The Importance of Superoxide in Nitric Oxide-Dependent Cerebral Ischemic Injury**This work was supported by grants HL46407, NS24338, and HL48676 from the National Institutes of Health and from the American Heart Association. J. S. Beckman is supported as an Established Investigator of the American Heart Association.

Abstract The role of nitric oxide in cerebral ischemic injury has become highly controversial as some laboratories have found significant protection by inhibiting nitric oxide synthesis, whereas other laboratories have found than stimulation of nitric oxide production can be protective. Nitric oxide is a vasodilator that can increase perfusion to ischemic tissue. Furthermore, nitric oxide inhibits platelet adhesion as well as neutrophil adherence to vascular endothelium. Thus, the continued production of nitric oxide can help ameliorate cerebral ischemia. Nitric oxide itself is not highly toxic, but it reacts rapidly with the oxygen radical, superoxide (O2-), to form the peroxynitrite anion (ONOO-). Activation of N-methyl-D-aspartate receptors by ischemia can increase endogenous nitric oxide concentrations to levels where nitric oxide will outcompete superoxide dismutase for superoxide. Inhibiting the reaction of superoxide with nitric oxide helps explain why intravenously administered superoxide dismutase can reduce the extent of cerebral ischemic injury. Peroxynitrite is highly toxic and leaves permanent markers that can be measured in ischemic tissue. One such marker is nitration of tyrosine residues in proteins. Understanding the multiple roles of nitric oxide and oxidants derived from nitric oxide in cerebral ischemia will help determine better approaches to intervene therapeutically.