Figure 3: ROS generation and signaling in the coronary microvascular endothelium. In the presence of sufficient substrate (L-arginine) and cofactor (tetrahydrobiopterin, BH4) endothelial nitric oxide synthase (eNOS) reduces molecular O2 to nitric oxide (NO•). When BH4 and/or L-arginine become limiting, is produced by “uncoupled” eNOS. NADPH oxidases, xanthine oxidase, and the respiratory chain are also sources of . Superoxide quickly reacts with to produce peroxynitrite (ONOO−). Endogenous superoxide dismutase (SOD) dismutates to form H2O2. Hydrogen peroxide (H2O2) acts as a vasodilator by producing membrane hyperpolarization and relaxation of the vascular smooth muscle; however, in the presence of catalytic transition metals (i.e., Fe2+), excess H2O2 produced by treatment with exogenous SOD could produce the potent cytotoxic radical, . Hydrogen peroxide can be eliminated from the cytosol through conversion to H2O and O2 by catalase. H2O2 can alter the activity of -generating enzymes in a feedback manner.