Current Drug Metabolism

Michael Sinz
Bristol Myers Squibb
Wallingford, CT
USA

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Asymmetric Dimethyl-L-Arginine (ADMA): A Possible Link Between Homocyst(e)ine and Endothelial Dysfunction

Author(s): Markus C. Stuhlinger and Olaf Stanger

Affiliation: Medical University of Innsbruck, Department of Internal Medicine, Division of Cardiology, Anichstrabe 35, A-6020 Innsbruck, Austria.

Abstract:

Hyperhomocyst(e)inemia is associated with an increased risk for atherosclerotic disease and venous thromboembolism. The impact of elevated plasma homocysteine levels seems to be clinically relevant, since the total cardiovascular risk of hyperhomocyst(e)inemia is comparable to the risk associated with hyperlipidemia or smoking. There is substantial evidence for impairment of endothelial function in human and animal models of atherosclerosis, occurring even before development of overt plaques. Interestingly endothelial dysfunction appears to be a sensitive indicator of the process of atherosclerotic lesion development and predicts future vascular events. NO is the most potent endogenous vasodilator known. It is released by the endothelium, and reduced NO bioavailability is responsible for impaired endothelium-dependent vasorelaxation in hyperhomocyst(e)inemia and other metabolic disorders associated with vascular disease. Substances leading to impaired endothelial function as a consequence of reduced NO generation are endogenous NO synthase inhibitors such as ADMA. Indeed there is accumulating evidence from animal and human studies that ADMA, endothelial function and homocyst(e)ine might be closely interrelated. Specifically elevations of ADMA associated with impaired endothelium-dependent relaxation were found in chronic hyperhomocyst(e)inemia, as well as after acute elevation of plasma homocyst(e)ine following oral methionine intake. The postulated mechanisms for ADMA accumulation are increased methylation of arginine residues within proteins, as well as reduced metabolism of ADMA by the enzyme DDAH, but they still need to be confirmed to be operative in vivo. Hyperhomocyst(e)inemia, as well as subsequent endothelial dysfunction can be successfully treated by application of folate and B vitamins. Since ADMA seems to play a central role in homocyst(e)ine-induced endothelial dysfunction, another way of preventing vascular disease in patients with elevated homocyst(e)ine concentrations could be supplementation with L-arginine to reverse the detrimental effects of ADMA.

Keywords: endothelium, arterial disease, atherosclerosis, endothelial function, nitric oxide, homocysteine, folic acid

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Article Details

VOLUME: 6
ISSUE: 1
Page: [3 - 14]
Pages: 12
DOI: 10.2174/1389200052997393