L-arginine and atherothrombosis.
L-arginine, the principal substrate for endothelial nitric oxide synthase, is oxidized to L-citrulline and nitric oxide. Endothelial dysfunction is associated with decreased bioactive nitric oxide production, an abnormality observed in atherothrombosis. Acute or chronic administration of supplemental L-arginine enhances endothelial nitric oxide production and improves endothelial function in the setting of atherothrombosis. The mechanisms by which L-arginine improves endothelial nitric oxide bioactivity include increased intracellular uptake via the high-affinity cationic transporter; substrate competition with asymmetric dimethylarginine, a naturally occurring inhibitor of nitric oxide synthase; direct antioxidant activity; stimulated release of histamine from mast cells, which produces a vasodilator response; decreased activity of norepinephrine, which promotes the effect of endogenous vasodilators including nitric oxide; and increased insulin secretion, which causes vasodilation. By virtue of its link to methyl group metabolism, supplemental L-arginine can, however, also increase the production of S-adenosylhomocysteine from S-adenosylmethionine through the methylation-dependent generation of creatine from guanidinoacetate. This reaction can theoretically lead to increased homocysteine synthesis from its S-adenosyl derivative, which itself can have adverse effects on endothelial function. The interrelationships among these effects of L-arginine are reviewed here, and the potential benefits and risks of L-arginine supplementation are discussed.
Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. jloscalz@bu.edu
Joseph
J
Loscalzo
D000818:Animals; D001120:Arginine / Q000009:adverse effects / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology*
D001120:Arginine