What is Arginine?
This in depth information on Arginine is from the Sloan Kettering Cancer
Institute at its website:
http://www.mskcc.org/mskcc/html/76400.cfm
Scientific Name: 2-amino-5-guanidinovaleric acid
Clinical Summary
Arginine is an amino acid that is
synthesized in the body. Oral arginine has been used for various conditions
such as hypertension, angina, atherosclerosis, migraine headache, and
erectile dysfunction. Its vasodilatory properties are thought to be
responsible for the beneficial effects.
Arginine has also been used to enhance wound healing, immune function, and
athletic performance.
Some studies support potential uses of arginine in coronary artery and
peripheral artery diseases (PADs) (10)
(11)
(12)
(13);
however, long term supplementation of arginine may actually worsen PAD
(14).
Furthermore, arginine supplementation does not benefit the blood pressure
and kidney function in women with preeclampsia (15).
Large doses of oral arginine improved subjective assessment of sexual
function in men with organic erectile dysfunction (16).
Arginine added to ibuprofen may increase pain relief in patients with
migraine headaches (17).
In addition, oral arginine has been studied for its effect on modifying or
preventing the development of nitrate tolerance during continuous
transdermal nitroglycerin therapy (18),
and may enhance growth hormone release by inhibition of endogenous
somatostatin (19).
Arginine supplementation by enteral feeding was shown to decrease shock in
severely burned patients (4).
Arginine supplementation has been studied in cancer patients. Postoperative
enteral formulas enhanced with arginine may improve wound healing (1)
and enhance immune status (27).
Food Sources
Nuts, seeds, soy foods, legumes,
and chocolate.
Purported uses
Fatigue
Hypertension
Angina
Atherosclerosis
Wound healing
Immune stimulation
Erectile dysfunction
Migraine headaches
Mechanism of Action
Arginine is unique among amino
acids for its vasodilatory properties (11).
Arginine acts as a precursor for the synthesis of endogenous nitric oxide
(NO) via the action of nitric oxide synthase (NOS). Nitric oxide's functions
as a paracrine-signaling molecule mediating vasodilation and inhibition of
platelet activation, monocyte and leucocyte adhesion, and smooth muscle cell
proliferation. Nitric oxide also helps to control vascular oxidative stress
and redox-regulated gene expression (22).
Arginine is also needed for the synthesis of creatine which is important in
muscle contraction (22).
In colorectal adenoma cells, arginine reduces the expression of survivin, an
inhibitor of apoptosis, and induces iNOS expression (23).
Pharmacokinetics
Absorption
Dietary arginine amounts to approximately 2-6g/day depending on protein
intake levels (21).
The kidney is the main organ for endogenous arginine synthesis from L-ornithine
and L-citrulline precursors. The liver also synthesizes arginine, but it is
reutilized in the urea cycle and therefore contributes little to plasma
arginine fluctuations (22).
After ingestion, a small amount of arginine is metabolized by the liver and
the enterocytes (24).
The enzyme arginase converts arginine to ornithine, with 50% of orally
ingested arginine undergoing this route.
Distribution
Data on the pharmacokinetics of oral arginine in humans is limited. Animal
studies found the highest tissue concentrations in the heart, skin, liver,
small intestine and stomach (22).
Metabolism/Excretion
Half of orally ingested arginine are converted to ornithine by the enzyme
arginase. Normally, most Arginine is reabsorbed in the kidneys.
Warnings
Limited studies suggest that
arginine supplementation may increase breast tumor growth, but more research
is needed to examine this (9)
(21).
Adverse Reactions
Large doses of > 10g/day are
not associated with reported significant side effects or toxicities.
Abdominal pain, bloating,
nausea and diarrhea have been reported with oral administration (5)
(8)
(20).
Herb-Drug Interactions
Large doses of arginine can
increase urinary excretion of lysine (21).
Due to arginines vasodilatory
properties, theoretically it may have additive hypotensive effects with
drugs such as antihypertensives, sildenafil and nitrates (11)
(20).
Lab Interactions
High doses of intravenous
arginine may results in the spillover into urine (22).
Literature Summary and Critique
Wilson
AM, et al. L-arginine supplementation in peripheral arterial disease: no
benefit and possible harm.
Circulation. Jul 10 2007;116(2):188-195.
Because arginine supplementation provides short-term benefits to patients
with peripheral artery disease (PAD), the objective of the Nitric Oxide in
Peripheral Arterial Insufficiency (NO-PAIN) study, a prospective,
randomized, double-blind, placebo-controlled trial, was to assess its
long-term benefits. After 6 months of arginine (3 g/day) or placebo, 133
participants with PAD were examined for claudication distance and NO
availability. Reduced improvements in NO, flow-mediated vasodilation, and
walking distance were detected in participants receiving arginine as
compared to the placebo group. The discordance between previously reported
short-term studies and this long-term study may be due to unknown
counterregulatory mechanisms such as arginase induction.
Lucotti P, et al. Beneficial effects of a
long-term oral L-arginine treatment added to a hypocaloric diet and exercise
training program in obese, insulin-resistant type 2 diabetic patients.
Am J Physiol
Endocrinol Metab. Nov 2006;291(5):E906-912.
The effect of arginine supplementation (8.3 g/day) was assessed in this
study of 33 middle-aged, obese, type 2 diabetic participants undergoing an
exercise training program and a hypocaloric diet. After 21 days,
participants receiving arginine supplementation showed greater improvements
in body composition as assessed by reduced fat mass and waste circumference
as well as improved glucose tolerance as compared to the control group.
Long-term studies are required to determine if arginine supplementation
further reduces cardiovascular disease in these subjects.
Matsuda A, Takasaki H, Suzuki H, et al.
Preoperative Oral Immune-Enhancing Nutritional Supplementation Corrects
Th1/Th2 Imbalance in Patients Undergoing Elective Surgery for Colorectal
Cancer. Dis Colon Rectum
2006 ;49(4):507-16.
Thirty-six patients with colorectal cancer scheduled for
surgery were randomly divided into two groups; 19 patients received
preoperative 750ml/day oral supplementation containing arginine, omega-3
fatty acids and ribonucleic acid for five days. The control group did not
receive oral supplementation pre or post-operatively. Peripheral blood
samples were drawn on the morning of surgery and 3, 7 and 14 days
postoperatively. Flow cytometry determined the proportions of CD4+ T cells
producing intracellular cytokines. Th1/Th2 balance shifted to Th2 dominance
in the control group. Th2 dominance is associated with immune suppression in
the cancer bearing state preoperatively, and surgical stress
postoperatively. The supplemented group maintained the preoperative levels
of Th1/Th2 until day 14. Preoperative immunonutrition may correct the
altered Th1/Th2 balance in the preoperative cancer-bearing state and
postoperatively.
Palloshi A, Fragasso G, Piatti P, et al. Effect of oral L-arginine on blood
pressure and symptoms and endothelial function in patients with systemic
hypertension, positive exercise tests, and normal coronary arteries.
Am J Cardiol. 2004;93(7):933-935.
Thirteen patients with grade 2 to 3 hypertension, microvascular angina and
positive exercise tests received 2 grams of oral Arginine for 4 weeks. The
patients were on full antihypertensive and antianginal therapy aimed at
optimal control of blood pressure. Compared with baseline measurements,
Arginine supplementation significantly decreased mean systolic blood
pressure at rest (166 +/- 27 to 146 +/- 12 mm Hg; p<0.005). The frequency of
angina attacks decreased from 12 +/- 3 to 4 +/- 1 per week, and
nitroglycerin use decreased from 9 +/ 2 to 3 +/- 1 per week. The patients
self-rated overall quality of life increased. (p values < 0.001) The authors
suggest that Arginine may represent a useful therapeutic option for
hypertension and microvascular angina, However, this study is based on a
small sample size. Large well-designed clinical trials are needed to confirm
this effect.
References
1. Farreras N, Artigas V, Cardona
D, Rius X, Trias M, Gonzalez JA.
Effect of early
postoperative enteral immunonutrition on wound healing in patients
undergoing surgery for gastric cancer. Clin Nutr.
2005;24(1):55-65.
2. de Luis DA, Izaola O, Cuellar L, Terroba MC, Aller R.
Randomized clinical trial with an enteral arginine-enhanced formula in
early postsurgical head and neck cancer patients.
Eur J Clin Nutr. 2004;58(11):1505-1508.
3. Casas-Rodera P, Gomez-Candela C, Benitez S, et al.
Immunoenhanced enteral nutrition formulas in head and neck cancer surgery:
a prospective, randomized clinical trial.
Nutr Hosp. Mar-Apr 2008;23(2):105-110.
4. Yan H, Peng X, Huang Y, Zhao M, Li F, Wang P.
Effects of early enteral arginine supplementation on resuscitation of
severe burn patients. Burns. Mar
2007;33(2):179-184.
5. Brittenden J, Park KG, Heys SD, et al.
L-arginine stimulates host defenses in patients with breast cancer.
Surgery. 1994;115(2):205-212.
6. Heys SD, Ogston K, Miller I, et al.
Potentiation of the response to chemotherapy in patients with breast
cancer by dietary supplementation with L-arginine: results of a randomised
controlled trial. Int J Oncol.
1998;12(1):221-225.
7. Chander V, Chopra K.
Effect of molsidomine and L-arginine
in cyclosporine nephrotoxicity: role of nitric oxide.
Toxicology. 28 2005;207(3):463-474.
8. Shihab FS, Bennett WM, Isaac J, Yi H, Andoh TF.
Nitric oxide modulates vascular endothelial growth factor and receptors in
chronic cyclosporine nephrotoxicity.
Kidney Int. 2003;63(2):522-533.
9. Park KG, Heys SD, Blessing K, et al.
Stimulation of human breast cancers by dietary L-arginine.
Clin Sci (Lond) 1992;82(4):413-417.
10. Gornik HL, Creager MA.
Arginine and endothelial and
vascular health. J Nutr. 2004;134(10
Suppl):2880S-2887S; discussion 2895S.
11. Huynh NT, Tayek JA.
Oral arginine reduces
systemic blood pressure in type 2 diabetes: its potential role in nitric
oxide generation.
J Am Coll Nutr. 2002;21(5):422-427.
12. Palloshi A, Fragasso G, Piatti P, et al.
Effect of oral L-arginine on blood pressure and symptoms and endothelial
function in patients with systemic hypertension, positive exercise tests,
and normal coronary arteries. Am J
Cardiol. 2004;93(7):933-935.
13. Siasos G, Tousoulis D, Vlachopoulos C, et al.
Short-term treatment with L-arginine prevents the smoking-induced
impairment of endothelial function and vascular elastic properties in young
individuals.Int
J Cardiol. Jun 6
2008;126(3):394-399.
14. Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP.
L-arginine supplementation in peripheral arterial disease: no benefit and
possible harm.Circulation.
Jul 10 2007;116(2):188-195.
15. Hladunewich MA, Derby GC, Lafayette RA, Blouch KL, Druzin ML, Myers BD.
Effect of L-arginine therapy on the glomerular injury of preeclampsia: a
randomized controlled trial.
Obstet Gynecol. 2006;107(4):886-895.
16. Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H.
Effect of oral administration of high-dose nitric oxide donor L-arginine
in men with organic erectile dysfunction: results of a double-blind,
randomized, placebo-controlled study.
BJU Int. 1999;83(3):269-273.
17. Sandrini G, Franchini S, Lanfranchi S, Granella F, Manzoni GC, Nappi G.
Effectiveness of ibuprofen-arginine in the treatment of acute migraine
attacks. Int J Clin Pharmacol Res.
1998;18(3):145-150.
18. Parker JO, Parker JD, Caldwell RW, Farrell B, Kaesemeyer WH.
The effect of supplemental L-arginine on tolerance development during
continuous transdermal nitroglycerin therapy.
J Am Coll Cardiol. 3 2002;39(7):1199-1203.
19. Loche S, Carta D, Muntoni AC, Corda R, Pintor C.
Oral administration of arginine enhances the growth hormone response to
growth hormone releasing hormone in short children.
Acta Paediatr.
1993;82(10):883-884.
20. Cheng JW, Baldwin SN.
L-arginine in the management
of cardiovascular diseases. Ann
Pharmacother. 2001;35(6):755-764.
21. Wilmore D.
Enteral and parenteral
arginine supplementation to improve medical outcomes in hospitalized
patients.
J Nutr. 2004;134(10 Suppl):2863S-2867S; discussion 2895S.
22. Boger RH, Bode-Boger SM.
The clinical pharmacology of
L-arginine. Annu Rev
Pharmacol Toxicol. 2001;41:79-99.
23. Ma Q, Wang Y, Gao X, Ma Z, Song Z.
L-arginine reduces cell proliferation and ornithine decarboxylase activity
in patients with colorectal adenoma and adenocarcinoma.
Clin Cancer Res. Dec 15 2007;13(24):7407-7412.
24. Paddon-Jones D, Borsheim E, Wolfe RR.
Potential ergogenic effects of arginine and creatine supplementation.
J Nutr. 2004;134(10 Suppl):2888S-2894S; discussion 2895S.
25. Lucotti P, Setola E, Monti LD, et al.
Beneficial effects of a long-term oral L-arginine treatment added to a
hypocaloric diet and exercise training program in obese, insulin-resistant
type 2 diabetic patients. Am J Physiol
Endocrinol Metab. Nov 2006;291(5):E906-912.
26. Matsuda A, Furukawa K, Takasaki H, et al.
Preoperative oral immune-enhancing nutritional supplementation corrects
TH1/TH2 imbalance in patients undergoing elective surgery for colorectal
cancer. Dis Colon Rectum. Apr
2006;49(4):507-516.
27. Okamoto Y, Okano K, Izuishi K, et al.
Attenuation of the Systemic Inflammatory Response and Infectious
Complications After Gastrectomy with Preoperative Oral Arginine and omega-3
Fatty Acids Supplemented Immunonutrition.
World J Surg. 2009, Jul 23. [Epub ahead of print]
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