In a series of studies using as the laboratory preparation focal incomplete ischemia and cortical seizures in the rabbit, this team of investigators will study various parameters of cerebral metabolism including: focal cortical blood flow (determined by the clearance curves of umbelliferone from an area of cortex 80 microns in diameter and Krypton85), parenchymal pH (determined by the ratio of fluorescence of the molecular and ionic forms of umbelliferone), extracellular calcium and potassium flux (determined by double- barreled microelectrodes with the possibility of nonivasive fluorometric calcium markers for extracellular calcium), intracellular redox state (measured by fluorescence of NADH-NADPH), electrical cortical activity (measured by electrocorticography), histology (light microscopy only), and microcirculatory changes (cortical photography through operating microscope and microcirculatory perfusion of arterioles and capillaries using colloidal carbon. Animal preparations and methods of measurements to be used in the studies have been standardized in this laboratory, except for the measurement of extracellular calcium and potassium using microelectrodes. We will evaluate various calcium channel blockers having different sites of action, barbiturates, and free radical scavengers in both acute and chronic models of focal ischemia. These agents will be studied in a systematic fashion progressing form acute preparations to chronic animals measuring infarct size. Studies to date from this laboratory indicate the incredible ability of calcium channel blockers to prevent ischemic induced focal vasoconstriction of cortical vessels in areas of incomplete ischemia resulting in both improved cortical blood flow and parenchymal pH. However, we have not yet established the method of action or ultimate effect on infarct size and neurological outcome. In addition, we have demonstrated impressive anticonvulsant properties of calcium antagonists in experimental seizures induced through ischemia, topical convulsants, and electrical cortical shock. Therefore calcium influx is a common phenomena between two pathological states: ischemia and epilepsy. We plan to investigate the metabolic and blood flow changes occurring in both acute and chronic seizure models through measurements of parenchymal pH, cortical blood flow, calcium and potassium fluxes, and intracellular redox states. The actions of calcium antagonists on these parameters will be assessed to facilitate understanding of how these agents exert their anticonvulsant effects.
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