PROPHYLACTIC HMG-COA REDUCTASE INHIBITORS IN STROKE

这项建议探讨了一氧化氮（NO）作为介体的作用， 细胞和分子事件，促进扩张， 脉管系统。 NO在血管和脑实质内形成， 酶NOS（一氧化氮合酶），两者都是潜在的介质 血管扩张的症状 NO的合成涉及分子的掺入， 氧和L-精氨酸[L-ARG]转化为NO和瓜氨酸。 联动 高碳酸血症时NO、扩张和rCBF增加，脑代谢 已经建立了L-精氨酸底物类似物，抑制NOS。 我们建议使用突变小鼠，其中血管（KV）或神经元 (KN已经选择性地敲除NOS的同种型以确定 NO在正常rCBF调节和缺血期间的作用。 为此， 我们已经：建立了一个专门的小鼠生理学单位（2站）， 其中rCBF、呼气CO2、动脉血压、核心和大脑 温度，EcoG可以从机械通风在线监测 动物和小鼠中建立线栓局灶性脑缺血模型。 这些实验的目的是：（目的I）表征响应 局部内皮依赖性舒张因子（EDRF） 和野生型和突变体中的非EDRF产生化合物，（目的II） 确定NO在高碳酸血症和皮质 桶场激活 (Aim III）检查NO在焦点中的作用， 全脑缺血 我们将比较和对比 大脑中动脉后野生型至KV和KN的梗死 闭塞（MCAO）（线模型）和缺血再灌注[双侧CCA （颈总动脉）+低血压]，并确定是否缺乏 神经元和/或血管NOS影响组织损伤的体积， 自由基的产生，细胞损伤的程度， 野生型，以及适应性循环反应， 局灶性和全脑缺血。 通过这样做，我们希望澄清是否 血管和/或神经元NO机制在对局灶性 缺血，从而阐明潜在的分子事件， 在健康和疾病期间对血管系统的调节。

This proposal examines the role of nitric oxide (NO) as a mediator of the cellular and molecular events which promote dilation in the cerebrovasculature. NO is formed within vessels and brain parenchyma by the enzyme NOS (nitric oxide synthase), and both are potential mediators of vasodilation. NO synthesis involves the incorporation of molecular oxygen and L-arginine [L-ARG] into NO and citrulline. Linkage between NO, dilation and rCBF increases during hypercapnia, and brain metabolism has been established by L-arginine substrate analogues that inhibit NOS. We propose to use mutant mice in which either vascular (KV) or neuronal (KN isoforms of NOS have been selectively knocked-out to determine the role of NO in normal rCBF regulation and during ischemia. To these ends, we have: established a dedicated mouse physiology unit (2 stations) in which rCBF, expiratory CO2, arterial blood pressure, core and brain temperature, EcoG can be monitored on-line from mechanically ventilated animals and developed in the mouse, the thread model of focal ischemia. The goals of these experiments are to: (AIM I) characterize the responses of pial vessels to topical endothelium-dependent relaxing factor (EDRF) and non-EDRF generating compounds in Wild type and mutants, (Aim II) determine the role and sources of NO during hypercapnia and cortical barrel field activation. (Aim III) examine the role of NO in focal and global cerebral ischemia. We will compare and contrast the evolution of infarction in the Wild type to KV and KN following middle cerebral artery occlusion (MCAO) (thread models) and ischemia reperfusion [bilateral CCA (common carotid artery) + hypotension] and determine whether the lack of neuronal and/or vascular NOS affects the volume of tissue injury, the production of free radicals, the extent of cellular injury as compared to Wild type, and the adaptive circulatory responses which characterize focal and global ischemia. By so doing, we hope to clarify whether vascular and/or neuronal NO mechanisms predominate in response to focal ischemia and to thereby clarify the molecular events underlying the regulation of the cerebrovasculature during health and disease.