L-arginine
Arginine/Drug Interactions:
ACE inhibitorsACE inhibitors: In humans, ACE inhibitors may enhance vasodilation and effects of L-arginine (137; 139). Based on experience with intravenous arginine, it is possible that the use of high-dose oral arginine might alter potassium levels in the body, especially in people with severe liver disease (132). This is a potential concern for individuals who take ACE inhibitors, which may increase potassium levels. AminophyllineAminophylline: Theoretically, aminophylline may decrease glucagon response to arginine.AnalgesicsAnalgesics: In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen?) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin? or Advil? with ibuprofen-arginate may increase the risk of toxic effects. Angiotensin II receptor antagonistAngiotensin II receptor antagonist: In humans, angiotensin II receptor antagonists enhanced vasodilation and effects of L-arginine (137; 139). In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including angiotensin II receptor antagonists. In animals, a losartan and L-arginine combination increased aortic blood flow and decreased aortic vascular resistance; urea clearance and SOD activity also increased (223). In human plasma and erythrocytes, irbesartan modulated L-arginine metabolism (224). Antacids, H2 blockers, proton pump inhibitorsAntacids, H2 blockers, proton pump inhibitors: Due to the theoretical potential for L-arginine to increase gastrin, and thus stomach acid, L-arginine may reduce the effectiveness of these agents, although clinical evidence is lacking.AntibioticsAntibiotics: In humans, arginine caused hyperkalemia (84; 85) and should theoretically be used cautiously with agents that may increase potassium, including certain anti-infective agents like trimethoprim-sulfamethoxazole and pentamidine. In human research, L-arginine had antibacterial effects in patients with tuberculosis (225; 226). According to results of meta-analyses, arginine supplemented diets reduced infection complications after surgery (227; 205). In vitro, L-arginine protected against the detrimental effects of Bartonella henselae; mechanisms of action included production of nitric oxide, by modulation of p38 kinase phosphorylation and by normalizing expression of genes (228). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In humans, L-arginine reduced platelet aggregation (91; 92; 93; 94; 95; 96; 97; 98). In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, such as the anticoagulant heparin. AnticonvulsantsAnticonvulsants: In humans, L-arginine lowered antiepileptic agent-increased homocysteine levels (16). AntidiabeticsAntidiabetics: In diabetics, L-arginine resulted in improved glucose profiles and fructosamine over exercise alone (106; 107), decreased glucose production (108), improved insulin sensitivity and insulin clearance (109; 110), and increased whole body glucose disposal (111). In diabetic patients, metformin and L-arginine had additive effects on blood pressure reduction, platelet aggregation inhibition, and blood viscosity reduction, and increased heart rate, plasma norepinephrine, and blood filterability (95). AntihypertensivesAntihypertensives: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers. Anti-inflammatoriesAnti-inflammatories: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with other agents that may increase potassium, such as nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., indomethacin, ibuprofen, ketorolac). In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen?) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin? or Advil? with ibuprofen-arginate may increase the risk of toxic effects. AntilipemicsAntilipemics: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230). In humans, fenofibrate increased plasma levels of L-arginine (231). In humans, simvastatin had a lack of an effect on vasodilation induced by L-arginine (232). In patients with elevated plasma triglycerides, L-arginine enhanced the triglyceride-lowering effect of simvastatin (230). AntimalarialsAntimalarials: In human research, recovery of endothelial function in patients with severe falciparum malaria was related to improvements in plasma L-arginine concentrations (30). AntineoplasticsAntineoplastics: In humans, L-arginine decreased cytotoxicity associated with chemotherapeutic agents (78), and in colorectal cancer patients, L-arginine resulted in increased numbers of cell subsets within the tumor expressing CD16 and CD56 surface markers (233). In human research, arginine supplementation has been reviewed and appears to stimulate both anticancer effects and tumor growth (141). Antiobesity agentsAntiobesity agents: In humans, L-arginine may have an additive effect to exercise, resulting in a further decrease in adipose fat mass, waist circumference, and the leptin:adiponectin ratio; preservation of fat free mass; and increased adiponectin levels (106). AspirinAspirin: In humans in pregnant women, aspirin facilitated the uptake of the NO precursor at low arginine concentrations (209). In humans, L-arginine reduced platelet aggregation (91; 92; 93; 94; 95; 96; 97; 98). Cardiac glycosidesCardiac glycosides: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis. Cardiovascular agentsCardiovascular agents: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers. In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis. Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension. In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146). ContraceptivesContraceptives: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235). CyclophosphamideCyclophosphamide: In animals, L-arginine alleviated cyclophosphamide-induced immunosuppression (236). Arginine increased white blood cell count and improved the lymphocyte percentage, increased the delayed-type hypersensitivity reaction, and attenuated the decrease of bovine serum albumin antibody level caused by cyclophosphamide. Serum interleukin-2 and interferon-gamma were increased. The decrease of serum interferon-gamma level was mitigated. CyclosporineCyclosporine: In animals and humans, L-arginine reduced nephrotoxicity associated with cyclosporine (237; 238; 187). In vitro, cyclosporin A suppressed the proliferation of endothelial progenitor cells; this affect was attenuated by L-arginine (239). DiureticsDiuretics: In humans, arginine caused hyperkalemia (84; 85) and should be use cautiously in patients using potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride). In humans, L-arginine increased renal plasma flow; decreased renal vascular resistance; and increased glomerular filtration rate, natriuresis, kaliuresis, and creatinine clearance (240; 241; 242; 110; 243; 192; 132; 244; 245; 136; 145). EstrogensEstrogens: In humans, estrogens found in birth control pills and hormone replacement therapies increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235). Gastrointestinal agentsGastrointestinal agents: In humans, L-arginine reduced basal early postprandial lower esophageal sphincter pressure and increased fasting and residual gallbladder volumes and transient lower esophageal sphincter relaxation times (246). In fasting subjects, L-arginine gel reduced anal resting pressure (247), proximal stomach relaxation (112), and the antral motility index, and increased basal gallbladder volume, with no effect on gastric emptying (248). Nausea, diarrhea, gastrointestinal discomfort, and bloating have been reported with L-arginine use (112; 113; 90; 114). GlucagonGlucagon: In humans, aminophylline and xylitol decreased the effect that arginine has on glucagon (249; 206). Growth hormonesGrowth hormones: In humans, L-arginine may stimulate growth hormone response (250; 251; 252; 253) and have additive effects with exercise on growth hormone release (254). Hormonal agentsHormonal agents: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235). ImmunosuppressantsImmunosuppressants: In humans, intravenous L-arginine inhibited neutrophil release of superoxide anion (100), as well as increased (101; 102; 103) and decreased (104) lymphocyte proliferation or activation, increased natural killer cell activity (105; 76; 103), and increased levels of IL-2 (105). Iron saltsIron salts: In animals, L-arginine protected myocardial tissue against iron overload stress (273).IsoproterenolIsoproterenol: In humans, vasodilation in response to isoproterenol was enhanced by L-arginine (265). Neurologic agentsNeurologic agents: In mountain climbers, L-arginine increased risk of developing a headache (89). Headache has occurred in other clinical trials (90; 86). Anecdotally, headache following rapid intravenous administration has also been described. L-arginine can have both beneficial and deleterious effects in terms of ischemic damage, depending on time of administration, due to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular system (207). NicotineNicotine: In human research, nebulized L-arginine reversed the cigarette-induced reduction of fractional exhaled nitric oxide in asthmatic smokers (274). In vitro, L-arginine enhanced the cigarette smoke-induced inhibition of endometrial epithelial cell proliferation (275). In animals, L-arginine restored the renal vasodilatory response to nicotine (276). NitratesNitrates: Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension.NitroderivativesNitroderivatives: In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146). PhenylephrinePhenylephrine: In animals, a combination of antioxidants (vitamin E, vitamin C), omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and L-arginine prevented the increased vascular response to phenylephrine in diabetic animals (277). Phosphodiesterase inhibitorsPhosphodiesterase inhibitors: Arginine should be used with caution with phosphodiesterase inhibitors (e.g., sildenafil [Viagra?]), due to the theoretical risk of additive vasodilation and hypotension. In animals, concurrent use of L-arginine and phosphodiesterase inhibitors, including sildenafil, resulted in synergistic effects and additive vasodilation (278). The effect of vardenafil, in addition to propionyl-L-carnitine, L-arginine, and nicotinic acid, has been examined in human research (279). Additive effects were lacking. Potassium saltsPotassium salts: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including potassium supplements. PropofolPropofol: In vitro, propofol attenuated the L-arginine-mediated enhancement of nitrative stress and tumor necrosis toxicity in endothelial cells (280). SertralineSertraline: In animals, L-arginine pretreatment reversed the protective effect of sertraline in terms of ischemia (281). SpironolactoneSpironolactone: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including spironolactone. In a case report, spironolactone and arginine monohydrochloride resulted in marked hyperkalemia, with fatal cardiac arrhythmia (85). Arginine/Herb/Supplement Interactions:
AnalgesicsAnalgesics: In humans, a combination of ibuprofen and arginine had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin? or Advil? with ibuprofen-arginate may increase the risk of toxic effects. AntacidsAntacids: Due to the theoretical potential for L-arginine to increase gastrin, and thus stomach acid, L-arginine may reduce the effectiveness of these agents.AntibacterialsAntibacterials: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including certain anti-infective agents. In human research, L-arginine had antibacterial effects in patients with tuberculosis (225; 226). In human trials, arginine-supplemented diets reduced infection complications after surgery (227; 205). In vitro, L-arginine protected against the detrimental effects of Bartonella henselae (228). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In humans, L-arginine infusion reduced blood viscosity and increased blood flow (91; 111; 148; 185; 255; 256; 93; 257; 258; 259; 115; 95) and increased endothelial-dependent flow-mediated vasodilation (129; 260; 261; 262; 244; 263; 264; 258; 265; 172; 266; 267; 268; 269; 270; 271; 272). In humans, L-arginine infusion reduced platelet aggregation (91; 92; 93; 94; 95; 96; 97; 98). In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium. AnticonvulsantsAnticonvulsants: In human research, L-arginine lowered antiepileptic agent-increased homocysteine levels (16). Anti-inflammatoriesAnti-inflammatories: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with other agents that may increase potassium, such as nonsteroidal anti-inflammatory agents (NSAIDs) (e.g., indomethacin, ibuprofen, ketorolac). In humans, a combination of ibuprofen and arginine (ibuprofen-arginate/Spedifen?) had a faster onset of pain relief than ibuprofen alone (220; 221; 222; 31). Use of other ibuprofen-based pain relievers such as Motrin? or Advil? with ibuprofen-arginate may increase the risk of toxic effects. AntilipemicsAntilipemics: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230). AntimalarialsAntimalarials: In human research, recovery of endothelial function in patients with severe falciparum malaria was related to improvements in plasma L-arginine concentrations (30). AntineoplasticsAntineoplastics: In humans, L-arginine decreased cytotoxicity associated with chemotherapeutic agents (78), and in colorectal cancer patients, L-arginine may result in increased numbers of cell subsets within the tumor expressing CD16 and CD56 surface markers (233). In human research, arginine supplementation has been reviewed and appears to stimulate both anticancer effects and tumor growth (141). Antiobesity agentsAntiobesity agents: In humans, L-arginine had an additive effect to exercise, resulting in a further decrease in adipose fat mass, waist circumference, and the leptin:adiponectin ratio; preservation of fat free mass; and increased adiponectin levels (106). AntioxidantsAntioxidants: In patients undergoing valve replacement, infusion of L-arginine resulted in increased nitric oxide, reduced lactic acid and malondialdehyde levels, and increased superoxide dismutase levels (282; 283; 106; 284). In humans, oral use of L-arginine may increase total antioxidant status and nitric oxide levels, or decrease levels of thiobarbituric acid reactive substances (TBARS) (285; 134; 272). In coronary stent patients, L-arginine may reduce the levels of oxidative LDL cholesterol (102) or lag time to oxidation (271). Antioxidant effects of L-arginine have been shown in other studies (98) Athletic performance enhancersAthletic performance enhancers: In patients with severe chronic heart failure, intravenous L-arginine reduced the ventilatory equivalent ratio for carbon dioxide (VE/VCO2) slope (286). Branched-chain amino acidsBranched-chain amino acids: In animals, arginine decreased plasma levels of branched-chain amino acids (287). Cardiac glycosidesCardiac glycosides: In humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that may increase potassium, including digitalis. Cardiovascular agentsCardiovascular agents: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers, and agents that may increase potassium, including digitalis. Theoretically, concurrent use of L-arginine and nitrates may result in additive vasodilation and hypotension. In humans, chronic oral intake of L-arginine resulted in decreased frequency and intensity of angina, as well as the number of nitroderivative tablets taken for analgesic purposes (146). CitrullineCitrulline: In humans, serum citrulline may increase with L-arginine supplementation in some (129; 288) but not all studies (289; 290). Conjugated linoleic acid (CLA)Conjugated linoleic acid (CLA): In animals, CLA and arginine were found to modulate adipose tissue metabolism by separate, but not additive, effects (39). CreatineCreatine: In human research, there was a lack of effect of creatine on the actions of L-arginine on vascular function (152). Based on a review, treatment of guanidinoacetate methyltransferase (GAMT) deficiency required dietary restriction of arginine (120). DiureticsDiuretics: Arginine may cause hyperkalemia (84; 85) and should be use cautiously in patients using potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride). Based on human subjects, L-arginine may increase renal plasma flow; decrease renal vascular resistance; and increase glomerular filtration rate, natriuresis, kaliuresis, and creatinine clearance (240; 241; 242; 110; 243; 192; 132; 244; 245; 136; 145). Gastrointestinal agentsGastrointestinal agents: In humans, L-arginine reduced basal early postprandial lower esophageal sphincter pressure and increased fasting and residual gallbladder volumes and transient lower esophageal sphincter relaxation times (246). In fasting subjects, L-arginine gel reduced anal resting pressure (247), proximal stomach relaxation (112), and the antral motility index, and increased basal gallbladder volume, with no effect on gastric emptying (248). Nausea, diarrhea, gastrointestinal discomfort, and bloating have been reported with L-arginine use (112; 113; 90; 114). GinkgoGinkgo: In humans, a combination of Ginkgo biloba extract, arginine, and magnesium reduced healing times of trophic lesions in the lower limbs caused by microangiopathy, and improved symptoms (136). Green tea extractGreen tea extract: Green tea extract protected the mesangial cells from arginine-induced nitric oxide-mediated cytotoxicity by scavenging nitric oxide (291). Hormonal agentsHormonal agents: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235). HypoglycemicsHypoglycemics: In diabetic subjects, L-arginine administration resulted in improved glucose profiles and fructosamine over exercise alone (106; 107), decreased glucose production (108), improved insulin sensitivity and insulin clearance (109; 110), and increased whole-body glucose disposal (111). HypotensivesHypotensives: In humans, L-arginine caused decreased blood pressure and improved endothelium-dependent dilation (EDD) and acetylcholine- and nitroglycerin-mediated vasodilation (125; 126; 127; 91; 128; 129; 130; 131; 132; 93; 133; 134; 115; 95; 229; 135; 145) and has resulted in hypotension or additive effects when used with antihypertensives (136; 137; 138; 145); it also decreased the need for hypotensive agents (177). In a systematic review, select trials reported a lack of significant improvement in blood pressure and EDD (145). In a human study, hypertensive exacerbation was noted in one subject following a heart transplant (179). Also, in humans, arginine caused hyperkalemia (84; 85) and so should be used cautiously with agents that increase potassium, including beta-blockers and alpha-blockers. ImmunosuppressantsImmunosuppressants: In humans, intravenous L-arginine inhibited neutrophil release of superoxide anion (100), as well as increased (101; 102; 103) and decreased (104) lymphocyte proliferation or activation, increased natural killer cell activity (105; 76; 103), and increased levels of IL-2 (105). IronIron: In animals, L-arginine protected myocardial tissue against iron overload stress (273).L-citrullineL-citrulline: In human and animal research, L-citrulline increased plasma L-arginine levels (292; 293). LysineLysine: Based on a systematic review, there is strong evidence for the use of herbal supplements containing combinations of L-lysine and L-arginine as treatments for anxiety symptoms and disorders (294). In humans, a combination of lysine and L-arginine increased adrenocorticotropic hormone, cortisol, adrenaline, and noradrenaline levels during psychological stress, and decreased basal trait and state anxiety scores and salivary cortisol and chromogranin A (53; 295). In humans, a combination of lysine and arginine had a lack of an effect on growth hormone levels (296). Theoretically, foods rich in arginine may result in a breakout of cold sores, thus reducing efficacy of lysine, traditionally used for cold sore treatment and prevention. In vitro, inotropic effects of L-lysine were not abrogated by L-arginine (297). In human research, L-arginine amplified the effect of a low-lysine diet; the authors suggested that this was due to competition with L-lysine at the blood-brain barrier (298). MagnesiumMagnesium: In humans, a combination of Ginkgo biloba extract, arginine, and magnesium reduced healing times of trophic lesions in the lower limbs caused by microangiopathy, and improved symptoms (136). N-acetyl cysteineN-acetyl cysteine: In human research, a combination if N-acetylcysteine plus arginine for six months resulted in reduced systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, oxidized LDL cholesterol, high-sensitive C-reactive protein, intracellular adhesion molecules, vascular cell adhesion molecules, nitrotyrosine, fibrinogen, and plasminogen activator inhibitor-1; it also improved the intima-media thickness during endothelial postischemic vasodilation and increased HDL cholesterol (299). The effect of L-arginine alone is unclear. Neurologic agentsNeurologic agents: In mountain climbers, L-arginine increased risk of developing a headache (89). Headache has occurred in other clinical trials (90; 86). Anecdotally, headache following rapid intravenous administration has also been described. L-arginine can have both beneficial and deleterious effects in terms of ischemic damage, depending on time of administration, due to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular system (207). Omega-3 fatty acidsOmega-3 fatty acids: In humans, a combination of arginine, RNA, and omega-3 fatty acids reduced the length of hospital stays and infections after surgery in gastrointestinal cancer patients (300); increased in the number of T lymphocytes and subsets, helper T cells, and activated T cells (CD3 and HLA-DR); and increased interferon-gamma concentrations, and immunoglobulin M and immunoglobulin G levels (301). In animals, a combination of antioxidants (vitamin E, vitamin C), omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and L-arginine prevented the increased vascular response to phenylephrine in diabetic animals (277). In animals, supplementation with docosahexaenoic acid increased arginine concentrations in the brain, but not in liver or muscle (302). OrnithineOrnithine: In humans, a combination of arginine and ornithine reduced urinary hydroxyproline (303). In strength-trained athletes, L-arginine and ornithine combination increased growth hormone and insulin-like growth factor-1 serum levels after heavy-resistance exercise (304). PhytoestrogensPhytoestrogens: Estrogens (found in birth control pills and hormone replacement therapies) increased the effects of arginine on growth hormone, glucagon, and insulin (234). In contrast, progestins (also found in birth control pills and some hormone replacement therapies) decreased the responsiveness of growth hormone to arginine (235). Pine bark extractPine bark extract: In human research, a combination of pine bark extract and L-arginine improved symptoms of erectile dysfunction and increased testosterone levels (305). PiplartinePiplartine: In vitro, L-arginine did not modify the inhibitory effect of piplartine on ADP-induced platelet aggregation (306). Pycnogenol?Pycnogenol?: In men with erectile dysfunction, a combination of arginine and Pycnogenol? (pine bark extract) increased sexual function (307). In human research, a combination of pine bark extract and L-arginine improved symptoms of erectile dysfunction and increased testosterone levels (305). SodiumSodium: In humans, use of L-arginine reduced renal sodium excretion with a low salt intake and increased renal excretion with a high salt intake (308). Vitamin CVitamin C: In humans, a combination of vitamin C and L-arginine increased renal plasma flow over L-arginine alone (245) and augmented L-arginine-dependent coronary segment vasodilation (309). In animals, a combination of antioxidants (vitamin E, vitamin C), omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and L-arginine prevented the increased vascular response to phenylephrine in diabetic animals (277). Vitamin EVitamin E: In humans, supplementation with vitamin E did not reverse L-arginine responsive endothelial dysfunction (310). In animals, a combination of antioxidants (vitamin E, vitamin C), omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid), and L-arginine prevented the increased vascular response to phenylephrine in diabetic animals (277). Vulnerary agentsVulnerary agents: In patients with lesions caused by microangiopathy, a combination of L-arginine, Ginkgo biloba, and magnesium reduced healing times (136). XylitolXylitol: Theoretically, xylitol may decrease glucagon response to arginine.YohimbineYohimbine: In patients with mild-to-moderate erectile dysfunction, a combination of yohimbine and arginine improved erectile function (311). In women, vaginal pulse amplitude responses to an erotic film were increased with a combination of yohimbine and arginine (51). Arginine/Food Interactions:
CreamCream: In human research, addition of 2.5g of L-arginine to a fatty meal containing cream prevented lipemia-induced endothelial dysfunction (312). Fats (cholesterol)Fats (cholesterol): In animals, dietary cholesterol increased levels of arginine in the brain, but not in liver or muscle (302). SaltSalt: In humans, use of L-arginine may reduce renal sodium excretion with a low salt intake and increase renal excretion with a high salt intake (308). The saltiness of Gouda cheese was increased by L-arginine (313). WatermelonWatermelon: In human research, watermelon was used as a source of L-citrulline (an L-arginine precursor) and L-arginine (1.3g of L-arginine in watermelon daily for six weeks) (314). In human and animal research, L-citrulline increased plasma L-arginine levels (292; 293). XylitolXylitol: The sweetening agent xylitol can decrease the effect that arginine has on glucagon (249; 206). Arginine/Lab Interactions:
AldosteroneAldosterone: In human research, L-arginine decreased serum levels of aldosterone (315). AmmoniaAmmonia: In human research, peak ammonia levels decreased following use of L-arginine (288). Anti-inflammatory mediatorsAnti-inflammatory mediators: In healthy postmenopausal women, L-arginine had a lack of an effect on levels of inflammatory mediators such as nitrogen oxide, E-selectin, intercellular adhesion molecule-1, or vascular cell adhesion molecule-1 (316). Antioxidant markersAntioxidant markers: In myocardial infarction patients, oral administration of L-arginine (3g daily for 15 days) resulted in increased activity of superoxide dismutase and levels of total thiols (T-SH) and ascorbic acid, and decreased lipid peroxidation, carbonyl content, and the activity of xanthine oxidase (317). In patients undergoing valve replacement, infusion of L-arginine resulted in increased nitric oxide levels, reduced lactic acid and malondialdehyde levels, and increased superoxide dismutase levels (282; 283; 106; 284). Decreased malondialdehyde levels were found in other human populations (318). In humans, oral use of L-arginine increased total antioxidant status and nitric oxide levels, or decreased levels of thiobarbituric acid reactive substances (TBARS) (285; 134; 272). In human research, L-arginine increased plasma glutathione (289). In animals, exercise-induced increases in xanthine oxidase and myeloperoxidase activities and MDA levels were attenuated (319). Apgar scoreApgar score: Human infants born to L-arginine-treated mothers had higher Apgar scores (123). ArginineArginine: In humans, L-arginine supplementation increased blood levels of arginine (320; 185; 316; 321; 322; 323; 93; 324; 289; 290; 180), as well as follicular arginine (167) and wound fluid arginine (180). In animals, L-arginine supplementation increased blood levels of arginine (325; 59). Asymmetric dimethylarginine (ADMA)Asymmetric dimethylarginine (ADMA): In animals, L-arginine resulted in decreased ADMA in a pre-eclampsia model (326). In human research, L-arginine increased the arginine:ADMA ratio (151). Atrial natriuretic peptideAtrial natriuretic peptide: In humans, L-arginine resulted in increases in atrial natriuretic peptide (206). Bone markersBone markers: In humans, L-arginine resulted in increases in procollagen type I propeptides (44). Branched-chain amino acidsBranched-chain amino acids: In animals, arginine decreased plasma levels of branched-chain amino acids (287). Cardiovascular testsCardiovascular tests: In humans, intravenous L-arginine prevented a decrease in graft blood flow and an increase in arterial pressure and coronary vascular resistance in patients undergoing coronary artery bypass graft surgery (189). In humans, L-arginine induced coronary stenosis dilation (329) and improved normalization of sinus rhythm, with reduced perioperative myocardial infarction in myocardial infarction patients undergoing bypass grafting (283). In humans, L-arginine increased functional status in heart failure patients (160). In human research, L-arginine prevented a reduction in aortic reflection time (327). CatecholaminesCatecholamines: Based on a review, L-arginine increased plasma catecholamines (330). Cerebral blood flowCerebral blood flow: In humans, L-arginine increased cerebral blood flow velocity (128; 331; 257; 332). CitrullineCitrulline: In humans, serum citrulline increased with L-arginine supplementation in some (129; 288) but not all studies (289; 290). Cognitive scoreCognitive score: In dementia patients, L-arginine increased cognitive scores (147). CollagenCollagen: In wound patients, collagen deposition increased with L-arginine treatment (80). CortisolCortisol: In animals, dietary arginine decreased plasma cortisol levels (12). CreatineCreatine: In animal research, in traumatized animals (laparotomy), a combination of L-arginine and glycine increased muscle creatine content (333). CreatinineCreatinine: In animals, arginine increased plasma creatinine (334). Cyclic guanosine monophosphate (cGMP)Cyclic guanosine monophosphate (cGMP): In humans, L-arginine increased urinary excretion and plasma levels of cGMP (240; 129; 130; 255; 93). CytokinesCytokines: In cardiac bypass patients, cytokines were reduced or improved (190; 191), and IL-2 receptor levels were reduced in these patients (191) and increased in others (103). In human burn patients, L-arginine decreased levels of serum TNF-alpha and IL-1-beta and increased TGF-beta (335). Electrocardiogram (ECG)Electrocardiogram (ECG): In animals, L-arginine significantly reduced hypercholesterolemia-induced QTc prolongation (336). Embolic Doppler signalsEmbolic Doppler signals: In patients undergoing carotid endarterectomy, L-arginine resulted in reductions in the number of Doppler embolic signals (337). Endothelin-1Endothelin-1: In humans, L-arginine resulted in a decrease in plasma endothelin (148; 255; 106; 162) Fat massFat mass: In humans, L-arginine had an additive effect to exercise, resulting in further decreased adipose fat mass and waist circumference, and preserved fat free mass (106). FibrinogenFibrinogen: In animals, L-arginine decreased fibrinogen levels (98). Free fatty acidsFree fatty acids: In human research, arginine one hour before lunch in diabetic subjects who had not eaten breakfast decreased free fatty acid levels (338). GastrinGastrin: Theoretically, use of L-arginine increased gastrin, and thus stomach acid. In humans, L-arginine had a lack of an effect on gastrin levels (339). Gastrointestinal testsGastrointestinal tests: In humans, L-arginine reduced basal early postprandial lower esophageal sphincter pressure and increased fasting and residual gallbladder volumes and transient lower esophageal sphincter relaxation times (246). In fasting subjects, L-arginine gel reduced anal resting pressure (247), proximal stomach relaxation (112), and the antral motility index, and increased basal gallbladder volume, with no effect on gastric emptying (248). GlucagonGlucagon: In humans, L-arginine use resulted in the release of glucagon and increased levels of urinary and plasma glucagon (249; 206). GlucoseGlucose: In diabetic and nondiabetic subjects, L-arginine resulted in improved glucose profiles and fructosamine over exercise alone (106; 127), decreased glucose production (108), improved insulin sensitivity (109; 151), and increased whole body glucose disposal (111). In type 2 diabetic patients, arginine decreased the lunch-induced increase in plasma glucose by approximately 40% (338). Decreased glucose levels have also been shown in animal research (287). Plasma glucose increased in one human study (184). GlutamineGlutamine: In animals, arginine decreased plasma glutamine levels (287). GlycerolGlycerol: In animals, arginine increased plasma glycerol (39). Growth hormoneGrowth hormone: In humans, L-arginine stimulated growth hormone response (250; 340; 206; 251; 252; 253) and had additive effects with exercise on growth hormone release (254). In strength-trained athletes, an L-arginine and ornithine combination increased growth hormone and insulin-like growth factor-1 serum levels after heavy-resistance exercise (304). Heart rateHeart rate: In humans, L-arginine increased heart rate (91; 129; 93) or had a lack of an effect (185; 341). HematocritHematocrit: In humans, L-arginine reduced hematocrit levels (99). HemoglobinHemoglobin: In humans, L-arginine increased levels of hemoglobin (342). HomocysteineHomocysteine: In humans, L-arginine resulted in decreased levels of homocysteine, in some (343; 188; 16), but not all studies (75; 152). In animals, L-arginine decreased blood homocysteine levels (25). HormonesHormones: In animals, L-arginine decreased concentrations of progesterone in maternal plasma, and amounts of progesterone, estrone, and estrone sulfate, in allantoic fluid (216). HydroxyprolineHydroxyproline: In humans, a combination of arginine and ornithine resulted in reduced urinary hydroxyproline (303). Immunological markersImmunological markers: In humans, intravenous L-arginine inhibited neutrophil release of superoxide anion (100), as well as increased (101; 102; 103) and decreased (104) lymphocyte proliferation or activation, increased natural killer cell activity (105; 76; 103), and increased levels of IL-2 (105). InsulinInsulin: In humans L-arginine improved insulin sensitivity and insulin clearance (109; 110), and increased plasma and urinary insulin (308; 107; 91; 109; 185; 249; 184; 344; 345). Insulin-like growth factorInsulin-like growth factor: In infertile females, L-arginine resulted in increased levels of insulin-like growth factor (167). Lactic acidLactic acid: In humans, arginine increased arterial blood content of lactic acid in burn patients (346). It has also been shown to decrease lactic acid (288). LeptinLeptin: In animals, L-arginine reduced serum leptin levels (287). Lipid profileLipid profile: In humans, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 230). In humans, L-arginine modified levels of lipoprotein (a) using some, but not all, methods of analysis (340). In coronary stent patients, L-arginine reduced the levels of oxidative LDL cholesterol (102) or lag time to oxidation (271). LysineLysine: In animals, arginine increased plasma lysine (334). Nitric oxideNitric oxide: In humans, L-arginine increased levels of plasma or urinary nitric oxide or NO2 and NO3 (308; 93; 248; 246; 347; 214; 131; 130; 348; 349) or had a lack of an effect (350; 316). In humans, L-arginine increased exhaled nitric oxide (117; 118; 351) and general nitric oxide production (352). In animals, L-arginine increased blood levels of NO2 (353; 325) and decreased blood levels of NO3 and nitrogen oxide (325). In children, changes in exhaled nitric oxide after ingestion of L-arginine were considered to be of little clinical significance (354). In animal research, the authors suggested that L-arginine prevention of atherosclerosis may have been due to effects on plasma nitrite (355). Increased levels of nitric oxide metabolites have been shown in animal research (287). In exercising animals, L-arginine increased urinary nitrate excretion (356). NoradrenalineNoradrenaline: In humans, L-arginine increased levels of plasma noradrenaline (357). OrnithineOrnithine: In humans and animals, serum ornithine increased with L-arginine supplementation (320; 289; 334; 290). Plasma catecholaminesPlasma catecholamines: In humans, L-arginine increased plasma catecholamines (91; 340). Plasma lipidsPlasma lipids: In humans and animals, dietary increases in L-arginine resulted in decreased levels of total cholesterol and triglyceride and increased levels of HDL cholesterol (127; 340; 358; 10; 287; 334; 230). Platelet aggregationPlatelet aggregation: In humans, L-arginine infusion reduced platelets and platelet aggregation (91; 92; 93; 94; 95; 96; 97; 359; 191). PotassiumPotassium: It has been suggested that L-arginine increases blood potassium levels. In renal failure patients, arginine-induced hyperkalemia occurred (84). PrealbuminPrealbumin: In humans, L-arginine improved levels of prealbumin in burned patients (105). ProlactinProlactin: In humans, both L-arginine and D-arginine (inactive amino acid) increased levels of prolactin (185). ProlineProline: It is known that L-arginine is metabolized to proline; thus proline levels increase. Plasma proline levels increased in animal research (59) ProteinProtein: In humans, L-arginine resulted in a decrease in proteinuria (360). This was also found in animal research (326). ReninRenin: In humans, L-arginine had a lack of an effect on plasma renin (206). Rennin (chymosin)Rennin (chymosin): In humans, L-arginine increased levels of plasma rennin (357). SelectinSelectin: In humans, L-arginine had a lack of an effect on soluble levels of E-selectin and P-selectin (361). SodiumSodium: In humans, use of L-arginine reduced renal sodium excretion with a low salt intake and increased renal excretion with a high salt intake (308; 240). Sperm motility/countSperm motility/count: In humans, L-arginine increased sperm count and motility (168; 169; 362). Stress hormonesStress hormones: In humans, a combination of lysine and L-arginine increased adrenocorticotropic hormone, cortisol, adrenaline, and noradrenaline levels during psychological stress, and decreased basal trait and state anxiety scores and salivary cortisol and chromogranin A (53; 295). Systemic pHSystemic pH: In humans, L-arginine decreased systemic pH (206). Transcutaneous oxygenTranscutaneous oxygen: In humans, in ischemic feet, L-arginine resulted in an increase in transcutaneous oxygen (359). TransferrinTransferrin: In burn patients, L-arginine improved levels of transferrin (105). Tricarboxylic acid metabolitesTricarboxylic acid metabolites: In animals, arginine increased tricarboxylic acid metabolites (334). TroponinTroponin: In cardiac bypass patients, L-arginine had a lack of an effect on release of troponin-1 (363), although it reduced troponin T (190; 2). Tumor surface markersTumor surface markers: In human colorectal cancer patients, L-arginine resulted in increased numbers of cell subsets within the tumor expressing CD16 and CD56 surface markers (233). TyrosineTyrosine: In animals, arginine increased plasma tyrosine (334). Umbilical artery pulsatility indicesUmbilical artery pulsatility indices: In humans, umbilical artery pulsatility indices values were lower following maternal L-arginine supplementation (123). UreaUrea: In humans, L-arginine increased levels of urinary urea (249). Plasma urea decreased in animal research (287; 334). Ventilatory equivalent ratio for carbon dioxideVentilatory equivalent ratio for carbon dioxide: In patients with severe chronic heart failure, intravenous L-arginine reduced the ventilatory equivalent ratio for carbon dioxide (VE/VCO2) slope (286). Very-long-chain fatty acidsVery-long-chain fatty acids: In patients with X linked adrenoleukodystrophy, very-long-chain fatty acids were reduced following L-arginine treatment (183). Von Willebrand factorVon Willebrand factor: In animal research, the authors suggested that L-arginine prevention of atherosclerosis may be due to inhibition of von Willebrand factor (355). White blood cellsWhite blood cells: In cardiac bypass patients given L-arginine in cardioplegic solution, leukocyte counts were reduced (191). In humans, intravenous L-arginine inhibited neutrophil release of superoxide anion (100), as well as increased (101; 102; 103) and decreased (104) lymphocyte proliferation or activation. Arginine/Other Interactions:
In vitro fertilizationIn vitro fertilization: L-arginine supplementation resulted in a lower cancelation rate of in vitro fertilization (IVF), an increased number of oocytes, an increased number of transferred embryos, and an improvement in follicular Doppler flow and pregnancy rate (167). In women undergoing IVF, arginine increased blood levels of arginine (208). In other research evaluating the effects of L-arginine in women undergoing IVF treatment, oral L-arginine supplementation in normally responding patients increased follicular recruitment and reduced the duration of pFSH treatment but had detrimental effects on embryo quality and pregnancy rate (208).