We propose to continue animal studies concerned with the effects of cerebral ischemia on cerebral blood flow (CBF), cerebral metabolism (CMR0-2), and neurologic outcome with the goal of identifying interventions (pharmacologic and otherwise) which might favorably alter the effects of ischemia. Three types of ischemia will be examined: complete ischemia (either by aortic ligation or a neck tourniquet); incomplete global ischemia (acute hemorrhagic ischemia); and incomplete focal ischemia (middle cerebral artery (MCA) occlusion). Following complete global ischemia in dogs we will determine the effectiveness of nimodipine in improving CBF when given at varying time intervals (up to 1 hour) following reperfusion. In this same model the effects of lidoflazine on CBF and neurologic outcome will be examined. Again in this model the effects of superoxide dismutase and catalase will be examined to determine if free radicals contribute to brain injury. The effect of nimodipine on incomplete focal ischemia will be examined in rabbits as determined by effects on brain metabolites, neurologic function, and brain infarction. In this same model the effects of isoflurane will be examined using similar indices for identifying any beneficial (or deleterious) effects. In the dog model of complete ischemia we will evaluate the effects of varying the volume of stagnant blood in the brain during the period of ischemia on post ischemic CBF and outcome. In the primate model of complete ischemia we will determine the impact of clinically relevant infusions of glucose on neurologic and histopathologic outcome. We will examine the dose response effects of 3 new drugs on CBF and CMR0-2 in the dog: sufentanil, triazolam and R0 15-1788 ( a benzodiazepine antagonist). In the dog we will determine the effects of succinylcholine on CBF, CMR0-2, ICP and EEG in an attempt to clarify the current confusion regarding the potential hazards of this drug. In cats we will determine whether atracurium alters seizure threshold to lidocaine. The effect of nitroprusside on cerebral vascular resistance with and without hypotension will be determined in dogs to separate autoregulatory effects from direct effects. Also in dogs the effect of halothane on autoregulation in response to changing cardiac output will be examined.
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