The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury.

Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with proteins, lipids, and DNA under conditions of inflammation and shock. Here we overview the role of peroxynitrite in circulatory shock and inflammation. Immunohistochemical and biochemical evidence demonstrate production of peroxynitrite in endotoxic and hemorrhagic shock, chronic bowel inflammation, and in various forms of ischemia-reperfusion injury. The reactivity and decomposition of peroxynitrite is determined by the chemical environment, and the ratio of superoxide versus NO. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase, with eventual severe energy depletion of the cells. Pharmacological evidence suggests that the peroxynitrite-poly-ADP ribosyl synthetase pathway importantly contributes to the cellular injury in endotoxic shock, inflammatory pancreatic islet cell destruction, and central nervous system ischemia. The proposal that peroxynitrite is a major cytotoxic mediator would change the interpretation of previous data on the effects of NO donors, NO synthase inhibitors, and superoxide neutralizing strategies in shock and inflammation.