L-Arginine Information

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Facts

L-arginine is a naturally occurring amino acid.

L-arginine is necessary for the production of nitric oxide and other mediators in the inflammatory process.

L-arginine is involved in the urea cycle, which converts ammonia to urea, in the synthesis of creatine, and in the production of agmatine (which may be a neurotransmitter).

Arginine is a basic amino acid which is considered semi-essential. Although it can be synthesized from amphibolic intermediates and 7 enzymes, it cannot be produced at rates sufficient to support growth and must therefore be ingested in the diet.

Functions Topic header down arrow

L-arginine is the principal physiologic precursor of nitric oxide (a key signaling molecule) which plays a versatile role in physiology.

L-arginine is the substrate for the enzyme nitric oxide synthase (NOS).

L-arginine also plays a role in maintaining the physiology of the gastrointestinal tract, and leads to the production of nitric oxide which affects a number of regulatory mechanisms including: vasodilatation and endothelial function, neurotransmission and neuromodulation, modulation of leukocyte adhesion, insulin sensitivity, inhibition of platelet aggregation, and reduction of oxidative stress.

Dosage Topic header down arrow

Arginine is classified as a semi-essential or conditionally essential amino acid. Although it can be made in the body from L-citrulline in an ATP-dependent process, it appears that dietary or supplemental L-arginine is key to adequate production of nitric oxide. Production of nitric oxide is mediated by nitric oxide synthase which is inhibited by hypercholesterolemia, oxidative stress, and asymmetrical dimethyl arginine (ADMA) which a methylated isomer of L-arginine derived from protein. Arginine is essential for critically ill patients, young children, certain rare genetic disorders causing impaired L-arginine synthesis, stress conditions including trauma, surgery, sepsis, and burns, vascular disease, and chronic renal failure.

Toxicity Topic header down arrow

L-arginine has been generally well tolerated by healthy volunteers as well as patients who have taken oral doses up 30 grams. Although the vasodilator action of L-arginine may lead to hypotension, the effects on blood pressure are usually low. Side effects are rare, mild, and dose dependent. Side effects include a bitter taste, nausea, and vomiting in about 3% of patients taking L-arginine higher doses. A metabolic condition involving elevated arginine levels is known as hyperargininemia results from a defect in urea synthesis. This condition is characterized by increased arginine levels in cerebrospinal fluid, low erythrocyte levels of arginase and a urinary amino acid pattern similar to that seen in patients with lysine-cystinuria. Hyperargininemia is not associated with L-arginine supplements

Dietary Sources Topic header down arrow

The typical dietary intake of L-arginine is 3.5 to 5.0 grams daily mainly derived from plant or animal foods. Small amounts of free L-arginine are found in fruits and vegetables and in some fermented foods such as miso and yogurt. Soy protein is particularly high in L-arginine, whereas other protein sources tend to be high in lysine which competes with L-arginine.

Drug-Supplement Interaction Topic header down arrow

L-arginine may enhance the intestinal absorption of low molecular weight heparin.

Ornithine and lysine (amino acids) compete with arginine for absorption from the gut.

L-arginine may counteract the sodium preserving (antinatriuretic) effect of cyclosporine.

Absorption of ibuprofen is enhanced by arginine.

Ascorbic acid is necessary to convert L-arginine to nitric oxide

Sidenafil citrate has theoretically been noted to have an increased effect when taken concomitantly with L-arginine. Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.

Research Summary Topic header down arrow

Topic: Cardiovascular health



	Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans.
	This double-blind, placebo-controlled study investigated the effect of dietary supplementation with L-arginine on vascular or platelet derived nitric oxide activity in hypercholesterolemic people. Twenty-three hypercholesterolemic people and 14 normocholesterolemic people participated in the trial. Hypercholesterolemic subjects were randomized to receive 8.4 g L-arginine hydrochloride daily or a placebo for two weeks. Platelet rich plasma samples were collected at baseline, after two weeks of supplementation, after two weeks of washout, and after an additional sixteen weeks of washout. At baseline, platelet aggregation was higher in hypercholesterolemic subjects than in controls. After two weeks of supplementation with L-arginine, platelet aggregation was modestly reduced. This benefit persisted for two weeks after supplementation was discontinued. By sixteen weeks, measures of aggregation had returned to baseline. These data are consistent with previous studies in hypercholesterolemic animals, and demonstrated that L-arginine restored endogenous nitric oxide activity and inhibited platelet aggregation.¹
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	Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans.
	A double-blind, randomized study evaluated the effect of oral L-arginine supplementation on coronary small-vessel endothelial function. Twenty-six people with nonobstructive coronary artery disease were randomly assigned to receive 3 g L-arginine three times daily or a placebo for six months. Endothelium dependent coronary blood flow was assessed at baseline and after six months of supplementation. Blood flow in response to acetylcholine was significantly increased after L-arginine supplementation. A decrease in plasma endothelin concentration and an improvement in symptoms also accompanied L-arginine supplementation. The authors concluded that L-arginine be a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease. ²
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	L-arginine improves endothelial function and reduces LDL oxidation in patients with stable coronary artery disease.
	A randomized, crossover design study investigated the effects of oral L-arginine on endothelial function, intravascular oxidative stress, and circulating inflammatory markers in patients with stable coronary artery disease. This 4 week long study supplemented 31 people with stable coronary artery disease (CAD) with 10 g L-arginine or 500 mg vitamin C daily. Both L-arginine and vitamin C significantly increased brachial artery flow-mediated dilation. Consumption of L-arginine for four weeks significantly improved measures of LDL cholesterol oxidation susceptibility. These results indicate that oral L-arginine supplementation improved endothelial function and reduced LDL oxidation in stable CAD patients but did not affect lipid profiles. ³
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	Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.
	Forty patients with severe congestive heart failure participated in a study to investigate the effects of L-arginine and exercise training on endothelial dysfunction. Subjects were randomized to receive daily 8 g L-arginine, handgrip training, both, or neither for four weeks. Internal radial artery diameter was increased by 8.8% with L-arginine supplementation, by 8.6% with daily handgrip training, and by 12.0% with both compared to control. These data indicate that dietary L-arginine supplementation and regular exercise improved agonist-mediated, endothelium-dependent vasodilation. Combination of exercise and L-arginine supplementation produced added benefits. ⁴
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	Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults.
	A randomized double-blind, crossover design study investigated the effects of 7 g L-arginine three times daily for four weeks on endothelium-dependent dilation. Twenty-seven young adults (between 19 and 40 years) received the L-arginine supplements or placebo for four weeks followed by a four week washout and then a crossover phase. L-arginine supplementation improved endothelium-dependent dilation from 1.7 to 5.6%. These results suggest that by affecting a favorable change in the balance between nitric oxide production and catabolism, L-arginine may provide vascular protection. The authors propose that these findings may provide another beneficial approach for treating individuals with cardiovascular disease risk factors. ⁵
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	Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans.
	The efficacy of L-arginine supplements for lowering plasma asymmetric dimethylarginine (ADMA) was evaluated in 24 hypercholesterolemic patients at the Stanford University Preventive Medicine and Vascular Medicine clinics. Ten patients were randomized to receive either 14 or 21 g L-arginine hydrochloride daily for twelve weeks; the remaining 14 hypercholesterolemic subjects did not take a supplement. The study also included ten normocholesterolemic, age-matched controls. Hypercholesterolemic patients had increased plasma ADMA levels at baseline. Increased plasma ADMA levels were associated with increased adhesiveness of mononuclear cells. L-arginine supplements normalized plasma L-arginine:ADMA ratios. Concomitant reductions of mononuclear cell adhesiveness were noted. These findings suggest that supplementing with L-arginine may be useful in circumventing the development of atherosclerosis.⁶
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	Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease.
	A prospective, double-blind, randomized crossover trial investigated the effects of L-arginine supplements on endothelium dependent dilation and mononuclear cell adhesiveness in men with coronary atherosclerosis. Ten men (aged 41 ± 2 years) with angiographically proven coronary atherosclerosis consumed 7 g L-arginine three times daily or a placebo for 3 days, separated by a 10 day washout period. Cell adhesion was then compared between samples taken from the two groups. Results showed that adhesion was significantly reduced following L-arginine supplementation compared to placebo. The authors concluded that oral L-arginine improves endothelium-dependent dilation and reduces monocyte and endothelial cell adhesion.⁷
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	Oral L-arginine improves endothelial function in healthy individuals older than 70 years
	In a prospective, double blind, randomized crossover trial, 12 healthy elderly subjects (over the age of 70) consumed L-arginine daily to assess the efficacy of this supplement for improving endothelial function. Each subject consumed 16 g L-arginine or a placebo for fourteen days separated by a fourteen day washout period. L-arginine supplementation normalized the L-arginine:ADMA ratio and significantly improved flow mediated dilation of the brachial artery. The authors concluded that endothelial function is likely impaired in the elderly due to an imbalance of L-arginine to asymmetric dimethyl L-arginine and that supplementing this nutrient may help to normalize this ratio. ⁸
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	A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease.
	A randomized, placebo-controlled evaluated the efficacy of L-arginine for people with peripheral artery disease (PAD). Eighty people with PAD enrolled in the study and were randomly assigned to consume 0, 3, 6, or 9 grams of L-arginine daily in three divided doses for 12 weeks. There was a statistically significant reduction in hematocrit for those who consumed L-arginine; no changes in claudication (pain and fatigue in the arms and legs) were noted. With the 3 g/day supplement, there was a trend to increase walking distance by twelve weeks, althouth this change did not reach significance. There was also a trend to improvement in walking speed for all subjects supplemented with L-arginine, also not statistically significant. This study indicates that L-arginine supplementation may be beneficial for people with PAD. Further studies are needed to investigate these possible benefits.⁹
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	Oral L-arginine improves endothelial dysfunction in patients with essential hypertension.
	A prospective randomized double blind trial, 35 people with essential hypertension received either 6 g L-arginine or placebo. Acute effects of L-arginine supplementation on flow mediated endothelium-dependent dilation were determined. Flow-mediated endothelium-dependent dilation was measured before and 1.5 hours after consumption of the L-arginine supplement or placebo. L-arginine resulted in a significant improvement of flow-mediated dilation. The authors concluded that, for people with essential hypertension, L-arginine supplementation acutely improves endothelium-dependent, flow-mediated dilation of the brachial artery.¹⁰
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	The effects of sustained-release-L-arginine formulation on blood pressure and vascular compliance in 29 healthy individuals.
	In this study, 29 healthy, asymptomatic individuals consumed 2.1 g L-arginine daily for one week. Systolic and diastolic blood pressure were non-significantly decreased in 62% and 69% of subjects, respectively. People who had borderline or frank hypertension exhibited significant reductions in blood pressure with an average decrease of 11 mmHg for systolic pressure. A 23% significant increase in large artery compliance and a 23% non-significant increase in small artery compliance resulted. Improvements in blood pressure for people with hypertension, as well as improved vascular compliance, were noted after one week of supplementation with L-arginine. ¹¹
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Topic: Neurology



	Endothelial dysfunction in MELAS improved by L-arginine supplementation.
	The endothelial dysfunction and stroke associated with mitochondrial myopathy, encephalopathy, lactic acidosis (MELA) were assessed by flow-mediated vasodilatation (FMD). Participants consumed oral L-arginine supplements for a period of two years. L-arginine supplementation improved endothelial function among the study group and normalized plasma levels of L-arginine. L-arginine may have potential to improve endothelial dysfunction and stroke associated with MELA. Further studies are necessary.¹²
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Topic: Diabetes and Obesity



	Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients.
	This three month long double blind study included 37 lean people with type 2 diabetes and included 40 normal controls. The goal was to determine whether oral supplementation with 3 grams of L-arginine 3 times daily could improve peripheral and hepatic insulin sensitivity. L-arginine significantly increased forearm blood flow (36%), decreased systolic blood pressure (14%) and decreased endogenous glucose production (29%). L-arginine also normalized basal cyclic GMP levels. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. The authors conclude that L-arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients.¹³
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	Beneficial effects of oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin resistant Type 2 diabetic patients.
	Thirty-three nonobese people with type 2 diabetes consumed a hypocaloric diet and participated in an exercise training program for 21 days. In addition, participants were randomly assigned to consume 8.3 g of L-arginine daily or a placebo. While diet and exercise reduced fat mass, L-arginine supplementation further decreased fat mass while preserving muscle-free fat-mass and decreased waist circumference. L-arginine supplementation also improved measures of glucose metabolism, insulin sensitivity, endothelial function, and oxidative stress. These data suggest that L-arginine with exercise and diet have an additive effect on glucose metabolism and insulin sensitivity. ⁴
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	L-Arginine reduces lipid peroxidation in patients with diabetes mellitus.
	This study focused on diabetic long term complications involving oxidative stress including lipid peroxidation. This was a blind, placebo-controlled, crossover-design study in which each group consumed 1 g L-arginine for three months, either preceeded or followed by three months of placebo. After three months of L-arginine supplementation, there was a significant decrease in malondialdehyde levels. The results showed evidence that L-arginine may counteract oxidative stress and thus may be beneficial for preventing long-term complications in diabetes mellitus.¹⁵
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Topic: Men’s health



	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.
	A double-blind, randomized, placebo-controlled study investigated the effects of L-arginine supplementation in men with organic erectile dysfunction. This six week study included 50 men with confirmed organic erectile dysfunction who were randomized after a 2-week placebo run-in period to receive either 5 g L-arginine or placebo daily. Thirty-one percent of the patients taking L-arginine reported significant subjective improvement in sexual function. All of the patients who responded to treatment had initially low urinary NOx levels. By the end of the study all of these patients’ NOx levels had improved. This small study suggests that L-arginine supplementation may improve organic erectile dysfunction for men with low urinary NOx levels.¹⁶
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Topic: Interstitial cystitis



	A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis.
	A double-blind, placebo-controlled crossover study focused on the effects of oral L-arginine supplementation on the severity of symptoms commonly associated with interstitial cystitis. Sixteen people with interstitial cystitis enrolled in the study and were randomized to receive either 2.4 g L-arginine or a placebo daily. After a two week washout period, subjects received the other supplement. Although recorded variables in regard to voided volume, frequency and nocturna were not significantly different between the group consuming L-arginine and the group taking the placebo, oral L-arginine produced a statistically significant improvement in the subjective symptom index. The authors do not recommend L-arginine supplements for interstitial cystitis. ¹⁷
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	A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis.
	A randomized, double-blind trial investigated the efficacy of oral L-arginine for the treatment of interstitial cystitis. Forty-six people with interstitial cystitis were randomized to receive 1.5 g L-arginine or a placebo for three months. At the end of the trial, 29% of the L-arginine supplemented group and 8% of the placebo group had improved symptoms. Oral supplementation with 1.5 grams with L-arginine may decrease pain and urgency symptoms for some people with interstitial cystitis. ¹⁸
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