The long-range aim of this proposal is to establish the role and mechanism of action of oxygen radicals in the vascular injury which occurs in fluid-percussion brain injury and during reperfusion following brain ischemia. In the preceding funding periods of this project we established that oxygen radicals are generated after fluid-percussion brain injury and during reperfusion following global ischemia. In the present proposal we plan to identify the mechanisms of the cerebral arteriolar vasodilation induced by superoxide, hydrogen peroxide and hydroxyl radical. Specifically, we will investigate the role of activation of guanylate cyclase and the activation of ATP-sensitive potassium channels. We will also investigate the mechanism by which oxygen radicals interfere with endothelium-dependent relaxation. These studies will target the identification of the chemical identity of endothelium-derived relaxing factor (EDRF) and examination of whether oxygen radicals stimulate increased generation of release of EDRF and whether peroxynitrite is formed by the interaction of nitric oxide and superoxide and eventually generates hydroxyl radical. We will also attempt to distinguish between hydroxyl radical generated via production of peroxynitrite from hydroxyl radical generated via the iron-catalyzed Haber-Weiss reaction. Other studies will investigate the mechanism of the abnormal response to CO2 in fluid-percussion injury and in ischemia/reperfusion. We will investigate the role of nitric oxide synthase-mediated effects and the role of activation of ATP-sensitive potassium channels. the mechanism of the cytoskeletal abnormalities in the breakdown of the blood-brain barrier induced by oxygen radicals will be evaluated with respect to the possible role of cytoskeletal contractile proteins and the role of phagocytic cells. Finally, we will investigate whether small reductions in temperature or blockade of the NMDA receptor are beneficial in brain injury and ischemia because they cause changes in the generation of oxygen radicals.
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