Adverse effects of supplemental L-arginine in atherosclerosis. Arterioscler Thromb Basc Biol

Atherothrombosis and its risk factors are associatedwith endothelial dysfunction,1 one manifestation ofwhich is inadequate production of bioactive endothe-lial NO. Two basic mechanisms account for the loss of endothelial NO: decreased synthesis and increased oxidative inactivation. In the atherothrombotic vessel, both mecha-nisms appear to be active. Vascular production of reactive oxygen species creates an environment in which NO can be oxidatively inactivated to peroxynitrite and other derivatives. The sources of one of these reactive oxygen species— superoxide anion—include NAD(P)H oxidase elaborated on the plasma membrane of leukocytes, endothelial cells, and vascular smooth muscle cells; mitochondria; and the NO synthases. Both endothelial NO synthase (eNOS) and induc-ible NO synthase (iNOS) isoforms are expressed in the atherothrombotic vasculature and, owing to a loss of substrate or reducing cofactors required for NO synthesis, underg