Reversible global and focal ischemia are important clinical problems. However, the precise pathways and mechanisms which cause brain injury are unclear. Recent interest has focussed on the potential pathways of nitric oxide (NO) in control of cerebral blood flow (CBF) under normal and pathologic situations. The primary goals of this project are to test the hypothesis that NO production contributes to post-ischemic hyperemia, that NO mediated changes in CBF are impaired during delayed hypoperfusion and that inhibition of NO synthesis results in improved neurologic and histologic recovery from transient global and focal ischemia. We will test whether NO plays a role in post-ischemic hyperemia by determining the CBF effects of NO-synthase inhibition and correlating the changes in CBF with changes in brain NO-synthase activity and cyclic GMP. We will test the integrity of NO mediated changes in CBF during delayed hypoperfusion by evaluating the CBF and pial vessel diameter effects of systemic administration of NO-synthase inhibitors and oxotremorine, a blood-brain barrier permeable muscarinic agonist that causes increased CBF via a NO mediated mechanism. In each of these protocols, we will measure pial vessel diameter to determine the exact time sequence of drug effects and to determine on which size vessel the majority of the vascular effect occurs. We will also investigate where abnormalities arise in the sequence of endothelial-smooth muscle coupling leading to impaired endothelial-dependent relaxation during delayed reperfusion. By using a variety of pharmacological probes, we will distinguish if impaired pial arteriolar responses are attributable to abnormalities in endothelial transduction to receptor activation, in NO synthesis, in smooth muscle response to NO, or in smooth muscle sensitivity to cyclic GNP. The hypothesis that superoxide anion inhibits NO dependent alterations in cerebrovascular tone will be tested by determining if liposomal-encapsulated superoxide dismutase improves reactivity to NO-mediated changes in CBF during reperfusion from ischemia. We will also determine if NO produced during ischemia and reperfusion is important in the mechanism of brain injury (histopathology and neurologic function) during transient global and focal ischemia since NO may react with superoxide anion and produce a toxic hydroxyl-like radical. The results of these studies will provide new, important information concerning the mechanisms of impaired vascular responses during reperfusion from ischemia and potentially offer ideas for therapeutic interventions.
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