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Oral Arginine Reduces Systemic Blood Pressure in
Type 2 Diabetes: Its Potential Role in Nitric Oxide
Generation
Nhan T. Huynh BSa & John A. Tayek MDa
a Department of Internal Medicine, Harbor-UCLA Medical Center, UCLA School of
Medicine, Torrance, California
Published online: 19 Jun 2013.
To cite this article: Nhan T. Huynh BS & John A. Tayek MD (2002) Oral Arginine Reduces Systemic Blood Pressure in Type 2
Diabetes: Its Potential Role in Nitric Oxide Generation, Journal of the American College of Nutrition, 21:5, 422-427, DOI:
10.1080/07315724.2002.10719245
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Original Research
Oral Arginine Reduces Systemic Blood Pressure in Type
2 Diabetes: Its Potential Role in Nitric Oxide Generation
Nhan T. Huynh, BS, and John A. Tayek, MD
Department of Internal Medicine, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California
Key words: blood pressure, nitric oxide, arginine
Objectives: Arginine is converted in the endothelial cells to nitric oxide (NO) and citrulline. NO is a potent
vasodilator in humans, but diabetics may have a reduced generation of NO which results in endothelial
dysfunction. The aim of this study was to evaluate the effects of oral arginine on nitric oxide production,
counter-regulatory hormones and blood pressure in mildly hypertensive type 2 diabetic patients.
Methods: A prospective, crossover clinical trial was performed over a three-day stay in the General Clinical
Research Center. Six patients with type 2 diabetes mellitus and mild hypertension consented and were given
orally three grams of arginine per hour for 10 hours on either day 2 or day 3. On both days 2 and 3, blood
pressure was monitored between 5 AM and 4 PM and mean pressure determined.
Results: Oral arginine increased plasma citrulline from 31.3 Ϯ 6.0 to 41.5 Ϯ 6.0 ␮mol/L (mean Ϯ SEM; p Ͻ
0.05) which may reflect an increased conversion of arginine into NO and citrulline. Arginine reduced systolic BP from
135 Ϯ 7 to 123 Ϯ 8 mmHg; p Ͻ 0.05. Diastolic BP fell from 86.9 Ϯ 1.7 to 80.7 Ϯ 2.4 mmHg; p Ͻ 0.05). The
reduction in BP was noted to occur two hours after starting oral arginine, and BP returned to normal within one hour
of stopping the arginine. The oral arginine had no effect on C-peptide, insulin or other hormone concentrations.
Conclusions: These data suggest that oral arginine may increase endothelial nitric oxide synthase (NOS) to
increase vascular NO and temporally reduce blood pressure in mildly hypertensive type 2 diabetic patients.
artery disease [4]. Administration of an analog of L-arginine
INTRODUCTION
(L-NAME) in normal volunteers increases mean blood pressure
by 8 mmHg [5]. The removal of arginine availability for its
conversion into NO may explain the rise in blood pressure ob-
served. As in the human model, mean arterial pressure increases
more in diabetic rats after the administration L-NAME than in
non-diabetic rats [6]. We know that tissue arginine concentration
are reduced in the rat [1]. While there are no reports of tissue
arginine concentration in humans, the administration of arginine to
humans has a blunted effect on blood pressure in type 2 diabetic
patients [7]. This suggests that there may be a state of arginine
resistance in that the effects of arginine are blunted in the type 2
diabetic patient compared to in a normal volunteer [7].
No one knows why diabetic patients have a sixfold increase
in cardiovascular disease when compared to non-diabetic indi-
viduals. Endothelial dysfunction may be one possible explana-
tion for the higher risk for coronary artery disease. Endothelial
dysfunction is common in type 2 diabetes [1]. Insufficient
arginine concentration in the endothelial cells may hamper the
ability to generate nitric oxide (NO).
Nitric oxide (NO) is generated by the conversion of arginine
into citrulline and NO. Nitric oxide synthase (NOS) enzymes
are known to exist in three forms (endothelial or eNOS, induc-
ible or iNOS and neuronal or nNOS). Of the three types, eNOS
is believed to be a major contributor to the endothelial dys-
function that occurs in type 2 diabetes and in non-diabetic
patients who have insulin resistance [2].
Overnight fasting plasma arginine concentrations have been
reported to be increased in patients with type 2 diabetes [8,9].
While a high salt diet can double plasma arginine (165 Ϯ 10 to
83 Ϯ 7 ␮mol/L) in rats [10], there are no published data in
humans. Plasma arginine remains significantly increased in
Arginine administration can improve endothelium dependent
vasodilation in normal volunteers [3] and in patients with coronary
Address reprint requests to: John A. Tayek, M.D., 1000 W. Carson Street, Box 428, Torrance, CA 90509. E-mail: tayek@humc.edu.
This study was supported by the NIH Clinical Investigator Award KO8DK02083 and MO1-RR-00425.
Journal of the American College of Nutrition, Vol. 21, No. 5, 422–427 (2002)
Published by the American College of Nutrition
422

Oral Arginine and Type 2 Diabetes
diabetic patients even after ingestion of a 55-gram protein meal
[9]. The exact mechanism and reason for an increased plasma
arginine concentration in diabetic patients are not known.
Additional arginine given as three grams, three times a day for
one month decreases systolic blood pressure in non-hypertensive
lean type 2 diabetic volunteers [11]. While plasma arginine con-
centrations were not determined in this study, the additional argi-
nine reduced systolic blood pressure. Arginine had no effect on
serum insulin, which can also lower blood pressure [11]. Recently,
oral arginine supplementation given to six healthy normal volun-
teers also reduced systolic and diastolic blood pressure [12].
The purpose of this study was to test if three grams an hour
of oral arginine would increase NO generation and reduce
systolic and diastolic blood pressure in mildly hypertensive
type 2 diabetic volunteers. NO bioavailability was estimated by
the increase in plasma citrulline when arginine was converted
into NO and citrulline by NOS. We also measured C-peptide,
insulin, epinephrine, norepinephrine and other hormones to
determine if this dose of arginine had an effect on hormone
secretion which may also influence blood pressure.
AM and 4:00 PM. All laboratory measurements were as de-
scribed previously [13]. BP was measured in the dominant arm
between 5:00 AM and 4:00 PM and at midnight on both days
2 and 3. Diabetic patients were given three grams of arginine
orally every hour for 10 hours (4:00 AM to 2:00 PM) on either
day-2 or day 3. The non-treatment day acted as the control day.
Four diabetics received arginine on day 2, and two diabetic
patients received arginine on day 3.
Statistical Analysis
All data are mean Ϯ SEM at each time interval. Compari-
sons were done by ANOVA. Significance was defined as p Ͻ
0.05. There was no order effect, so that the arginine treatment
day was compared to the non-treatment day. The hormonal data
are represented at hourly measurements and amino acids every
two hours. A paired t test was done on groups only if ANOVA
was significant.
RESULTS
The administration of arginine had no effect on the hourly
mean C-peptide secretion (0.88 Ϯ 0.11 vs. 0.86 Ϯ 0.13 pg/mL,
arginine vs. no-arginine treatment, respectively). Oral arginine also
had no effect on hourly mean cortisol (10.4 Ϯ 2.0 vs. 10.4 Ϯ 2.2
␮g/dL), epinephrine (42 Ϯ 5.4 vs. 37 Ϯ 4) or norepinephrine
(421 Ϯ 60 vs. 328 Ϯ 100) concentration. In addition, arginine had
no effect on insulin, glucagon, GH, IGF-1 (data not shown).
Resting energy expenditure was similar with arginine administra-
tion (2520 Ϯ 350 vs. 2510 Ϯ 280 kcals/day, mean Ϯ SEM). There
was no difference in the hourly mean blood glucose while taking
oral arginine (212 Ϯ 33 vs. 212 Ϯ 34 mg/dL). There were no GI
or other side effects to taking arginine.
METHODS
Study Population
Six patients with mild hypertension, stable weight and a
history of type 2 diabetes consented after approval by the
institutional review committee. The diabetic patients had type 2
diabetes for five years; the other characteristics are listed in
Table 1. Blood pressure and diabetic medications were with-
drawn on the evening prior to admission. All volunteers were
admitted for three days on a low sodium diet into the General
Clinical Research Center. Patients were randomized to arginine
on day 2 or day 3 of the study. A placebo was not used on the
non-arginine treatment day. Resting energy expenditure was
measured on days 2 and 3 by indirect calorimeter (Delta track,
Sensor Medics, Yorba Linda, CA).
After two hours of ingesting three grams of arginine per
hour, plasma arginine concentrations doubled and remained
doubled over the eight-hour study period (Fig. 1). Plasma
ornithine concentrations doubled after two hours of starting
Measurements
Blood measurements for glucagon, catecholamines, C-pep-
tide, GH, IGF-1, cortisol and glucose were obtained hourly
between 6:00 AM and 4:00 PM on both days. Plasma arginine
and citrulline were determined every two hours between 6:00
Table 1. Patient charactertistics
Age (years)
40 Ϯ 4.0
127 Ϯ 17
44 Ϯ 4
Weight (kg)
BMI (kg/m2)
TSF (mm)
35 Ϯ 8
Waist Circumference (cm)
HbA1c (%)
124 Ϯ 10
7.0 Ϯ 0.9
Fig. 1. This figure demonstrates the mean plasma arginine concentra-
Mean Ϯ SEM.
tion with or without oral arginine supplements.
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
423

Oral Arginine and Type 2 Diabetes
in plasma citrulline over the entire 10-hour ingestion period
(Fig. 3). The failure to increase citrulline may reflect an inabil-
ity to increase conversion of arginine into NO and citrulline in
the patients with type 2 diabetes mellitus.
Arginine reduced blood pressure (BP) between hour 6:00 and
14:00 in the diabetic volunteers studied. Mean systolic blood
pressure was decreased from 135 Ϯ 7 to 123 Ϯ 8 mmHg; p Ͻ
0.05. Mean diastolic blood pressure decreased from 86.9 Ϯ 1.7 to
80.7 Ϯ 2.4 mmHg; p Ͻ 0.05). The hourly time changes can be
seen for both systolic and diastolic blood pressure in Figs. 4 and 5.
Both systolic and diastolic blood pressures were not reduced at
5:00 AM. Oral arginine was stopped at 2:00 PM, and the hypo-
tensive influence was lost at 15:00 hours (3:00 PM).
Fig. 2. This figure demonstrates the mean ornithine with or without oral
arginine supplements. There was a significant difference by ANOVA
(p Ͻ 0.01) and a significant increase over time (p Ͻ 0.05).
DISCUSSION
Oral Arginine and Blood Pressure
oral arginine and its concentration continued to increase during
the eight-hour study period to become 3.6-fold higher at 2:00
PM (Fig. 2). While taking three grams of oral arginine per hour,
it took approximately 2.5 hours for plasma ornithine to reach
half-maximal concentration. On the other hand, it appears that
plasma citrulline was at a maximum concentration as early as
two hours after starting oral arginine. Mean plasma citrulline
concentrations increased by only 30% above baseline (31.3 Ϯ
6.0 to 41.5 Ϯ 6.0 ␮mol/L; p Ͻ 0.05, Fig. 3). At individual time
points, citrulline was increased at hours 10 and 12. In compar-
ison, six normal volunteers under a similar protocol increased
citrulline to 50.9 Ϯ 6.0 ␮mol/L (unpublished data). In compar-
ison to the doubling of plasma ornithine concentration while
taking oral arginine, plasma citrulline increased by only 30% in
the diabetic patients. In addition, there was no further increase
As little as nine grams a day of oral arginine in the diet has
been shown to reduce blood pressure in a small group of normal
volunteers [12]. Nine grams a day also increased blood flow,
reduced systemic vascular resistance and systolic blood pressure
in non-hypertensive type 2 diabetic patients [11]. In the current
study, three grams per hour reduced both systolic and diastolic
blood pressure. The blood pressure was significantly decreased
two hours after starting the oral arginine. However, one hour after
stopping arginine, the hypotensive influence observed while on
arginine was lost (Figs. 4 and 5; Time 15:00).
It is well known that acute arginine increases insulin secretion
which can reduce blood pressure. However, type 1 diabetic pa-
tients have insulin deficiency, yet arginine reduces blood pressure
in type 1 diabetic patients [14]. The influence on blood pressure is
short lived. Within 10 minutes of stopping intravenous arginine,
blood pressure returned to normal in hypertensive patients with
type 2 diabetes mellitus [14]. An elevation in blood pressure
occurred just after stopping the arginine even though serum insulin
concentrations were still elevated. Therefore, the influence of
serum insulin was not substantial enough to maintain an effect, if
any, on blood pressure after stopping arginine. Since insulin and
c-peptide concentrations were not altered while taking arginine in
the current study, the effects on blood pressure were likely related
to the arginine-nitric oxide system.
In NO production, citrulline is produced when arginine is
converted by NOS into NO. Citrulline concentration increased
by 30% which suggests that arginine was able to induce NO
generation (Fig. 3). Other cationic amino acids such as lysine
do not decrease blood pressure [15]. The vasodilatory proper-
ties of amino acids appear to be unique to that of L-arginine.
Fig. 3. This figure demonstrates the mean citrulline concentration while
taking oral arginine supplements. The mean difference between the
arginine and the non-arginine ingestion day was significant (p Ͻ 0.05).
Individual determinations at each time point resulted in significant
differences at time 10:00 and 12:00 after correction for multiple com-
parisons (p Ͻ 0.05).
Hyperglycemia and Nitric Oxide (NO) Availability
Acute hyperglycemia is associated with a reduced NO gen-
eration as demonstrated by a reduction in leg blood flow and an
increase in both systolic and diastolic blood pressures in normal
424
VOL. 21, NO. 5

Oral Arginine and Type 2 Diabetes
Fig. 4. This figure demonstrates the hourly mean systolic blood pressure (mean Ϯ SEM) in volunteers with or without oral arginine supplements. ANOVA
testing demonstrated a significant difference during the treatment period (Hour 5:00 to Hour 14:00, i.e., 5:00 AM to 2:00 PM). The effect of arginine on
systolic blood pressure was not significant until 7:00 AM. There was no difference between groups after arginine was discontinued (Hours 15:00 and 16:00).
Please note that the arginine was stopped at hour 14:00 or 2:00 PM. The hypotensive influence was not present one hour after stopping the arginine for systolic
measurements. A significant difference between the two groups at each time point by paired testing is indicated by a star (p Ͻ 0.05).
volunteers [16]. Hyperglycemia has also been shown to reduce
NO production in cultured cells; this may explain why diabetic
patients have a reduced bioavailability of NO [17]. Infusion of
an arginine analog (L-NAME) under hyperglycemic conditions
increases blood pressure more than hyperglycemia alone [16].
This suggests that, while hyperglycemia may increase blood
pressure, the competitive removal of arginine with L-NAME
can increase blood pressure even further. Under hyperglycemic
conditions, arginine administration returns blood pressure to
normal [16]. This suggests that arginine prompts vasodilation
via NO generation even in hyperglycemia.
Similarly to what is seen with acute hyperglycemia, patients
with type 2 diabetes have impaired coronary artery dilation
[18]. While arginine can decrease systemic blood pressure,
intravenous arginine does not improve coronary vasodilation in
patients with type 2 diabetes mellitus [18]. These authors
suggest that the coronary arteries of diabetic patients have an
increased inactivation of nitric oxide. This is consistent with the
current study which demonstrates loss of the hypotensive in-
fluence within one hour of stopping the oral arginine (Figs. 4
and 5). However, other mechanisms [19] may be responsible,
such as a rebound in the sympathetic system or changes in the
renin-aldosterone system [20]. Unfortunately neither of these
were measured in our patients after stopping the oral arginine.
Tissue Arginine and Tetrahydrobiopterin (BH4)
Concentrations in Diabetes
Arginine has been reported to be reduced in the plasma [7,8]
and lacrimal fluid of diabetic patients [21] and in the plasma [1]
and aorta of diabetic animals [19]. Plasma arginine concentra-
tion in the current study (131 Ϯ 5 ␮mol/L) was similar to that
concentration seen in earlier work in obese non-hypertensive
diabetic patients (120 Ϯ 5 ␮mol/L) [8]. Obese non-diabetic
subjects have a lower concentration of plasma arginine (76 Ϯ
4 ␮mol/L; p Ͻ 0.05) when compared to obese diabetic volun-
teers [8]. Normal-weight healthy volunteers also have a re-
duced arginine concentration when compared to normal-weight
diabetic patients (110 Ϯ 7 vs. 85 Ϯ 3 ␮mol/L; p Ͻ 0.05; [8]).
An increased plasma arginine in diabetic patients has also been
seen by others [9]. The reason for the greater arginine concen-
tration in type 2 diabetes is unclear. It is possible that the higher
plasma levels of arginine reflect a deficient intracellular state of
arginine. This may be true because recent data suggests that
arginine fails to improve coronary dilation in patients with type
2 diabetes mellitus [18].
In addition to tissue arginine concentrations, endothelial
tetrahydrobiopterin (BH4) is also reduced in a rat model of
diabetes [22]. BH4 is an important cofactor for NOS which aids
JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION
425

Oral Arginine and Type 2 Diabetes
Fig. 5. This figure demonstrates the hourly mean diastolic blood pressure in volunteers with or without oral arginine supplements. ANOVA testing
demonstrated a significant difference during the treatment period (Hour 5:00 to Hour 14:00, i.e., 5:00 AM to 2:00 PM). There was no difference
between groups after arginine was discontinued (Hour 15:00, 16:00 and 24:00 or 0:00). Please note that the arginine was stopped at hour 14:00 or
2:00 PM. The hypotensive influence was not present one hour after stopping the arginine. Significant difference between the two groups at each time
point by paired testing is indicated by a star (p Ͻ 0.05).
in the binding of arginine for the generation of NO. In the
diabetic rats, tissue concentration of BH4 was only 12% of that
concentration seen in normal rats. The activity of NOS is
dependent on the availability of the cofactor BH4. Administra-
tion of BH4 has recently been shown to improve endothelium-
dependent vasodilation by increasing nitric oxide activity in
patients with type 2 diabetes mellitus [23]. It has also been
shown to increase coronary blood flow in normal volunteers
[24]. Therefore, the administration of arginine may have facil-
itated NO generation, but the transient nature of the effect may
be due to a limitation of other co-factors such as BH4 [22]. This
might explain the shorter half life of NO known to occur in
patients with type 2 diabetes [1,2].
Recently it has also been suggested that deficiency of BH4
may cause NOS to be uncoupled where superoxide production
is increased and NO activity is reduced [18]. In the placenta of
patients with type 1 diabetes mellitus, there is an increased
endothelial generation of superoxide products such as per-
oxynitrite [24]. Oxidation products such as peroxynitrite can
oxidize BH4 and reduce its tissue bioavailability for the gen-
eration of NO [24]. Also, as mentioned above, the BH4 tissue
concentration is reduced in animals with diabetes [22]. Plasma
levels are not reliable due to its rapid oxidation. It has recently
been demonstrated that NOS expression in cardiac muscle is
similar in diabetics and non-diabetics [25]. Therefore, NOS
concentration is less likely to be reduced in diabetes.
Lastly, there has been recent evidence that nitric oxide may
play a role in salt sensitive hypertension. In a rat model of
hypertension, the administration of intravenous L-arginine in-
creases nitric oxide production and prevents salt sensitive hy-
pertension [26]. Intravenous arginine’s influence was also tran-
sient; this suggests other factors play a role in the maintenance
of blood pressure.
In summary, oral arginine increases NO generation as esti-
mated by a small increase in the plasma citrulline concentration in
patients with type 2 diabetes. Oral arginine administration has a
hypotensive influence, but its influence is very short lived. The
limited influence of oral arginine on increasing plasma citrulline
concentrations and decreasing blood pressure in all patients would
suggest that factors such as BH4 may be required to normalize NO
production in patients with type 2 diabetes mellitus.
ACKNOWLEDGMENT
We would like to thank Stephanie Griffiths, Mario Paredes and
Maria Lajoie from the GCRC lab, Jennifer Naritomi, Leah Abel-
lon, Rose Umali, Edmund Aception and Connie Soriano from the
426
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Oral Arginine and Type 2 Diabetes
GCRC, for all their help with obtaining the blood samples and
performing all the biochemical measurements.
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Received January 18, 2002; revision accepted May 20, 2002.
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