L-arginine
Common Name(s): L-arginine
Clinical Overview
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Uses of L-arginine
L-arginine is a nonessential amino acid suggested to play an important role in the treatment of cardiovascular and other diseases. It has been promoted as a growth stimulant and as a treatment of erectile disfunction in men.
L-arginine Dosing
L-arginine has been studied at oral doses of 6 to 30 g/day for a variety of conditions. Parenteral administration has also been used.
Contraindications
Absolute contraindications have not yet been identified. L-arginine is not recommended in patients following an acute myocardial infarction.
Pregnancy/Lactation
Specific information regarding safety and efficacy in pregnancy and lactation is lacking, although several trials have been conducted in pregnant women without notable ill effects.
L-arginine Interactions
L-arginine has unpredictable effects on insulin and cholesterol-lowering agents. L-arginine may potentiate the effects of isosorbide mononitrate and other nitric oxide donors such as glyceryl trinitrate and sodium nitroprusside.
L-arginine Adverse Reactions
L-arginine has few reported adverse reactions. Nausea and diarrhea have been reported infrequently.
Toxicology
Parenteral administration of L-arginine in high doses has caused metabolic acidosis. High concentrations of nitric oxide are considered toxic to brain tissue.
Sources of the amino acid arginine are meats, milk, ground nuts, and eggs. 1 The physiologically active form, L-arginine, is the natural product obtained by enzymatic or chemical hydrolysis of proteins. In the laboratory, arginine can be precipitated from gelatin hydrolysate. L-arginine can also be synthesized from L-ornithine and cyanamide in aqueous solution in the presence of Ba(OH) 2 . 2 Because L-arginine can be synthesized endogenously from L-citrulline, it is classified as a nonessential amino acid in adults. However, in children and in people with certain conditions (eg, infection, trauma), L-arginine synthesis may become compromised and it then may be considered semiessential. 3
History
L-arginine is commonly sold as a health supplement claimed to be capable of improving vascular health 4 and treating erectile disfunction in men. 5 L-arginine, which is promoted as a human growth stimulant, 6 has also been used in bodybuilding. 7
L-arginine Uses and Pharmacology
The use of L-arginine supplementation to raise nitric oxide levels has been suggested to be beneficial in many areas. Nitric oxide is produced by a variety of animal and human cells and is involved in many physiological and pathophysiological processes. 8 It is generated from L-arginine by the enzyme nitric oxide synthase. 9
Most studies affirm stereospecificity of nitric oxide synthase for L-arginine, but trial results in steroid-naive asthmatic patients found concentrations of exhaled nitric oxide to be similar for patients administered either L- or D-arginine, suggesting an alternate mechanism of action. 10
Nutritional/metabolic/immunostimulatory actionAnimal data
Arginine is classified as a nonessential amino acid but may be considered essential or semiessential in stressful situations, including periods of growth (ie, during childhood or pregnancy) or trauma to the body (eg, liver disease, severe sepsis, wound healing). 11 , 12 , 13
In jaundiced rats, L-arginine supplementation demonstrated anabolic and immunostimulatory properties. 14 Anabolic actions were also confirmed in studies of L-arginine supplementation and improved wound healing, 8 , 15 , 16 , 17 including healing of bone, burns, GI tract, and tendons. 9 , 18 , 19 , 20 Researchers suggest one mechanism to be credited to the enzyme arginase, which produces a favorable environment for fibroblast and collagen production. 21 L-arginine exhibited protective effects in spinal cord injury in animals 22 and in cortical impact injury in rats. 23 In another study, exogenous L-arginine resulted in decreased hepatic ischemia/reperfusion injury. 24
Clinical dataIn a randomized clinical trial of HIV-negative patients with tuberculosis, arginine supplementation resulted in increased weight gain, higher sputum conversion rates, and faster reduction of symptoms such as cough. 25 However, these improvements were not seen in HIV-positive patients in the same trial nor in HIV-positive patients in another small trial. 25 , 26
Despite achieving an improvement in airway nitric oxide levels in a clinical trial of patients with cystic fibrosis, researchers were not able to show clinical improvement in forced expiratory volume. 27
Studies in malnourished patients with head and neck cancer showed significantly lower fistula rates, decreased length of stay, and a trend toward improved survival, while other trials were unable to demonstrate a positive clinical outcome. 28 , 29 , 30
In severely burned patients, net arginine loss increased and parenteral supplementation of arginine was considered essential to maintain adequate levels of nitric oxide. 31
In 2 randomized clinical trials of premature infants, arginine supplementation reduced the risk of necrotizing enterocolitis. This effect was thought to be related to nitric oxide regulation of vasomotor functioning of the intestinal vessels, as well as to regulation of peristalsis and modulation of inflammatory response in the intestine. 32 , 33 Another study in healthy volunteers failed to demonstrate an effect on intestinal cytokines, making the role of arginine in inflammatory bowel disease unclear. 34 Caution is advised in recommending arginine as a supplement for premature infants because of its ability to alter homeostasis (with hypo- and hyperglycemia demonstrated) and because of histaminic side effects. 35
Cardiovascular healthStudies in animal models and clinical trials have described some properties of nitric oxide that may influence cardiovascular health. 36 , 37 , 38 , 39 , 40
Nitric oxide had a direct scavenging effect on superoxide radicals, inhibited platelet adhesion and aggregation, and modulated endothelial permeability. 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 A deficiency in nitric oxide or impaired nitric oxide synthesis has been linked to arterial stiffness, 46 , 49 , 50 , 51 , 52 , 53 and a neuromodulatory effect on the vagus has been described. 50 , 54 In human microvascular endothelial cells, nitric oxide regulated tissue factor, reducing its endotoxin and cytokine-induced expression. 55
Increased concentrations of L-arginine may improve vascular disease by maintaining nitric oxide levels. 36 , 37 , 38 , 56
Clinical dataIn a randomized clinical trial designed to evaluate the effect of L-arginine supplementation for 6 months (9 g/day) following an acute ST-segment elevation myocardial infarction, no significant change in vascular stiffness or left ejection fraction was shown. However, in the L-arginine group, 8.6% of the patients died, while no deaths occurred in the control group ( P = 0.01) and the trial was terminated. Researchers concluded that L-arginine should not be given to patients following an acute myocardial infarction and suggested that diffuse atherosclerosis in older patients may worsen the clinical outcome. 53
L-arginine produced peripheral vasodilation in coronary heart disease patients in one trial. 57 In another clinical trial, oral L-arginine therapy was ineffective in improving nitric oxide bioavailability in coronary artery disease patients. 58 Patients with angina showed improved exercise tolerance after L-arginine supplementation. 59
Patients with peripheral artery disease experienced improved walking distances with L-arginine supplementation of 16 g daily for 14 days. 4
L-arginine was demonstrated to improve cardiac performance in severe congestive heart failure (CHF) patients, 41 , 61 but in another trial of patients with CHF, all hemodynamic variables remained unchanged with L-arginine supplementation. In the same study, L-arginine caused an increase in stroke volume and cardiac index in healthy controls. 45
Low-dose, L-arginine-enriched blood demonstrated a protective effect in ischemia/reperfusion injury, with a lower incidence of perioperative myocardial infarction and a decreased length of stay in the intensive care unit and hospital. 51
StrokeA Cochrane review of randomized clinical trials concluded that there is insufficient evidence on the effects of nitric oxide donors, L-arginine, or nitric oxide synthase inhibitors to recommend their use in acute ischemic stroke. Nitric oxide may act as a vasodilator and as an inhibitor of platelet aggregation, among other possible mechanisms. 62 , 63
High concentrations of nitric oxide are considered toxic to brain tissue. 62
Renal diseaseDespite a theoretical rationale for nitric oxide supplementation in renal disease 64 , 65 and positive results derived in animal models, arginine supplementation did not improve endothelial dysfunction in children with chronic renal failure, 66 nor was it protective against contrast media-induced nephrotoxicity in adults with chronic renal failure. 67
DiabetesA long-term study of L-arginine supplementation (9 g daily for 1 month) in lean, type 2 diabetic patients improved peripheral and hepatic insulin sensitivity. No changes in body weight, glycated hemoglobin, serum potassium, diastolic blood pressure, or heart rate were demonstrated. Systolic blood pressure was significantly decreased in the L-arginine group. 68
In a smaller trial, oral administration of low-dose arginine similar to that ingested in a high-protein meal did not produce an increase in insulin concentration but did enhance glucagon levels. 69
In a study of the vasodilator effects of L-arginine, co-infusion with insulin enhanced the potency of arginine with increases in renal and ocular hemodynamic parameters. 70 In a trial studying the effect of an acute infusion of arginine 3 g in type 2 diabetic patients, total plasma homocysteine concentration was decreased, oxidative stress was counteracted, and availability of nitric oxide was increased. 71
Obstetrics/gynecologyIn a randomized clinical trial of hypertensive pregnant women, an infusion of arginine 20 g per 500 mL produced a hypotensive effect on systolic and diastolic pressure. Fetal heart rate was not affected. 72 Another trial in women with preeclampsia showed no effect on mean diastolic pressure after 2 days of oral treatment with 12 g/day arginine. 73
A clinical trial evaluating intrauterine growth restriction therapy with L-arginine 3 g/day for 20 days compared with no intervention demonstrated an improvement in the weight of the newborn infants. 74
In a randomized clinical trial of adjuvant arginine 16 g/ day in ovarian hyperstimulation, an increased recruitment of follicles was found, but embryo quality and pregnancy rate were higher in the placebo arm. 75
OphthalmicIn a randomized clinical trial of an infusion of arginine 1 g/min for 30 minutes in healthy adults, a reduction in mean arterial pressure and an increase in retinal and choroidal blood flow was shown. The effect was apparent for 30 minutes after the infusion ended, and researchers suggest a role for arginine in ocular diseases associated with endothelial dysfunction, such as in diabetes or glaucoma. 76
In another study of the vasodilator effects of arginine in healthy adults, similar hemodynamic effects were demonstrated. 70
Other usesOther reported effects of L-arginine include increasing quantity and cytotoxic capability of lymphokine-activated and natural killer T-cells in breast cancer. 77
Relaxation of cavernous smooth muscle in the penis requires nitric oxide synthesized by L-arginine, suggesting a role in erectile dysfunction. Studies in rats produced an erectile response and altered vascular tone, 78 but in a clinical trial in humans, no difference was established between L-arginine 500 mg 3 times daily and placebo. 79
Dosage
L-arginine has been studied at oral doses of 6 to 30 g/day for a variety of conditions. Parenteral administration has also been used.
Pregnancy/Lactation
Specific information regarding safety and efficacy in pregnancy and lactation is lacking, although several trials have been conducted in pregnant women without notable ill effects. 72 , 73 , 74 , 75
Interactions
L-arginine has unpredictable effects on insulin and cholesterol-lowering agents. 68 , 69 , 80 L-arginine may potentiate the effects of isosorbide mononitrate and other nitric oxide donors such as glyceryl trinitrate and sodium nitroprusside. 50
Adverse Reactions
Oral administration of L-arginine (up to 30 g/day) in humans does not appear to cause any major adverse reactions, with only infrequent reports of nausea and diarrhea. 33 , 75 In a trial of malnourished patients with head and neck cancer, the incidence of diarrhea was higher compared with standard therapy. 30 No adverse reactions were reported with L-arginine 9 g/day over 6 months. 59 L-arginine may exacerbate sickle cell crisis and may trigger onset of herpes infection, although there is no solid evidence to confirm either effect. 81
Toxicology
Parenteral administration of L-arginine in high doses has caused metabolic acidosis, including elevated potassium levels caused by effects on intra- and extracellular potassium balance. 3 High concentrations of nitric oxide are considered toxic to brain tissue. 62
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46. Lekakis JP , Papathanassiou S , Papaioannou TG , et al . Oral L-arginine improves endothelial dysfunction in patients with essential hypertension . Int J Cardiol . 2002;86:317-323.
47. Brandes RP , Brandes S , Boger RH , Bode-Boger SM , Mugge A . L-arginine supplementation in hypercholesterolemic rabbits normalizes leukocyte adhesion to non-endothelial matrix . Life Sci . 2000;66:1519-1524.
48. Garlichs CD , Beyer J , Zhang H , et al . Decreased plasma concentrations of L-hydroxy-arginine as a marker of reduced NO formation in patients with combined cardiovascular risk factors . J Lab Clin Med . 2000;135:419-425.
49. Nagaya N , Uematsu M , Oya H , et al . Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension . Am J Respir Crit Care Med . 2001;163:887-891.
50. Stokes GS , Barin ES , Gilfillan KL , Kaesemeyer WH . Interactions of L-arginine, isosorbide mononitrate, and angiotensin II inhibitors on arterial pulse wave . Am J Hypertens . 2003;16(9 pt 1):719-724.
51. Kiziltepe U , Tunctan B , Eyileten ZB , et al . Efficiency of L-arginine enriched cardioplegia and non-cardioplegic reperfusion in ischemic hearts . Int J Cardiol . 2004;97:93-100.
52. Lim DS , Mooradian SJ , Goldberg CS , et al . Effect of oral L-arginine on oxidant stress, endothelial dysfunction, and systemic arterial pressure in young cardiac transplant recipients . Am J Cardiol . 2004;94:828-831.
53. Schulman SP , Becker LC , Kass DA , et al . L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial . JAMA . 2006;295:58-64.
54. Chowdhary S , Nuttall SL , Coote JH , Townend JN . L-arginine augments cardiac vagal control in healthy human subjects . Hypertension . 2002;39:51-56.
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