine +
only only exercise
*P<0.05 young vs. old Marcell et al. 1999
 No study has shown that oral supplementation of
L-arginine in conjunction with resistance training
increases the GH response to the exercise stimulus
Arginine and nitric oxide
 Smooth
Muscle Relaxation
McArdle, Katch and Katch, 2006
Nitric oxide has numerous
functions
z Vasodilation
z Neurotransmission
z Metabolic regulation
z Excitation-contraction coupling
z Platelet aggregation
z Immune function
z Cell growth
 Palloshi et al. 2004

To investigate the effects of 4 wks oral

administration of L-arginine on blood pressure
and endothelial functions in patients with
hypertension

13 hypertensive patients / 2 g arginine - 3x/day for 4 weeks

Palloshi et al. 2004
Palloshi et al. 2004
Palloshi et al. 2004
 Oka et al. 2005
Try to identify the lowest effective oral dose of L-arginine to
improve walking distance

80 patients with peripheral artery disease (PAD) and

intermittent claudication

Randomly assigned to 3 oral doses (0, 3,6, 9 g of L arginine – daily in

3 equal doses for 12 wk)

No difference in walking between grps

Trend for increase in walking speed in all arginine groups
compared to the controls
z Intravenous infusion of L-arginine during exercise
in healthy and patients with coronary heart disease
had no effect on HR or BP

z Chronic oral arginine supplementation: improves

VO2 max in patients with cardiovascular disease and
with hypercholesterolemia
z No effect on VO2 max test time in healthy
individuals

z Acute l-arginine infusion does not affect VO2

max, even in those individuals with chronic
heart failure and those with
hypercholesterolemia
z Infusion of L-arginine, NO donors and NOS
inhibitors has effects on BP,HR and blood flow
at rest
z BUT these agents have little effect on
hemodynamics during exercise in humans
Arginine and glucose uptake
z Evidence to suggest that NO is playing a role in the
regulation of skeletal muscle glucose uptake

z In healthy individuals → femoral artery infusion of NO

synthase inhibitor reduced leg glucose uptake during
exercise by 40-50% with no effect on leg blood flow, blood
pressure or insulin
Inhibitor
ARGININE
Nitric Oxide Synthase
(eNOS)
+ -
Nitric oxide

NOS inhibition greater reduction in people with T2D

than controls
Postulate that any effects of L-arginine infusion on glucose kinetics during
exercise most likely occur independent of changes in hemodynamics.
 McConell et al. 2006

z Determine whether l-arginine infusion during

exercise increases glucose disposal in humans

z To determine whether l-arginine infusion influences

prolonged exercise performance in healthy humans
Bolus 6,6 2H glucose

6,6 2H glucose
30 g arginine
or saline

Subject cycled for 120 min 249KJ

72% VO2 peak ride

-120 0 75 120

9 endurance trained males

McConell et al. 2006
n = 9; *P < 0.05 vs. CON
z L-arginine infusion during exercise augmented the
normal exercise induced increases in glucose
disposal in humans
z due to increased NO production?
z which may increase the level of glucose utilization
by increased GLUT4 translocation

z NO is a central regulator of skeletal muscle glucose

uptake during exercise

Sooooo …… What effect would oral arginine

supplementation have on glucose uptake,
particularly in a population who has high glucose
levels?
 Lucotti et al. 2006

z Evaluated the effects of a long-term oral L-

arginine treatment + hypocaloric diet and
aerobic and resistance exercise plan on fat
mass lean mass, mean glucose levels,
insulin sensitivity, endothelial function in
severely obese type 2 diabetics.
z 33 middle ages adults (~56 y)
z Mean BMI ~39, and all had metabolic syndrome
z Diabetics not receiving any medications for glucose levels

Hypocaloric diet (~1000kcal) +

Exercise (70% VO2 max, 3x/wk, 45 min)

8.3 g arginine/day or placebo

0 21

days
 Change in score for anthropometric and metabolic variables

L-arginine Placebo
Weight (kg) -3 -3
Fat mass -3 -2.1*
Waist -9.3 -2.1*
Systolic BP -23 0**
Diastolic BP -12 -1**
Fasting Insulin -8 -3*
Fasting TG -0.61 -1.51
Mean daily glc -57 -33**

*P<0.05 between groups; **P<0.01 between groups Lucotti et al. 2006

 Change score for endothelial and hormonal variables

L-arginine Placebo
Incremental area 22.6 -0.4**
nitric oxide/nitric
nitrite
Fasting cGMP 1.26 0.50**
Fasting ET-1 -3.1 4.2**
Adiponectin 1.6 0*
Leptin -14 -5

*P<0.05 between groups; **P<0.01 between groups Lucotti et al. 2006

In obese insulin-resistant, type 2 diabetic patients:

z Prolonged oral L-arginine supplementation can

further ameliorate glucose metabolism and insulin
sensitivity, endothelial function, oxidative stress,
and adipokine releases

z Arginine helped to preserve FFM during a period of

hypocaloric diet when associated with an exercise
training program
z Question arise:
z does the L-arginine act through the
NO/cGMP pathway by normalizing it thus
ameliorating the poor peripheral and
hepatic insulin sensitivity in lean type 2
diabetic patients
ARGININE

GTP O2

guanylyl
+ ↑ Nitric
cyclase
oxide

cGMP
 Piatti et al. 2001
12 type 2 diabetics

Placebo therapy Placebo therapy

3x/d 3x/d
Control period Placebo therapy L-arginine therapy
3x/d 3 g - 3x/d

Diet to maintain body weight

* *
-30 -15 -0 15 30 15 30

Day
Visit to dietician; * euglycemic-hyperinsulinemic clamp
 cGMP
6
month 1
*
5 month 2

4
nmol/L

0
placebo arginine

*P<0.05 vs. placebo month

 Forearm blood Peripheral vascular
flow resistance
Forearm blood flow 60
month 1
ml/100 ml forearm/min

4 50 * month 2
*
3 40

month 130
2

UI
month 2
20
1
10

0 0
placebo arginine month 1 month 2

*P<0.05 vs. placebo month

 Insulin sensitivity
18 * month 1
16 month 2
14
12
µg/kg/min

10
8
6
4
2
0
placebo arginine

Arginine increased insulin sensitivity by 34%

*P<0.05 vs. placebo month
z ↑ NO availability induced by L-arginine
administration ↑ insulin sensitivity even if it was not
normalized

z Suggests that insulin resistance is associated with an

impairment in the ability of NO decrease cGMP
generation, and a decline in insulin’s ability to
produce vasodilation
 Take Home Message
z Improves aerobic exercise capacity in various cardiovascular
diseases – those associated with endothelial dysfunction
z Increases production of nitric oxide
z Healthy individuals arginine has little impact- no impact
on VO2 max

z Based on little research – L-arginine infusion and oral L-

arginine supplementations increases glucose uptake
z May be due to increases in nitric oxide production
z Also increases cGMP production

z Oral arginine can increase GH responses at rest but seems to

blunt the response if taken prior to resistance exercise
Questions?