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(Hypertension. 2006;48:278.)
© 2006 American Heart Association, Inc.

Original Articles

Adverse Effects of Cigarette Smoke on NO Bioavailability

Role of Arginine Metabolism and Oxidative Stress

Wei-Zheng Zhang; Kylie Venardos; Jaye Chin-Dusting; David M. Kaye

From the Wynn Departments of Metabolic Cardiology (W-Z.Z., K.V., D.M.K.) and Vascular Pharmacology (J.C-D.), Baker Heart Research Institute, Melbourne, Australia.

Correspondence to David M. Kaye, Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail david.kaye{at}baker.edu.au

Endothelial dysfunction is a hallmark of cardiovascular disease, and the L-arginine:NO pathway plays a critical role in determining endothelial function. Recent studies suggest that smoking, a well-recognized risk factor for vascular disease, may interfere with L-arginine and NO metabolism; however, this remains poorly characterized. Accordingly, we performed a series of complementary in vivo and in vitro studies to elucidate the mechanism by which cigarette smoke adversely affects endothelial function. In current smokers, plasma levels of asymmetrical dimethyl-arginine (ADMA) were 80% higher (P=0.01) than nonsmokers, whereas citrulline (17%; P<0.05) and N-hydroxy-L-arginine (34%; P<0.05) were significantly lower. Exposure to 10% cigarette smoke extract (CSE) significantly affected endothelial arginine metabolism with reductions in the intracellular content of citrulline (81%), N-hydroxy-L-arginine (57%), and arginine (23%), while increasing ADMA (129%). CSE significantly inhibited (38%) arginine uptake in conjunction with a 34% reduction in expression of the arginine transporter, CAT1. In conjunction with these studies, CSE significantly reduced the activity of eNOS and NO production by endothelial cells, while stimulating the production of reactive oxygen species. In conclusion, cigarette smoke adversely affects the endothelial L-arginine NO synthase pathway, resulting in reducing NO production and elevated oxidative stress. In conjunction, exposure to cigarette smoke increases ADMA concentration, the latter being a risk factor for cardiovascular disease.

Key Words: smoking • endothelium • metabolism

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