{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T17:23:18Z","timestamp":1788888198715,"version":"build-2803163510"},"reference-count":96,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN-2016-03951"],"award-info":[{"award-number":["RGPIN-2016-03951"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["Alexander Graham Bell Graduate Scholarship"],"award-info":[{"award-number":["Alexander Graham Bell Graduate Scholarship"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Oral L-arginine supplements are popular mainly for their nitric oxide mediated vasodilation, but their physiological impact is not fully known. L-arginine is a substrate of several enzymes including arginase, nitric oxide synthase, arginine decarboxylase, and arginine: glycine amidinotransferase (AGAT). We have published a study on the physiological impact of oral L- and D-arginine at 500 mg\/kg\/day for 4 wks in male Sprague-Dawley rats. We investigated the effects of oral L-arginine and D-arginine at a higher dose of 1000 mg\/kg\/d for a longer treatment duration of 16 wks in 9-week-old male Sprague-Dawley rats. We measured the expression and activity of L-arginine metabolizing enzymes, and levels of their metabolites in the plasma and various organs. L-arginine did not affect the levels of L-arginine and L-lysine in the plasma and various organs. L-arginine decreased arginase protein expression in the upper small intestine, and arginase activity in the plasma. It also decreased AGAT protein expression in the liver, and creatinine levels in the urine. L-arginine altered arginine decarboxylase protein expression in the upper small intestine and liver, with increased total polyamines plasma levels. Endothelial nitric oxide synthase protein was increased with D-arginine, the presumed metabolically inert isomer, but not L-arginine. In conclusion, oral L-arginine and D-arginine at a higher dose and longer treatment duration significantly altered various enzymes and metabolites in the arginine metabolic pathways, which differed from alterations produced by a lower dose shorter duration treatment published earlier. Further studies with differing doses and duration would allow for a better understanding of oral L-arginine uses, and evidence based safe and effective dose range and duration.<\/jats:p>","DOI":"10.1371\/journal.pone.0289476","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T17:28:52Z","timestamp":1690910932000},"page":"e0289476","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["The effects of a comparatively higher dose of 1000 mg\/kg\/d of oral L- or D-arginine on the L-arginine metabolic pathways in male Sprague-Dawley rats"],"prefix":"10.1371","volume":"18","author":[{"given":"Dain (Raina)","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9355-4528","authenticated-orcid":true,"given":"Kaushik","family":"Desai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,1]]},"reference":[{"issue":"6 Suppl 2","key":"pone.0289476.ref001","doi-asserted-by":"crossref","first-page":"1650s","DOI":"10.1093\/jn\/137.6.1650S","article-title":"The pharmacodynamics of L-arginine.","volume":"137","author":"RH B\u00f6ger","year":"2007","journal-title":"J Nutr"},{"issue":"2","key":"pone.0289476.ref002","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1017\/S0007114519002691","article-title":"The effects of oral arginine on its metabolic pathways in Sprague-Dawley rats","volume":"123","author":"S Martin","year":"2020","journal-title":"Br J Nutr"},{"key":"pone.0289476.ref003","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/B978-012056250-3\/50030-5","volume-title":"Bioavailability of Nutrients for Animals.","author":"A. Lewis","year":"1995"},{"issue":"10 Suppl","key":"pone.0289476.ref004","doi-asserted-by":"crossref","first-page":"2743S","DOI":"10.1093\/jn\/134.10.2743S","article-title":"Enzymes of arginine metabolism.","volume":"134","author":"SM Morris","year":"2004","journal-title":"J Nutr"},{"issue":"Pt 1","key":"pone.0289476.ref005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3360001","article-title":"Arginine metabolism: nitric oxide and beyond","volume":"336","author":"G Wu","year":"1998","journal-title":"Biochem J"},{"issue":"2","key":"pone.0289476.ref006","first-page":"109","article-title":"Nitric oxide: physiology, pathophysiology, and pharmacology.","volume":"43","author":"S Moncada","year":"1991","journal-title":"Pharmacological reviews."},{"issue":"1","key":"pone.0289476.ref007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00726-009-0269-0","article-title":"Amino acids: metabolism, functions, and nutrition","volume":"37","author":"G. Wu","year":"2009","journal-title":"Amino Acids"},{"issue":"13","key":"pone.0289476.ref008","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1161\/CIRCULATIONAHA.105.602532","article-title":"Endothelial nitric oxide synthase in vascular disease: from marvel to menace","volume":"113","author":"U F\u00f6rstermann","year":"2006","journal-title":"Circulation"},{"issue":"Pt 2","key":"pone.0289476.ref009","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1113\/jphysiol.2007.128959","article-title":"Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans","volume":"581","author":"LA Holowatz","year":"2007","journal-title":"J Physiol"},{"issue":"2","key":"pone.0289476.ref010","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1152\/physrev.00037.2016","article-title":"Arginase: A Multifaceted Enzyme Important in Health and Disease","volume":"98","author":"RW Caldwell","year":"2018","journal-title":"Physiol Rev"},{"issue":"4","key":"pone.0289476.ref011","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1095\/biolreprod.113.114637","article-title":"Arginine decarboxylase and agmatinase: an alternative pathway for de novo biosynthesis of polyamines for development of mammalian conceptuses","volume":"90","author":"X Wang","year":"2014","journal-title":"Biol Reprod"},{"issue":"10 Suppl","key":"pone.0289476.ref012","doi-asserted-by":"crossref","first-page":"2791S","DOI":"10.1093\/jn\/134.10.2791S","article-title":"Renal arginine metabolism","volume":"134","author":"ME Brosnan","year":"2004","journal-title":"J Nutr"},{"issue":"1","key":"pone.0289476.ref013","first-page":"52","article-title":"Metabolism of guanido-labeled (C-14)arginine in rats, mice, and man.","volume":"21","author":"CG Frondoza","year":"1980","journal-title":"J Nucl Med"},{"issue":"5","key":"pone.0289476.ref014","doi-asserted-by":"crossref","first-page":"972","DOI":"10.3945\/ajcn.112.048025","article-title":"Kinetics of the utilization of dietary arginine for nitric oxide and urea synthesis: insight into the arginine-nitric oxide metabolic system in humans","volume":"97","author":"F Mariotti","year":"2013","journal-title":"Am J Clin Nutr"},{"issue":"2","key":"pone.0289476.ref015","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/1550-2783-1-2-35","article-title":"The ergogenic potential of arginine.","volume":"1","author":"BI Campbell","year":"2004","journal-title":"J Int Soc Sports Nutr"},{"issue":"2","key":"pone.0289476.ref016","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1056\/NEJM199201093260203","article-title":"Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission","volume":"326","author":"J Rajfer","year":"1992","journal-title":"N Engl J Med"},{"issue":"2","key":"pone.0289476.ref017","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1530\/eje.0.1430143","article-title":"Erectile dysfunction: from biochemical pharmacology to advances in medical therapy","volume":"143","author":"M Maggi","year":"2000","journal-title":"Eur J Endocrinol"},{"issue":"6","key":"pone.0289476.ref018","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.ahj.2011.09.012","article-title":"Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials","volume":"162","author":"JY Dong","year":"2011","journal-title":"Am Heart J"},{"issue":"8","key":"pone.0289476.ref019","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1172\/JCI118632","article-title":"Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults","volume":"97","author":"P Clarkson","year":"1996","journal-title":"J Clin Invest"},{"issue":"5","key":"pone.0289476.ref020","doi-asserted-by":"crossref","first-page":"875","DOI":"10.2337\/diacare.24.5.875","article-title":"Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients","volume":"24","author":"PM Piatti","year":"2001","journal-title":"Diabetes care"},{"issue":"2","key":"pone.0289476.ref021","doi-asserted-by":"crossref","first-page":"94","DOI":"10.4103\/0976-500X.72351","article-title":"Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research","volume":"1","author":"C Kilkenny","year":"2010","journal-title":"J Pharmacol Pharmacother"},{"issue":"1","key":"pone.0289476.ref022","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbrc.2014.10.029","article-title":"Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability","volume":"454","author":"M Morita","year":"2014","journal-title":"Biochem Biophys Res Commun"},{"issue":"9","key":"pone.0289476.ref023","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1007\/s00726-015-1992-3","article-title":"Safety of long-term dietary supplementation with L-arginine in rats","volume":"47","author":"Y Yang","year":"2015","journal-title":"Amino Acids"},{"issue":"8","key":"pone.0289476.ref024","doi-asserted-by":"crossref","first-page":"Pl131","DOI":"10.1016\/S0024-3205(96)80013-0","article-title":"The effects of arginine administration on the levels of arginine, other amino acids and related amino compounds in the plasma, heart, aorta, vena cava, bronchi and pancreas of the rat","volume":"58","author":"FM Noeh","year":"1996","journal-title":"Life Sci"},{"key":"pone.0289476.ref025","author":"FDA","year":"2005","journal-title":"Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers"},{"issue":"3","key":"pone.0289476.ref026","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1007\/s00421-013-2636-5","article-title":"Blood pressure regulation: every adaptation is an integration?","volume":"114","author":"MJ Joyner","year":"2014","journal-title":"Eur J Appl Physiol"},{"issue":"4","key":"pone.0289476.ref027","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1681\/ASN.V541057","article-title":"Nitric oxide in essential and renal hypertension","volume":"5","author":"R MacAllister","year":"1994","journal-title":"J Am Soc Nephrol"},{"issue":"9","key":"pone.0289476.ref028","article-title":"The Causal Relationship between Endothelin-1 and Hypertension: Focusing on Endothelial Dysfunction, Arterial Stiffness, Vascular Remodeling, and Blood Pressure Regulation","volume":"11","author":"K. Kostov","year":"2021","journal-title":"Life (Basel)."},{"issue":"5","key":"pone.0289476.ref029","doi-asserted-by":"crossref","first-page":"E906","DOI":"10.1152\/ajpendo.00002.2006","article-title":"Beneficial effects of a long-term oral L-arginine treatment added to a hypocaloric diet and exercise training program in obese, insulin-resistant type 2 diabetic patients","volume":"291","author":"P Lucotti","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"12","key":"pone.0289476.ref030","first-page":"1375","article-title":"Supplementation with L-arginine does not influence arterial blood pressure in healthy people: a randomized, double blind, trial.","volume":"15","author":"J Ast","year":"2011","journal-title":"Eur Rev Med Pharmacol Sci."},{"issue":"12","key":"pone.0289476.ref031","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1080\/14779072.2018.1540301","article-title":"Pathophysiology of essential hypertension: an update","volume":"16","author":"T Saxena","year":"2018","journal-title":"Expert Rev Cardiovasc Ther"},{"issue":"2 Pt 1","key":"pone.0289476.ref032","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/ajh\/4.2.177","article-title":"Mechanisms of hypertension in diabetes","volume":"4","author":"JR Sowers","year":"1991","journal-title":"Am J Hypertens"},{"issue":"3","key":"pone.0289476.ref033","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/0026-0495(95)90167-1","article-title":"Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress?","volume":"44","author":"D Giugliano","year":"1995","journal-title":"Metabolism"},{"issue":"12","key":"pone.0289476.ref034","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.autrev.2010.07.016","article-title":"From endothelial dysfunction to atherosclerosis","volume":"9","author":"S Sitia","year":"2010","journal-title":"Autoimmun Rev"},{"key":"pone.0289476.ref035","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.arr.2016.01.007","article-title":"Hypertension and aging","volume":"26","author":"TW Buford","year":"2016","journal-title":"Ageing Res Rev"},{"issue":"4","key":"pone.0289476.ref036","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1590\/S0100-879X1997000400014","article-title":"Neural reflex regulation of arterial pressure in pathophysiological conditions: interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex","volume":"30","author":"EC Vasquez","year":"1997","journal-title":"Braz J Med Biol Res"},{"key":"pone.0289476.ref037","first-page":"S35","article-title":"Pressure-volume regulation in hypertension","volume":"55","author":"JE Hall","year":"1996","journal-title":"Kidney Int Suppl"},{"issue":"2\u20133","key":"pone.0289476.ref038","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0167-5273(02)00413-8","article-title":"Oral L-arginine improves endothelial dysfunction in patients with essential hypertension","volume":"86","author":"JP Lekakis","year":"2002","journal-title":"Int J Cardiol"},{"issue":"3","key":"pone.0289476.ref039","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1172\/JCI119166","article-title":"Insulin and the arginine paradox","volume":"99","author":"S Kurz","year":"1997","journal-title":"J Clin Invest"},{"issue":"3","key":"pone.0289476.ref040","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1172\/JCI119177","article-title":"The vascular effects of L-Arginine in humans. The role of endogenous insulin","volume":"99","author":"D Giugliano","year":"1997","journal-title":"J Clin Invest"},{"issue":"8793","key":"pone.0289476.ref041","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","article-title":"Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure","volume":"339","author":"P Vallance","year":"1992","journal-title":"Lancet"},{"issue":"6","key":"pone.0289476.ref042","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1071\/RD9951581","article-title":"Effect of asymmetric dimethyl arginine on nitric oxide synthase activity in normal and pre-eclamptic placentae","volume":"7","author":"RG King","year":"1995","journal-title":"Reprod Fertil Dev"},{"issue":"2","key":"pone.0289476.ref043","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1006\/bbrc.1996.0279","article-title":"Elevated L-arginine\/dimethylarginine ratio contributes to enhanced systemic NO production by dietary L-arginine in hypercholesterolemic rabbits","volume":"219","author":"SM Bode-B\u00f6ger","year":"1996","journal-title":"Biochem Biophys Res Commun"},{"issue":"2","key":"pone.0289476.ref044","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1191\/1358863x03vm474oa","article-title":"Oral L-arginine improves endothelial function in healthy individuals older than 70 years.","volume":"8","author":"SM Bode-B\u00f6ger","year":"2003","journal-title":"Vasc Med."},{"issue":"6","key":"pone.0289476.ref045","doi-asserted-by":"crossref","first-page":"12230","DOI":"10.3390\/ijms160612230","article-title":"The Arginine\/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine.","volume":"16","author":"SJ Brinkmann","year":"2015","journal-title":"Int J Mol Sci."},{"issue":"5","key":"pone.0289476.ref046","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/cbf.1491","article-title":"Effects of oral L-arginine supplementation on blood pressure and asymmetric dimethylarginine in stress-induced preeclamptic rats","volume":"26","author":"ZS Altun","year":"2008","journal-title":"Cell Biochem Funct"},{"issue":"12","key":"pone.0289476.ref047","first-page":"1665","article-title":"Oral L-arginine supplementation in patients with mild arterial hypertension and its effect on plasma level of asymmetric dimethylarginine, L-citruline, L-arginine and antioxidant status.","volume":"16","author":"A Jabecka","year":"2012","journal-title":"Eur Rev Med Pharmacol Sci."},{"issue":"9","key":"pone.0289476.ref048","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.metabol.2009.03.029","article-title":"Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass","volume":"58","author":"P Lucotti","year":"2009","journal-title":"Metabolism"},{"issue":"2","key":"pone.0289476.ref049","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1161\/01.RES.87.2.99","article-title":"LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases","volume":"87","author":"RH B\u00f6ger","year":"2000","journal-title":"Circ Res"},{"issue":"1","key":"pone.0289476.ref050","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.atherosclerosis.2005.12.007","article-title":"Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes","volume":"189","author":"K Krzyzanowska","year":"2006","journal-title":"Atherosclerosis"},{"issue":"4 Pt 1","key":"pone.0289476.ref051","first-page":"E532","article-title":"Dietary arginine uptake by the splanchnic region in adult humans","volume":"265","author":"L Castillo","year":"1993","journal-title":"Am J Physiol"},{"issue":"6 Suppl 2","key":"pone.0289476.ref052","doi-asserted-by":"crossref","first-page":"1673s","DOI":"10.1093\/jn\/137.6.1673S","article-title":"Pharmacokinetics and safety of arginine supplementation in animals","volume":"137","author":"G Wu","year":"2007","journal-title":"J Nutr"},{"issue":"5","key":"pone.0289476.ref053","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1046\/j.1365-2125.1998.00803.x","article-title":"L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship","volume":"46","author":"SM Bode-B\u00f6ger","year":"1998","journal-title":"Br J Clin Pharmacol"},{"issue":"3","key":"pone.0289476.ref054","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1046\/j.1365-2125.1999.00883.x","article-title":"Pharmacokinetics of intravenous and oral L-arginine in normal volunteers","volume":"47","author":"O Tangphao","year":"1999","journal-title":"Br J Clin Pharmacol"},{"issue":"9","key":"pone.0289476.ref055","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jnutbio.2004.03.005","article-title":"Biochemical responses of healthy subjects during dietary supplementation with L-arginine","volume":"15","author":"RW Evans","year":"2004","journal-title":"J Nutr Biochem"},{"issue":"2","key":"pone.0289476.ref056","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1152\/physrev.1998.78.2.487","article-title":"Transporters for cationic amino acids in animal cells: discovery, structure, and function.","volume":"78","author":"R Dev\u00e9s","year":"1998","journal-title":"Physiol Rev."},{"issue":"3\u20134","key":"pone.0289476.ref057","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0304-4157(85)90015-2","article-title":"The transport of cationic amino acids across the plasma membrane of mammalian cells","volume":"822","author":"MF White","year":"1985","journal-title":"Biochim Biophys Acta"},{"issue":"4","key":"pone.0289476.ref058","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1016\/j.bbrc.2011.09.112","article-title":"Intracellular L-arginine concentration does not determine NO production in endothelial cells: implications on the \"L-arginine paradox\".","volume":"414","author":"S Shin","year":"2011","journal-title":"Biochem Biophys Res Commun"},{"issue":"50","key":"pone.0289476.ref059","doi-asserted-by":"crossref","first-page":"50000","DOI":"10.1074\/jbc.M305903200","article-title":"Transcriptional control of the arginine\/lysine transporter, cat-1, by physiological stress","volume":"278","author":"J Fernandez","year":"2003","journal-title":"J Biol Chem"},{"issue":"12","key":"pone.0289476.ref060","doi-asserted-by":"crossref","first-page":"5560","DOI":"10.2527\/jas.2014-7690","article-title":"Orally supplemented L-arginine impairs amino acid absorption depending on dose in horses","volume":"92","author":"DE Kelley","year":"2014","journal-title":"J Anim Sci"},{"issue":"2","key":"pone.0289476.ref061","first-page":"161","article-title":"Competitive inhibition and exchange transport between arginine and lysine in the process of absorption from the caecum in pigs","volume":"29","author":"A. Olszewski","year":"1978","journal-title":"Acta Physiol Pol"},{"issue":"2","key":"pone.0289476.ref062","first-page":"90","article-title":"To give or not to give? Lessons from the arginine paradox","volume":"4","author":"FS Dioguardi","year":"2011","journal-title":"J Nutrigenet Nutrigenomics."},{"key":"pone.0289476.ref063","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.exger.2017.01.023","article-title":"Effects of a chronic l-arginine supplementation on the arginase pathway in aged rats","volume":"90","author":"J Moretto","year":"2017","journal-title":"Exp Gerontol"},{"issue":"2","key":"pone.0289476.ref064","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1172\/JCI113923","article-title":"Differential expression of the two human arginase genes in hyperargininemia. Enzymatic, pathologic, and molecular analysis","volume":"83","author":"WW Grody","year":"1989","journal-title":"J Clin Invest"},{"key":"pone.0289476.ref065","doi-asserted-by":"crossref","first-page":"112840","DOI":"10.1016\/j.biopha.2022.112840","article-title":"Arginase: An emerging and promising therapeutic target for cancer treatment","volume":"149","author":"F Niu","year":"2022","journal-title":"Biomed Pharmacother"},{"issue":"3","key":"pone.0289476.ref066","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1159\/000094344","article-title":"Effect of chronic renal failure on arginase and argininosuccinate synthetase expression.","volume":"26","author":"H Moradi","year":"2006","journal-title":"Am J Nephrol"},{"issue":"12","key":"pone.0289476.ref067","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1096\/fj.99-0960com","article-title":"Physiological cyclic stretch directs L-arginine transport and metabolism to collagen synthesis in vascular smooth muscle","volume":"14","author":"W Durante","year":"2000","journal-title":"Faseb j"},{"issue":"2","key":"pone.0289476.ref068","first-page":"155","article-title":"Arginine stimulates wound healing and immune function in elderly human beings","volume":"114","author":"SJ Kirk","year":"1993","journal-title":"Surgery"},{"issue":"1","key":"pone.0289476.ref069","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/j.1524-475X.2006.00186.x","article-title":"Supplemental L-arginine enhances wound healing following trauma\/hemorrhagic shock","volume":"15","author":"HP Shi","year":"2007","journal-title":"Wound Repair Regen"},{"issue":"6174","key":"pone.0289476.ref070","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/333664a0","article-title":"Vascular endothelial cells synthesize nitric oxide from L-arginine","volume":"333","author":"RM Palmer","year":"1988","journal-title":"Nature"},{"issue":"1","key":"pone.0289476.ref071","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.pathophys.2008.11.003","article-title":"l-Arginine supplementation enhances eNOS expression in experimental model of hypercholesterolemic rabbits aorta","volume":"16","author":"SH Javanmard","year":"2009","journal-title":"Pathophysiology"},{"key":"pone.0289476.ref072","doi-asserted-by":"crossref","first-page":"1179546820902843","DOI":"10.1177\/1179546820902843","article-title":"l-arginine Supplementation Increased Only Endothelium-Dependent Relaxation in Sprague-Dawley Rats Fed a High-Salt Diet by Enhancing Abdominal Aorta Endothelial Nitric Oxide Synthase Gene Expression.","volume":"14","author":"A Adejare","year":"2020","journal-title":"Clin Med Insights Cardiol"},{"issue":"2","key":"pone.0289476.ref073","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/15910199211025107","article-title":"L-Arginine reduces downstream vascular contractility after flow-diverting device deployment: A preliminary study in a rabbit model.","volume":"28","author":"J Ayers-Ringler","year":"2022","journal-title":"Interv Neuroradiol"},{"issue":"11","key":"pone.0289476.ref074","doi-asserted-by":"crossref","first-page":"F1292","DOI":"10.1152\/ajprenal.00176.2014","article-title":"Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation","volume":"307","author":"H You","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"pone.0289476.ref075","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.niox.2022.06.004","article-title":"Downregulation of eNOS and preserved endothelial function in endothelial-specific arginase 1-deficient mice","volume":"125\u2013126","author":"SK Heuser","year":"2022","journal-title":"Nitric Oxide"},{"issue":"3","key":"pone.0289476.ref076","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2165\/11538590-000000000-00000","article-title":"L-Arginine as a potential ergogenic aid in healthy subjects.","volume":"41","author":"TS Alvares","year":"2011","journal-title":"Sports Med."},{"issue":"4","key":"pone.0289476.ref077","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1111\/j.1523-1755.2002.kid555.x","article-title":"Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure","volume":"62","author":"KJ Bennett-Richards","year":"2002","journal-title":"Kidney Int"},{"issue":"1","key":"pone.0289476.ref078","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s00726-008-0210-y","article-title":"Arginine metabolism and nutrition in growth, health and disease","volume":"37","author":"G Wu","year":"2009","journal-title":"Amino Acids"},{"issue":"3\u20134","key":"pone.0289476.ref079","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.niox.2007.07.001","article-title":"Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle","volume":"17","author":"BR Flam","year":"2007","journal-title":"Nitric Oxide"},{"issue":"4","key":"pone.0289476.ref080","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3945\/jn.116.240382","article-title":"Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice","volume":"147","author":"U Agarwal","year":"2017","journal-title":"J Nutr"},{"issue":"3","key":"pone.0289476.ref081","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s40272-020-00384-5","article-title":"Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review.","volume":"22","author":"J Rashid","year":"2020","journal-title":"Paediatr Drugs"},{"issue":"4","key":"pone.0289476.ref082","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ymgme.2015.10.003","article-title":"Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide.","volume":"116","author":"S Stockler-Ipsiroglu","year":"2015","journal-title":"Mol Genet Metab"},{"key":"pone.0289476.ref083","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0003-2670(02)00777-8","article-title":"Quantitation of agmatine by liquid chromatography with laser-induced fluorescence detection","volume":"470","author":"S Zhao","year":"2002","journal-title":"Analytica Chimica Acta"},{"issue":"1","key":"pone.0289476.ref084","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/15360280902728161","article-title":"Agmatine levels in the cerebrospinal fluid of normal human volunteers","volume":"23","author":"S Regunathan","year":"2009","journal-title":"J Pain Palliat Care Pharmacother"},{"issue":"12","key":"pone.0289476.ref085","doi-asserted-by":"crossref","first-page":"2579S","DOI":"10.3945\/jn.115.226621","article-title":"Arginine Metabolism Revisited.","volume":"146","author":"SM Morris","year":"2016","journal-title":"J Nutr"},{"issue":"5","key":"pone.0289476.ref086","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1046\/j.1471-4159.2000.0742201.x","article-title":"Characterization of arginine decarboxylase in rat brain and liver: distinction from ornithine decarboxylase","volume":"74","author":"S Regunathan","year":"2000","journal-title":"J Neurochem"},{"issue":"11","key":"pone.0289476.ref087","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1212\/01.wnl.0000220197.36849.1e","article-title":"Endothelial dysfunction in MELAS improved by l-arginine supplementation","volume":"66","author":"Y Koga","year":"2006","journal-title":"Neurology"},{"issue":"5","key":"pone.0289476.ref088","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1475-097X.2008.00809.x","article-title":"The effect of L-arginine administration on muscle force and power in postmenopausal women.","volume":"28","author":"O Fricke","year":"2008","journal-title":"Clin Physiol Funct Imaging"},{"issue":"4","key":"pone.0289476.ref089","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.clnu.2008.05.007","article-title":"New indications and controversies in arginine therapy.","volume":"27","author":"D Coman","year":"2008","journal-title":"Clin Nutr"},{"issue":"5","key":"pone.0289476.ref090","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1152\/japplphysiol.00503.2010","article-title":"Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance","volume":"109","author":"SJ Bailey","year":"2010","journal-title":"J Appl Physiol"},{"issue":"4","key":"pone.0289476.ref091","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1172\/JCI115987","article-title":"L-arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans","volume":"90","author":"MA Creager","year":"1992","journal-title":"J Clin Invest"},{"issue":"2","key":"pone.0289476.ref092","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1002\/ajmg.c.30091","article-title":"Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency","volume":"142C","author":"F Scaglia","year":"2006","journal-title":"Am J Med Genet C Semin Med Genet"},{"issue":"4","key":"pone.0289476.ref093","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1177\/0884533616652576","article-title":"When Is It Appropriate to Use Arginine in Critical Illness?","volume":"31","author":"JJ Patel","year":"2016","journal-title":"Nutr Clin Pract."},{"issue":"23","key":"pone.0289476.ref094","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1056\/NEJM198206103062303","article-title":"Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion","volume":"306","author":"ML Batshaw","year":"1982","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0289476.ref095","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1006\/mgme.2001.3257","article-title":"Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation","volume":"74","author":"A Schulze","year":"2001","journal-title":"Mol Genet Metab"},{"issue":"4","key":"pone.0289476.ref096","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1212\/01.WNL.0000151976.60624.01","article-title":"L-arginine improves the symptoms of strokelike episodes in MELAS","volume":"64","author":"Y Koga","year":"2005","journal-title":"Neurology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289476","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T17:29:51Z","timestamp":1690910991000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289476"}},"subtitle":[],"editor":[{"given":"Kanhaiya","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,1]]},"references-count":96,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0289476","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,1]]}}}