Common Name(s): L-arginine
Uses of L-arginine
L-arginine is a nonessential amino acid that may play an important role in the treatment of cardiovascular disease due to its antiatherogenic, anti-ischemic, antiplatelet, and antithrombotic properties. It has been promoted as a growth stimulant and as a treatment for erectile dysfunction in men.
L-arginine has been studied at oral doses of 6 to 30 g/day for a variety of conditions. Parenteral, enteral, intramural, and topical formulations have been used.
Absolute contraindications have not yet been identified. L-arginine is not recommended in patients following an acute myocardial infarction.
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 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. Bitter taste may occur with higher doses. Due to its vasodilatory effects, hypotension may occur. Intravenous (IV) preparations containing L-arginine hydrochloride have a high chloride content that may increase the risk for metabolic acidosis in patients with electrolyte imbalances. Hyperkalemia and elevations in serum urea nitrogen (BUN) levels may occur in patients with renal and/or hepatic impairment.
High concentrations of nitric oxide are considered toxic to brain tissue.
Sources of amino acid arginine are meats, milk, soy protein, peanuts, walnuts, and eggs. 1 , 2 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 barium hydroxide. 3 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 then may be considered semiessential. 2 , 4
L-arginine is commonly sold as a health supplement claiming to improve vascular health 5 and treat erectile dysfunction in men. 6 L-arginine, which is promoted as a human growth stimulant, 7 has also been used in bodybuilding. 8 In the 1800s, it was first isolated from animal horn as the stereoisomer of arginine. 9
L-arginine Uses and Pharmacology
The use of L-arginine supplementation to raise nitric oxide levels may be beneficial in cardiovascular disease, erectile dysfunction, and sickle cell disease. Nitric oxide is produced by a variety of animal and human cells and is involved in many physiological and pathophysiological processes. 10 Four enzymes use L-arginine as a substrate: nitric oxide synthases, arginases, arginine glycine amidinotransferase, and L-arginine decarboxylase. 11 Nitric oxide, along with L-citrulline, is generated from L-arginine by the enzyme nitric oxide synthase. 4 , 11 , 12 Arginases metabolize L-arginine to L-ornithine and urea. 11 Following oral administration, L-arginine undergoes presystemic (ie, GI flora) and systemic elimination (ie, gut and liver arginases). 4
Most studies affirm stereospecificity of nitric oxide synthase for L-arginine, but trial results in steroid-naive patients with asthma found concentrations of exhaled nitric oxide to be similar for patients administered either L- or D-arginine, suggesting an alternate mechanism of action. 13
L-arginine is a vital amino acid required for the survival of certain parasites, such as Leishmania spp., the causative agent of leishmaniasis. 14Nutritional/Metabolic/Immunostimulatory action
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 (eg, liver disease, severe sepsis, wound healing, cancer). 11 , 15 , 16 , 17 Normal serum levels of L-arginine range from 50 to 150 mcM. 11 Because most arginine in the American diet is obtained from meat and fish, providing about 5.5 g, vegetarians may be at risk for arginine deficiency. 9 In jaundiced rats, L-arginine supplementation demonstrated anabolic and immunostimulatory properties. 18 Anabolic actions were also confirmed in studies of L-arginine supplementation and improved wound healing, 10 , 19 , 20 , 21 as well as healing of bone, burns, GI tract, and tendons. 12 , 22 , 23 , 24 Researchers credit one mechanism to the enzyme arginase, which produces a favorable environment for fibroblast and collagen production. 25 L-arginine exhibited protective effects in spinal cord injury in animals 26 and in cortical impact injury in rats. 27 In another study, exogenous L-arginine resulted in decreased hepatic ischemia/reperfusion injury. 28Clinical data
In a randomized clinical trial of HIV-negative patients with tuberculosis, arginine supplementation resulted in weight gain, higher sputum conversion rates, and faster reduction of symptoms (eg, cough). 29 However, these improvements were not seen in patients with HIV in the same trial nor in patients with HIV in another small trial. 29 , 30
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. 31
Studies in malnourished patients with head and neck cancer showed lower fistula rates, decreased length of hospital stay, and a trend toward improved survival, while other trials were unable to demonstrate a positive clinical outcome. 32 , 33 , 34 In a study of patients who had undergone surgery for esophageal cancer, L-arginine given enterally as part of an immuno-enhanced diet with omega-3 fatty acids and RNA was found to inhibit the decrease in platelets following surgery and reduce prothrombin activity and thrombin-antithrombin III complex levels. Additionally, the proportion of T-cells was higher in patients receiving this enteral product on postoperative days 1 and 7. Thus, an immuno-enhanced diet containing L-arginine may be beneficial in patients following surgery for esophageal cancer to reduce the risk for infectious complications. 35
In severely burned patients, net arginine loss increased and parenteral supplementation of arginine was considered essential to maintain adequate levels of nitric oxide. 36 In a randomized, double-blind pilot study, the efficacy of L-arginine 36.2 g given enterally was compared with placebo (alanine 51.2 g) in patients undergoing skin transplantation as part of reconstructive surgery. No differences were noted between the 2 treatment groups in relation to angiogenesis, reepithelialization, and neutrophil count. Most of the patients found the solutions difficult to drink due to bad taste, which may have influenced the results given the small study sample. 37
In 2 randomized clinical trials of premature infants, arginine supplementation reduced the risk of necrotizing enterocolitis, an effect 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. 38 , 39 Investigators continued to follow the premature infants to assess the long-term risk for neurodevelopmental disability following L-arginine administration. After 36 months, major neurodevelopmental disabilities were present in 8.1% of infants who received L-arginine compared with 12.6% who received placebo (relative risk 0.64 [95% confidence interval (CI), 0.22 to 1.82], P = 0.4). 40 However, 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 adverse reactions. 41 Another study in healthy volunteers failed to demonstrate an effect on intestinal cytokines, making the role of arginine in inflammatory bowel disease unclear. 42
Nitric oxide exerts nonadrenergic and noncholinergic inhibitory effects in the GI tract. In 8 healthy volunteers, the effects of enterally administered L-arginine 15 g, L-arginine 30 g, and placebo were assessed on proximal stomach tone. L-arginine administration increased barostat bag volumes at both doses, signifying stomach relaxation. 43Cardiovascular health
Studies in animal models and clinical trials have described some properties of nitric oxide that may influence cardiovascular health. 44 , 45 , 46 , 47 , 48 L-arginine may impart its beneficial effects through antiatherogenic, anti-ischemic, antiplatelet, and antithrombotic properties. 9
Nitric oxide had a direct scavenging effect on superoxide radicals, inhibited platelet adhesion and aggregation, and modulated endothelial permeability. 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 A deficiency in nitric oxide or impaired nitric oxide synthesis has been linked to arterial stiffness, 54 , 57 , 58 , 59 , 60 , 61 and a neuromodulatory effect on the vagus has been described. 58 , 62 In human microvascular endothelial cells, nitric oxide regulated tissue factor, reducing endotoxin and cytokine-induced expression. 63
In a randomized clinical trial designed to evaluate the effect of L-arginine 9 g/day supplementation for 6 months following an acute ST-segment elevation myocardial infarction, no significant change in vascular stiffness or left ejection fraction was shown. However, 8.6% of the patients died in the L-arginine group 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. 61
Intramural administration of L-arginine (6 mL of 100 mg/mL) was found to significantly reduce the neointimal volume compared with saline (25 vs 39 mm 3 , P = 0.049) following stent deployment. At the 6-month follow-up, patients who received L-arginine had a significantly less neointimal volume percentage compared with those receiving saline (17 ± 13% vs 27 ± 21%, P = 0.048), suggesting that L-arginine may be a viable option for the prevention of restenosis. 65
In patients with 1 or 2 vessel coronary artery disease, L-arginine 150 mcmol min (−1) given via intracoronary infusion was found to increase postenotic coronary flow while having no effect on nondiseased vessels. Additionally, the use of angiotensin-converting enzyme (ACE) inhibitors and a favorable lipid panel were associated with a positive response to L-arginine treatment. 66
L-arginine produced peripheral vasodilation in coronary artery disease patients in 1 trial. 67 In another clinical trial, oral L-arginine therapy was ineffective in improving nitric oxide bioavailability in patients with coronary artery disease. 68 Patients with angina showed improved exercise tolerance after L-arginine supplementation. 69 Patients with long-term limb ischemia who underwent implantation of autologous bone marrow cells and received antioxidants and L-arginine daily for 6 weeks experienced improvements in ankle brachial index at 3- and 12-months posttreatment. There was also an improvement in ischemic ulcers, with 2 of the 18 patients requiring amputation of the ischemic limb. 70
In a case report, a 41-year-old woman with a 35-year history of type 1 diabetes and exertional angina pectoris was diagnosed with microvascular angina and started on L-arginine supplementation with 2 dietary bars a day ( HeartBar ), each containing L-arginine 3.3 g. While consuming these dietary bars, the patient reported that her angina episodes disappeared and her exercise capacity increased. However, after 8 weeks of therapy, L-arginine supplementation was replaced with atorvastatin 40 mg daily because of availability issues with the supplement. The patient's angina episodes reemerged within 1 week and her exercise capacity worsened after 8 weeks. She was restarted on the L-arginine supplement with subsequent disappearance in angina symptoms, suggesting that L-arginine supplementation may be a potential treatment option for patients with diabetes mellitus suffering from microvascular angina. 71
In patients with coronary artery disease, angina pectoris functional class IV, and previous revascularization receiving maximum medical therapy, L-arginine 9 g/day for 3 months improved the functional class (from IV to II) in 7 of 10 patients. Upon discontinuation of L-arginine, symptoms deteriorated back to functional class IV. 72
Patients who underwent coronary artery bypass grafting were randomized in 2 × 2 factorial model to receive either ten 200 mcg injections of vascular endothelial growth factor (VEGF)-165 plasmid DNA or placebo in the anterior myocardium, plus oral L-arginine 6 g/day or placebo for 3 months. Combination therapy with VEGF-165 and L-arginine was associated with improved anterior wall perfusion at 3 months compared with baseline. 73
In a randomized, double-blind, placebo-controlled study, the effects of L-arginine 8.4 g/day on platelet reactivity were assessed in 36 subjects. An insignificant reduction in platelet aggregability was noted in the subjects receiving L-arginine (52.6%) compared with controls (65.1%, P = 0.07). 74
An intracoronary infusion of L-arginine (3,200 mcmoles over 10 minutes) was found to augment endothelium-dependent vascular relaxation (defined as peak coronary blood flow) at a greater level in black patients without coronary artery disease compared with matched white subjects, suggesting that L-arginine supplementation may offer cardiovascular benefits in certain populations. 75
L-arginine supplementation of 700 mg 4 times daily prevented nitrate tolerance when transdermal nitroglycerin was given continuously. Treadmill walking time increased 4 hours and 24 hours after nitroglycerin patch application and was significantly greater than time with placebo ( P < 0.05). 76
Patients with peripheral artery disease improved their walking distances with L-arginine supplementation of 16 g daily for 14 days. 5 The Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) prospective, single-center, randomized, double-blind, placebo-controlled study funded by the National Heart, Lung, and Blood Institute was the largest to date in patients with peripheral artery disease. One hundred thirty-three patients with intermittent claudication were randomized to receive L-arginine 3 g/day or placebo for 6 months. Plasma L-arginine levels significantly increased among those receiving supplementation. Although absolute claudication distance improved in those receiving L-arginine (mean improvement, 11.5%), it was significantly less in than those receiving placebo (28.3%, P = 0.024) suggesting an adverse effect with prolonged treatment that could be attributed to a derangement in the nitric oxide synthase pathway caused by arginine, yielding a reduction in nitric oxide production. 77
L-arginine improved in patients with cardiac performance in patients with severe congestive heart failure (CHF), 49 , 78 , 79 but in another trial of CHF patients 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. 53 When given in combination with losartan 50 mg on 2 consecutive days in 9 patients with stable New York Heart Association class II or III heart failure, IV L-arginine (20 g after second dose of losartan) improved cardiac index and stroke volume compared with losartan alone. 80
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. 59
In men with hypertension and type 2 diabetes mellitus, L-arginine 1,200 mg/day in combination with 600 mg N-acetylcysteine twice daily was found to improve endothelial function by enhancing nitric oxide bioavailability. Specifically, this combination was found to reduce systolic ( P < 0.05) and diastolic mean arterial blood pressure ( P < 0.05), total cholesterol ( P < 0.01), low density lipoprotein cholesterol ( P < 0.005), and high-sensitive C-reactive protein ( P < 0.05), improve intima-media thickness during endothelial postischemic vasodilation ( P < 0.02), and increase high-density lipoprotein levels ( P < 0.05). 81
In 84 normocholesterolemic adults with type 1 diabetes mellitus, L-arginine given at a dose of 7 g twice daily for 6 weeks did not significantly effect endothelial function as measured by a change in flow-mediated dilation (FMD; −0.51%; 95% CI, −1.54 to 0.51, P = 0.32). However, atorvastatin 40 mg/day for a 6-week period did improve FMD (1.26%, 95% CI, 0.22 to 2.3, P = 0.018). 82
Statins have been shown to up-regulate the production of nitric oxide synthase. Ninety-eight elderly patients had their asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, levels screened. They were randomized to receive simvastatin 40 mg/day, L-arginine 3 g/day, or combination therapy for 3 weeks. In patients with high ADMA levels, simvastatin alone did not affect endothelium-dependent vasodilation (EDD). Although L-arginine alone was associated with improvements in EDD, there was a greater effect with combination therapy. In patients with low ADMA levels, simvastatin alone, L-arginine alone, and combination therapy all improved endothelial function. 83
Cigarette smoking increases leukocyte adhesion to endothelial cells and is associated with abnormalities in endothelial function. In one study, an increase in monocyte/endothelial cell adhesion was noted in smokers versus non-smokers (46.4 ± 4.5% vs 27 ± 5.2%, P < 0.001). After administration of 7 g of L-arginine, monocyte/endothelial cell adhesion declined to 35.1 ± 4% (down from 46.4 ± 4.5%, P = 0.002). No reversibility was noted with vitamin C. 84
In various disease states, arginase levels are elevated and limit the production of nitric oxide. Investigators suggested the use of the global arginine bioavailability ration (GABR = arginine/ornithine + citrulline) to assess arginine, as well as major catabolic products (ornithine and citrulline), levels as a better predictor for the development and progression of major adverse cardiovascular events compared with arginine levels. In assessing plasma samples of 1,010 patients, those with obstructive coronary artery disease had lower plasma arginine levels but higher ornithine and citrulline levels, resulting in lower median GABR levels. GABR remained associated with obstructive coronary artery disease even after adjusting for risk factors, high-sensitivity C-reactive protein, and creatinine clearance. 85Stroke
A 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. 86 , 87
High concentrations of nitric oxide are considered toxic to brain tissue. 86
Intravenous L-arginine dosed between 50 and 250 mg/kg improved the survival rate during heatstroke (54 to 245 minutes). Specifically, L-arginine reduced intracranial hypertension and increased the levels of nitric oxide metabolite in the hypothalamus. 88Renal disease
Despite a theoretical rationale for nitric oxide supplementation in renal disease 89 , 90 and positive results derived in animal models, arginine supplementation did not improve endothelial dysfunction in children with chronic renal failure 91 nor was it protective against contrast media-induced nephrotoxicity in adults with chronic renal failure. 92
Progressive renal dysfunction in patients with decompensated cirrhosis may be due to increased levels of nitric oxide. In a prospective, collaborative study, plasma nitric oxide and L-arginine levels increased progressively with worsening renal function with both levels being higher in patients with hepatorenal syndrome type II. 93Diabetes
L-arginine administration stimulates insulin secretion and enhances insulin-mediated glucose disposal, with various mechanisms suggested: 1. beta-cells in the pancreas take up positively charged L-arginine molecules, resulting in plasma membrane depolarization; 2. metabolism of L-arginine by arginase yields ornithine and urea; 3. nitric oxide is produced from L-arginine by the enzyme nitric oxide synthase. 9 , 94
A long-term study of L-arginine supplementation (9 g/day for 1 month) in patients with type 2 diabetes resulted in 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 decreased in the L-arginine group. 95
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. 96
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. 97 In a trial studying the effect of an acute infusion of arginine 3 g in patients with type 2 diabetes, total plasma homocysteine concentration decreased, oxidative stress was counteracted, and availability of nitric oxide increased. 98
Patients with diabetes have low levels of L-arginine and increased levels of asymmetric dimethylarginine, an inhibitor of nitric oxide synthase. In a double-blind, vehicle-controlled, 2-period, crossover pilot study, the efficacy of a cream containing L-arginine 4 mg/cm 2 in improving vascular function of the feet was assessed. The topical preparation improved both flow and temperature in the feet. Originally, the study sought to assess the effects after a washout period of 1 week that was later determined to be inadequate. The protocol was changed to assess the cumulative effect of L-arginine administration. The unique L-arginine formulation may be a potential treatment option for improving blood flow and, ultimately, reducing microvascular complications associated with diabetes. 99 Another clinical study demonstrated that 8 (73%) of 11 patients with diabetic ulcers who received L-arginine 10 mM subcutaneously at the wound site reached total wound healing. The remaining 3 patients left the study due to relocation but showed improvement. 100
In a study of healthy male athletes, arginine 0.1 g/kg (L-arginine 45.5%) increased glucose and insulin 15 and 30 minutes, respectively, after exercise. Free fatty acid levels were reduced in the 30 and 45 minute postexercise recovery periods. 94Obstetrics/Gynecology
In 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 blood pressure. Fetal heart rate was not affected. 101 Another trial in women with preeclampsia showed no effect on mean diastolic pressure after 2 days of oral treatment with arginine 12 g/day. 102
A clinical trial evaluating intrauterine growth restriction therapy with L-arginine 3 g/day for 20 days demonstrated an improvement in the weight of newborn infants compared with no intervention. 103
In a randomized clinical trial of adjuvant arginine 16 g/day in ovarian hyperstimulation, recruitment of follicles increased but embryo quality and pregnancy rate were higher in the placebo arm. 104
In healthy menopausal women, L-arginine 9 g/day for 1 month increased L-arginine plasma levels; however, when compared with placebo, there was no change in serum nitric oxide levels or effects on flow-mediated dilation during hyperemia, brachial artery diameters, or nitroglycerin-induced dilation. 105
Postmenopausal women commonly experience a reduction in muscle mass, force, and power. In a randomized, double-blind, placebo-controlled study, L-arginine given for 6 months was associated with an improvement in peak jump force per kilogram. It was concluded that L-arginine may be beneficial in preventing the decline in muscle force following menopause. 106Ophthalmic
In a randomized clinical trial studying 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, suggesting a role for arginine in ocular diseases associated with endothelial dysfunction, such as in diabetes or glaucoma. 107
In another study of the vasodilator effects of arginine in healthy adults, similar hemodynamic effects were demonstrated. 97Erectile dysfunction
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, 108 but in a human clinical trial, no difference was established between L-arginine 500 mg 3 times daily and placebo. 109 A study of L-arginine in combination with pycnogenol (an extract of French maritime pine bark consisting of procyanidins, catechin, and taxifolin) demonstrated improved sexual function in 80% of treated men. Further increases in pycnogenol amount achieved improvement in 92.5% of men by the end of the study. Treatment with L-arginine was associated with 5% of patients achieving a normal erection. 110
L-arginine has been studied in combination with the standard of care, oral type-5 phosphodiesterase (PDE-5) inhibitors, for erectile dysfunction. The efficacy of a combination of L-arginine, nicotinic acid, and propionyl-L-carnitine (PLC) with and without the PDE-5 inhibitor, vardenafil, was assessed in men with diabetes and erectile dysfunction. Erectile function, measured by the International Index of Erectile Function (IIEF), improved by 2 points in those receiving the combination of L-arginine, nicotinic acid, and PLC. The group receiving vardenafil improved by 4 points, whereas the group receiving the combination of L-arginine, nicotinic acid, and PLC plus vardenafil improved by 5 points. Those receiving placebo did not show an incremental improvement. 111 When added as adjuvant therapy to men nonresponsive to tadalafil 20 mg, L-arginine 600 mg/day was associated with improved responses to 2 IIEF questions related to the ability to achieve and maintain an erection sufficient for sexual activity. 112HIV-wasting
L-arginine is believed to impact muscle proteolysis. Thus, in a study of patients infected with HIV with documented weight loss of at least 5% in the previous 3 months, supplementation with L-arginine 14 g, beta-hydroxy-beta-methylbutyrate 3 g, and L-glutamine 14 g given in 2 divided doses for 8 weeks was associated with weight gain. Specifically, the subjects receiving the mixture gained 3 ± 0.5 kg of body weight compared with 0.37 ± 0.84 kg ( P = 0.009) in those receiving placebo. The body weight gain was mostly an increase in lean body mass, suggesting that L-arginine in combination with L-glutamine and beta-hydroxy-beta-methylbutyrate may be a potential treatment option to increase body weight in patients suffering from HIV-wasting syndrome. 113Cystic fibrosis
In cystic fibrosis, a deficiency in nitric oxide formation in the airways may contribute to airway obstruction. In a clinical study, the effects of nebulized L-arginine (18 mL of a 7% solution containing L-arginine 1.3 g) given to patients with cystic fibrosis was compared with a saline (placebo) solution given to healthy controls. Inhaled L-arginine was associated with increased nitric oxide concentrations ( P < 0.0001) as measured by fractional exhaled nitric oxide (FE NO ; single-breath online measurements assessing lower airway nitric oxide performed at a constant expiratory flow of 50 mL × min -1 ). A significant increase in mean forced expiratory volume at 1 second (FEV 1 ) occurred 4 hours after L-arginine inhalation ( P < 0.0005). No change in forced vital capacity was noted. Patients treated with nebulized saline experienced a small but statistically significant improvement in FE NO , but the FEV 1 declined after inhalation. Therefore, nebulized L-arginine may be a treatment option to improve lung function in patients with cystic fibrosis. 114Sickle cell disease
In patients with sickle cell disease, endothelial cells become activated and are damaged by neutrophils that release harmful substances. Vaso-occlusive events and tissue damage are mediated by neutrophils. Superoxide anion released from endothelial cells and neutrophils play a role in breaking down nitric oxide. This production of superoxide anion in these cells is enhanced in a state of L-arginine deficiency. 115 , 116 , 117
In a clinical study of 5 patients with sickle cell disease, the L-arginine precursor, L-citrulline 0.1 g/kg twice daily, improved the sense of well-being in patients. Supplementation was also associated with increased arginine levels, and reduced total leukocyte counts and segmented neutrophil counts. Continuous L-citrulline therapy maintained the lower total leukocyte counts and segmented neutrophil counts. 115
In 10 patients with sickle cell disease and pulmonary hypertension (mean, 32.7 ± 15 years of age) given oral L-arginine 0.1 g/kg 3 times daily for 5 days, supplementation was associated with a 15.2% mean reduction in pulmonary artery systolic pressure (63.9 ± 13 to 54.2 ± 12 mm Hg, P = 0.002). Of the 9 compliant patients, follow-up echocardiography results at 1 month showed that 4 patients reverted back to baseline pulmonary artery systolic pressure values, 1 patient worsened and was admitted for acute chest syndrome, and 4 patients persistently improved; 2 of the patients who improved were started on transfusion therapy, and 1 of these patients continued treatment with L-arginine therapy at a dose of 0.1 g/kg twice daily. 118
The effects in patients with sickle cell disease of L-arginine 0.1 to 0.2 g/kg divided 3 times daily versus sildenafil 25 to 100 mg 3 times daily on safety, cardiopulmonary function, and fetal hemoglobin were assessed. L-arginine did not improve pulmonary pressure or 6-minute walking distances, while sildenafil did. However, fetal hemoglobin levels were insignificantly reduced by 2.9% ± 16.1% from baseline in patients receiving L-arginine. In those treated with sildenafil, fetal hemoglobin levels increased. 119Other uses
Other reported effects of L-arginine include increased quantity and cytotoxic capability of lymphokine-activated and natural killer T-cells in breast cancer. 120 Specifically, patients with cancer have reduced levels of L-arginine due to the increased production of arginase I, causing a decrease in T-cell proliferation and impaired T-cell function. One study found a reduction in stimulated T-cell proliferation when cultured without L-arginine. However, the addition of L-arginine or citrulline allowed for recovery of T-cell proliferation. The investigators concluded that tumor cell regulation of amino acid availability is possibly what allows these cells to escape the immune response. 121 The efficacy of L-arginine was assessed in women with interstitial cystitis due to high levels of nitric oxide in the bladder because of this condition. When given at a dose of 3 or 10 g daily for 5 weeks, L-arginine did not affect nitric oxide levels or improve symptom scores. 122
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) syndrome is an inherited mitochondrial disorder in which patients have reduced levels of L-arginine, the amino acid important for the promotion of endothelium-dependent vasodilation. In a study of 15 patients with MELAS, 2 years of L-arginine supplementation improved flow-mediated vasodilation when compared with baseline (113.1 ± 2.4 vs 104.7 ± 1.8; P < 0.05), an improvement comparable with L-arginine levels seen in control patients (112.2 ± 1.7). 123
In patients with Raynaud phenomenon and scleroderma, L-arginine administered as an infusion reduced attacks. 124
L-arginine has been studied at oral doses of 6 to 30 g/day for a variety of conditions. Parenteral, enteral, intramural, and topical formulations have been used.
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. 101 , 102 , 103 , 104
L-arginine has unpredictable effects on insulin and cholesterol-lowering agents. 95 , 96 , 125 L-arginine may potentiate the effects of isosorbide mononitrate and other nitric oxide donors, such as glyceryl trinitrate and sodium nitroprusside. 58
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. 39 , 104 In a trial of malnourished patients with head and neck cancer, the incidence of diarrhea was higher compared with standard therapy. 34 No adverse reactions were reported with L-arginine 9 g/day over 6 months. 69 Higher doses may be associated with a bitter taste and may affect patient compliance. 126 Due to L-arginine's vasodilatory properties, hypotension may occur. Intravenous preparations containing L-arginine hydrochloride have a high chloride content that may be dangerous for patients with electrolyte imbalances. Because L-arginine hydrochloride preparations are acidic, metabolic acidosis due to a sudden drop in pH may occur and cause arrhythmias. Hyperkalemia may occur in patients with hepatic and/or renal impairment who are receiving L-arginine treatment, resulting from the displacement of intracellular potassium. In patients with renal impairment receiving L-arginine therapy, an increase in BUN and urea may occur because of a diminished ability to eliminate urea. 127
High concentrations of nitric oxide are considered toxic to brain tissue. 86 A 21-month old received an accidental overdose of L-arginine when being tested for growth hormone deficiency. She developed cardiopulmonary arrest, and 36 hours after successful resuscitation, she developed fatal myelinolysis. 127 , 128
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