Therapeutic potency of L-arginine in cardiovascular diseases

April 22, 2019

The review focuses on the place and role of exogenous L-arginine in treatment of cardiovascular diseases. The theoretical background of using exogenous L-arginine as a donor of nitric oxide and a modulator of endothelial function is served. The data of preclinical and clinical studies characterizing the efficacy and safety of L-arginine in cardiovascular diseases are given.

Published: 22.04.2019


  • Berezyn A.E. (2010) Klynycheskaia lypydolohyia. Sovremennaia stratehyia dyahnostyky, profylaktyky y lechenyia hyperlypydemyi. MORYON, Kyev, 384 s.
  • Berezyn A.E. (2007) Otsenka hlobalnoho kardyovaskuliarnoho ryska. Preymushchestva y ohranychenyia multy-faktoryalnoho podkhoda. Ukr. med. chasopys, 3(59): 37–44.
  • Berezyn A.E. (2017) Prohrammы pervychnoi y vtorychnoi preventsyy kardyovaskuliarnыkh zabolevanyi: fokus na atorvastatyn. Ukr. med. chasopys, 4(120): 105–110.
  • Acevedo M., Valentino G., Kramer V. et al. (2017) Evaluation the American College of Cardiology and American Heart Association Predictive score for cardiovascular diseases. Rev. Med. Chil., 145(3): 292–298.
  • Adams M.R., McCredie R., Jessup W. et al. (1997) Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis, 129(2): 261–269.
  • Ast J., Jablecka A., Bogdanski P. et al. (2010) Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med. Sci. Monit., 16(5): CR266–CR271.
  • Berezin A. (2018) Neutrophil extracellular traps: the core player in vascular complications of diabetes mellitus. Diabetes Metab. Syndr. [Epub ahead of print].
  • Berezin A.E. (2017) Are inflammatory cytokines and angiogenic factors a predictive biomarker of diabetes retinopathy? Diabetes Metab. Syndr., 11(Suppl. 2): S735–S736.
  • Berkowitz D.E., White R., Li D. et al. (2003) Arginase reciprocally regulates nitric oxide synthase activity and contributes to endothelial dysfunction in aging blood vessels. Circulation, 108(16): 2000–2006.
  • Blum A., Hathaway L., Mincemoyer R. et al. (2000) Oral L-arginine in patients with coronary artery disease on medical management. Circulation, 101(18): 2160–2164.
  • Bocchi E.A., Vilella de Moraes A.V., Esteves-Filho A. et al. (2000) L-arginine reduces heart rate and improves hemodynamics in severe congestive heart failure. Clin. Cardiol., 23(3): 205–210.
  • Bode-Boger S.M., Muke J., Surdacki A. et al. (2003) Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc. Med., 8(2): 77–81.
  • Bogdanski P., Szulinska M., Suliburska J. et al. (2013) Supplementation with L-arginine favorably influences plasminogen activator inhibitor type 1 concentration in obese patients. A randomized, double blind trial. J. Endocrinol. Invest, 36(4): 221–226.
  • Boger R.H. (2008) L-Arginine therapy in cardiovascular pathologies: beneficial or dangerous? Curr. Opin Clin. Nutr. Metab. Care, 11(1): 55–61.
  • Boger R.H., Bode-Boger S.M. (2001) The clinical pharmacology of L-arginine. Ann. Rev. Pharmacol. Toxicol., 41: 79–99.
  • Boger R.H., Bode-Boger S.M., Kienke S. et al. (1998) Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterolfed rabbits. Atherosclerosis, 136(1): 67–77.
  • Chaturvedi R., Asim M., Lewis N.D. et al. (2007) L-arginine availability regulates inducible nitric oxide synthase-dependent host defense against Helicobacter pylori. Infect. Immun, 75(9): 4305–4315.
  • Chicoine L.G., Paffett M.L., Young T.L. et al. (2004) Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol., 287(1): L60–L68.
  • Clarkson P., Adams M.R., Powe A.J. et al. (1996) Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J. Clin. Invest., 97(8): 1989–1994.
  • Dumont Y., D’Amours M., Lebel M., Lariviere R. (2001) Supplementation with a low dose of L-arginine reduces blood pressure and endothelin-1 production in hypertensive uraemic rats. Nephrol. Dial. Transplant., 16(4): 746–754.
  • Forstermann U., Munzel T. (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation, 113(13): 1708–1714.
  • Gogoi M., Datey A., Wilson K.T., Chakravortty D. (2016) Dual role of arginine metabolism in establishing pathogenesis. Curr. Opin. Microbiol., 29: 43–48.
  • Hein T.W., Zhang C., Wang W. et al. (2003) Ischemia-reperfusion selectively impairs nitric oxide mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J., 17(15): 2328–2330.
  • Jia Y.X., Pan C.S., Yang J.H. et al. (2006) Altered L-arginine/nitric oxide synthase/nitric oxide pathway in the vascular adventitia of rats with sepsis. Clin. Exp. Pharmacol. Physiol., 33(12): 1202–1208.
  • Jungnickel K.E.J., Parker J.L., Newstead S. (2018) Structural basis for amino acid transport by the CAT family of SLC7 transporters. Nat. Commun., 9(1): 550.
  • Koifman B., Wollman Y., Bogomolny N. et al. (1995) Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J. Am. Coll. Cardiol., 26(5): 1251–1256.
  • Lee C.W., Li D., Channon K.M., Paterson D.J. (2009) L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats. J. Mol. Cell Cardiol., 47(1): 149–155.
  • Lerman A., Burnett J.C. Jr., Higano S.T. et al. (1998) Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation, 97(21): 2123–2128.
  • Lillico R., Sobral M.G., Stesco N., Lakowski T.M. (2016) HDAC inhibitors induce global changes in histone lysine and arginine methylation and alter expression of lysine demethylases. J. Proteomics., 133: 125–133.
  • Loscalzo J. (2003) Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler. Thromb. Vasc. Biol., 23(1): 3–5.
  • Magee L.A., Pels A., Helewa M. et al.; Canadian Hypertensive Disorders of Pregnancy Working Group (2014) Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J. Obstet. Gynaecol. Can., 36(5): 416–441.
  • Maxwell A.J., Cooke J.P. (1998) Cardiovascular effects of L-arginine. Curr. Opin Nephrol. Hypertens, 7(1): 63–70.
  • Miller M.W., Knaub L.A., Olivera-Fragoso L.F. et al. (2013) Nitric oxide regulates vascular adaptive mitochondrial dynamics. Am. J. Physiol. Heart Circ. Physiol., 304(12): H1624–H1633.
  • Morris S.M.Jr. (2005) Arginine metabolism in vascular biology and disease. Vasc. Med., 10(Suppl. 1): S83–S87.
  • Nagase S., Takemura K., Ueda A. et al. (1997) A novel non-enzymatic pathway for the generation of nitric oxide by the reaction of hydrogen peroxide and D- or L-arginine. Biochem. Biophys. Res. Commun., 233(1): 150–153.
  • Ohta K., Hirata Y., Shichiri M. et al. (1991) Urinary excretion of endothelin-1 in normal subjects and patients with renal disease. Kidney Int., 39(2): 307–311.
  • Paulson N.B., Gilbertsen A.J., Dalluge J.J. et al. (2014) The arginine decarboxylase pathways of host and pathogen interact to impact inflammatory pathways in the lung. PLoS One, 9: e111441.
  • Piatti P.M., Monti L.D., Valsecchi G. et al. (2001) Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care, 24(5): 875–880.
  • Rafikov R., Fonseca F.V., Kumar S. et al. (2011) eNOS activation and NO function: structural motifs responsible for the posttranslational control of endothelial nitric oxide synthase activity. J. Endocrinol., 210(3): 271–284.
  • Schulman S.P., Becker L.C., Kass D.A. et al. (2006) L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA, 295(1): 58–64.
  • Soskic S.S., Dobutovic B.D., Sudar E.M. et al. (2011) Regulation of Inducible Nitric Oxide Synthase (iNOS) and its Potential Role in Insulin Resistance, Diabetes and Heart Failure. Open Cardiovasc Med. J., 5: 153–163.
  • Stuehr D.J. (1997) Structure-function aspects in the nitric oxide synthases. Ann. Rev. Pharmacol. Toxicol, 37: 339–359.
  • Sukhovershin R.A., Gilinsky M.A. (2013) The influence of acute renal injury on arginine and methylarginines metabolism. Ren. Fail., 35(10): 1404–1411.
  • Susic D., Francischetti A., Frohlich E.D. (1999) Prolonged L-arginine on cardiovascular mass and myocardial hemodynamics and collagen in aged spontaneously hypertensive rats and normal rats. Hypertension, 33(1 Pt. 2): 451–455.
  • Susic D., Varagic J., Frohlich E.D. (2001) Isolated systolic hypertension in elderly WKY is reversed with L-arginine and ACE inhibition. Hypertension, 38(6): 1422–1426.
  • Suzuki T., Morita M., Hayashi T., Kamimura A. (2017) The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males. Biosci. Biotechnol. Biochem., 81(2): 372–375.
  • Suzuki Y.J. (2019) Oxidant-Mediated Protein Amino Acid Conversion. Antioxidants (Basel), 8(2): 50.
  • Takeuchi K., McGowan F.X., Danh H.C. et al. (1995) Direct detrimental effects of Larginine upon ischemia — reperfusion injury to myocardium. J. Mol. Cell Cardiol., 27(7): 1405–1414.
  • Tapiero H., Mathe G., Couvreur P., Tew K.D.I. (2002) Arginine. Biomed. Pharmacother., 56(9): 439–445.
  • Tousoulis D., Antoniades C., Tentolouris C. et al. (2002) L-arginine in cardiovascular disease: dream or reality? Vasc. Med., 7(3): 203–211.
  • Walker J.B. (1979) Creatine: biosynthesis, regulation, and function. Adv. Enzymol. Relat. Areas Mol. Biol., 50: 177–242.
  • Wesche J., Kühn S., Kessler B.M. et al. (2017) Protein arginine methylation: a prominent modification and its demethylation. Cell Mol. Life Sci., 74(18): 3305–3315.
  • Wilson A.M., Harada R., Nair N. et al. (2007) L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation, 116(2): 188–195.
  • Wu G. (1997) Synthesis of citrulline and arginine from proline in enterocytes of postnatal pigs. Am. J. Physiol., 272(6 Pt. 1): G1382–G1390.
  • Wu G., Morris S.M.Jr. (1998) Arginine metabolism: nitric oxide and beyond. Biochem. J., 336 (Pt. 1): 1–17.
  • Wyss M., Kaddurah-Daouk R. (2000) Creatine and creatinine metabolism. Physiol. Rev., 80(3): 1107–1213.
  • Xie L., Gross S.S. (1997) Argininosuccinate synthetase overexpression in vascular smooth muscle cells potentiates immunostimulant-induced NO production. J. Biol. Chem., 272(26): 16624–16630.
  • Yang Z., Ming X.F. (2013) Arginase: the emerging therapeutic target for vascular oxidative stress and inflammation. Front. Immunol., 4: 149.
  • Zakula Z., Koricanac G., Putnikovic B. et al. (2007) Regulation of the inducible nitric oxide synthase and sodium pump in type 1 diabetes. Med. Hypotheses, 69(2): 302–306.
  • Zhang C., Hein T.W., Wang W. et al. (2004) Upregulation of vascular arginase in hypertension decreases nitric oxide-mediated dilation of coronary arterioles. Hypertension, 44(6): 935–943.