Atherosclerosis 154 (2001) 255 – 267 Review article Therapeutic modification of the L-arginine-eNOS pathway in cardiovascular diseases George Goumas *, Costas Tentolouris, Dimitris Tousoulis, Christodoulos Stefanadis, Pavlos Toutouzas Cardiology Unit, Hippokration Hospital, Athens Uniersity Medical School, Vas. Sofias 114, 11528 Athens, Greece Received 9 June 2000; received in revised form 4 October 2000; accepted 9 November 2000 Abstract L-Arginine is the substrate for nitric oxide production. Endothelium dysfunction could be attributed to L-arginine deficiency or the presence of L-arginine endogenous inhibitors. This hypothesis leads to the assumption that provision of L-arginine could be the key for endothelial function improvement. Many studies have proven that L-arginine has a beneficial effect on endothelium dependent vasoreactivity, as well as on the interaction between vascular wall, platelets and leucocytes. Therefore, individuals with risk factors for atherosclerosis and patients with coronary artery disease or heart failure, could benefit from therapy with L-arginine. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Endothelium; L-Arginine; Nitric oxide; Atherosclerosis www.elsevier.com/locate/atherosclerosis 1. Introduction Furchgott and Zawadski [1] were the first in 1980 to suggest the existence of endothelium-derived relaxing factor (EDRF). In the following years Ignarro and coworkers [2–4] identified EDRF as nitric oxide (NO) and since then, a large number of experimental studies have proved the important role of NO in cardiovascu- lar system function. L-Arginine, a semi-essential amino acid found in large quantities in fish, chicken and beans, is the sub- strate for the production of nitric oxide. NO — a major component of endothelium derived relaxing fac- tor — is formed from L-arginine by oxidation of its terminal guanidine nitrogen and is responsible for the maintenance of endothelium dependent vasodilation through the physical activation of endothelial cells. This activation takes place when shear stress or certain substances (such us acetylcholine, substance P, bradycinin, ADP, histamine, serotonin) act on specific endothelial receptors and lead to the expression of nitric oxide synthase (NOS). NOS, the catalyzing en- zyme, is found in three isoforms: (1) the NOS I isoform which is constitutively expressed in central and periph- eral nervous tissue; (2) The NOS II isoform which is induced by cytokines in inflammatory processes and produces large amounts of NO in a calcium indepen- dent reaction and (3) the NOS III isoform which is constitutively expressed in endothelial cells and con- verts L-arginine (taken up from plasma by a y + trasporter) to NO and L-citrulline in a calcium requir- ing reaction that uses flavin mononucleotide, flavin adenine dinucleotide and tetrahydrobiopterin as cofac- tors [5]. L-Citrulline is recycled to L-arginine [6], while D-arginine is no substrate for NO production. NO produced by endothelial cells and released into the bloodstream, binds to the ferrous iron in the heme prosthetic group of soluble guanylate cyclase. This re- action converts GTP to cGMP and this messenger mediates most of the biological effects of NO, accord- ing to the direction of NO release and the site of cyclic GMP activation. For example, when that happens at vascular smooth muscle cells underlying the endothe- * Corresponding author. Tel.: +30-1-7782466; fax: +30-1- 7784590. 0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(00)00736-X