Pathological implications of nitric oxide, superoxide and peroxynitrite formation.

Introduction Approximately 6 years ago, nitric oxide was identified as the endothelium-derived relaxing factor (EDRF), the endogenous vasodilator mimicked by nitroglycerin and nitroprusside [ 1-41. An astonishing variety of tissues synthesize nitric oxide, which has important roles in the control of systemic blood pressure, respiration, digestion, penile erection, platelet aggregation, cerebral blood flow and neuronal synaptic plasticity [ 51. Furthermore, nitric oxide, or a secondary oxidant derived from it, contributes to the microbicidal and tumoricidal activities of activated macrophages and neutrophils [6,7]. Endothelium and neurons produce nitric oxide by a calmodulin-activated enzyme, which oxidizes arginine to citrulline and requires biopterin, NADPH and oxygen [8, 91. The biopterin remains tightly bound to the enzyme and may be recycled within it. Nitric oxide synthase also contains FAD, FMN and ferric haem as essential cofactors. The macrophage enzyme is not regulated by calmodulin, and gene sequences reveal significant differences between the brain, endothelial and macrophage enzymes [ 101. Pathological conditions can substantially upregulate the production of nitric oxide. Stimulated macrophages and neutrophils produce significantly greater fluxes of nitric oxide than endothelium by the inducible calcium-independent nitric oxide synthase. Endotoxin (lipopolysaccharide) and cytokines induce the calcium-independent nitric oxide synthase in many tissues that do not normally produce nitric oxide [ll]. For example, the acute