L218	Methylarginines and endothelial control of vascular disease.
R.H.Böger
Institute of Experimental and Clinical Pharmacology, University Hospital Hamburg-Eppendorf, Hamburg, DE.

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NO synthase. ADMA inhibits vascular NO production in concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intraarterially; given systemically, it has been shown to increase peripheral arterial resistance in humans. ADMA acts by displacing L-arginine from the substrate-binding moiety of the NO synthase. Thus, elevated ADMA levels may explain the »L-arginine paradox«; i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Km of the isolated, purified endothelial NO synthase in vitro. The biochemical and physiological pathways related to ADMA are well understood by now: Dimethylarginines are the result of degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) is the major pathway of elimination for ADMA, while both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion. DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases, as suggested by mice overexpressing the human DDAH-1 gene. ADMA is increased in plasma of humans with various pathophysiological conditions in the cardiovascular system. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation and reduced urinary nitrate excretion. In several prospective and cross-sectional studies, ADMA has evolved as a marker of cardiovascular risk in patients with end-stage renal disease, coronary artery disease, as well as in the general population. Therefore, prospective clinical studies have suggested that ADMA may play a role as a novel cardiovascular risk factor.

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