ANESTHETICS, ISCHEMIA, AND CNS CALCIUM CHANNELS

这项提案的长期目标是确定电压 依赖的钙通道(VDCC)是挥发性钙离子的主要作用部位 麻醉剂、氟烷和异氟烷，以及异氟醚是否可以 减轻VDCC中已观察到的缺血性改变。越多 有限的目标是确定氟烷和异氟烷对 钙通道拮抗剂与VDCC的结合特性 钙离子在单个钙离子通道和钙离子群间的迁移 频道。钙离子动态平衡和VDCC的活性也被 与缺血性中枢神经系统损伤的病理生理机制有关，并初步 数据表明，异氟醚可能通过作用于中枢神经系统而减轻中枢神经系统损害。 VDCC。本提案将研究异氟醚、VDCC和 确定缺血后通道密度和钙离子流量是否发生变化 会发生，并可被异氟醚减弱。放射性配基结合分析， 用Fura-2测定分离和培养的突触体的钙离子通量 神经元，并对单个钙离子通道进行电生理测量 将在重组膜中进行，以达到特定的目的。 异氟醚及其相关化合物在临床上的潜在治疗优势 预防或减轻缺血性损害将在随后的 如果从所描述的研究中得出的结果表明 合理的治疗方法。

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.