Endothelial alterations in hypercholesterolemia: More than simply vasodilator dysfunction

Occlusive vascular disease begins with an alteration of the endothelium, wh ich is characterized by a decrease in nitric oxide (NO) activity. Endogenou s NO inhibits many key processes in atherogenesis, including monocyte adher ence, platelet activation, and smooth muscle proliferation. The mechanism b y which NO activity is reduced in hypercholesterolemia and in other metabol ic disorders associated with atherogenesis appears to be multifactorial. It includes increased production of oxygen-derived free radicals, alterations in NO synthase, and the accumulation of endogenous inhibitors (ADMA of NO synthase. Plasma concentrations of ADMA are elevated in hypercholesterolemi c humans. Elevated ADR IA concentrations are associated with impaired endot helium-dependent, NO-mediated vasodilatation and reduced urinary nitrate ex ertion. These effects of ADMA are counteracted by administration of the NO precursor L-arginine. It is likely that basic insights regarding the mechan isms of endothelial dysfunction will lead to new therapeutic strategies for atherosclerosis.