The long term objectives of this proposal are to determine whether voltage dependent Ca2+ channels (VDCC) are a major site of action of the volatile anesthetics, halothane and isoflurane, and whether isoflurane can attenuate the ischemic changes that have been observed in VDCC. The more limited aims are to define the effects of halothane and isoflurane on the binding properties of Ca2+ channel antagonists to VDCC, and on the movement of Ca2+ through single Ca2+ channels and populations of Ca2+ channels. Ca2+ homeostasis and the activity of VDCC have also been implicated in the pathophysiology of ischemic CNS damage, and preliminary data suggest that isoflurane might ameliorate CNS damage by an action on VDCC. This proposal will examine the interaction of isoflurane, VDCC, and ischemia to determine whether changes in channel density and Ca2+ flux occur and can be attenuated by isoflurane. Radioligand binding assays, Ca2+ flux measurements with fura 2 in isolated synaptosomes and cultured neurons, and with electrophysiologic measurements of single Ca2+ channels in reconstituted membranes will be performed to achieve the specific aims. The potential therapeutic advantage of isoflurane and related compounds in preventing or lessening ischemic damage would be addressed in subsequent proposals if findings derived from the described studies suggest a rational therapeutic approach.
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