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Supplement: Arginine Metabolism: Enzymology, Nutrition, and Clinical Significance

L-Arginine and Atherothrombosis^1,2

Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, MA 02118

³To whom correspondence should be addressed. E-mail: jloscalz{at}bu.edu.

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.

KEY WORDS: • arginine • atherothrombosis • vasodilation • nitric oxide

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