ROLE OF NITRIC OXIDE IN CEREBRAL BLOOD FLOW CONTROL IN CEREBRAL ISCHEMIA

可逆性全脑缺血和局灶性缺血是重要的临床问题。 然而，导致脑损伤的确切途径和机制是 不清楚。最近的兴趣集中在潜在的途径上。 一氧化氮(NO)对正常状态下脑血流量的控制作用 以及病态的情况。该项目的主要目标是测试 有一种假设认为一氧化氮的产生会导致缺血后充血， 延迟性低灌流时脑血流NO介导的变化受损 抑制NO合成会改善神经学和 短暂性全脑和局灶性脑缺血的组织学恢复。我们会 通过检测NO在脑缺血后充血中的作用 一氧化氮合酶抑制对脑血流的影响及其相互关系 脑血流与脑组织一氧化氮合酶活性和环磷酸鸟苷的变化。我们会 检测延迟性脑血流中NO介导的变化的完整性 评价脑血流量和软脑膜血管内径对低灌注率的影响 一氧化氮合酶抑制剂和氨甲喋呤的全身性应用 血脑屏障通透性毒扁豆碱激动剂导致 CBF通过NO介导的机制实现。在每个协议中，我们都将 测量软脑膜血管直径以确定药物的准确时间序列 影响并确定大多数人在什么大小的血管上 血管效应就会发生。我们还将调查哪里有异常 出现在内皮-平滑肌偶联的序列中，导致 延迟再灌流期间内皮依赖性松弛受损。通过 使用各种药理探针，我们将区分是否 软脑膜小动脉反应受损可归因于 内皮转导至受体激活，在NO合成中，在 平滑肌对NO的反应，或在平滑肌对周期的敏感性 国民生产总值。超氧阴离子抑制一氧化氮依赖的假说 脑血管张力的改变将通过确定是否 脂质体包裹的超氧化物歧化酶提高对 NO介导的脑缺血再灌注过程中脑血流量的变化。我们会 也要确定在缺血和再灌流过程中产生的NO是否 在脑损伤机制中的重要作用(组织病理学和神经学 在短暂性全脑缺血和局灶性缺血期间)，因为NO可能发生反应 与超氧阴离子结合，产生有毒的类羟基自由基。这个 这些研究的结果将提供新的重要信息 关于血管反应受损的机制 缺血再灌注，有可能为治疗提供思路 干预措施。

Reversible global and focal ischemia are important clinical problems. However, the precise pathways and mechanisms which cause brain injury are unclear. Recent interest has focussed on the potential pathways of nitric oxide (NO) in control of cerebral blood flow (CBF) under normal and pathologic situations. The primary goals of this project are to test the hypothesis that NO production contributes to post-ischemic hyperemia, that NO mediated changes in CBF are impaired during delayed hypoperfusion and that inhibition of NO synthesis results in improved neurologic and histologic recovery from transient global and focal ischemia. We will test whether NO plays a role in post-ischemic hyperemia by determining the CBF effects of NO-synthase inhibition and correlating the changes in CBF with changes in brain NO-synthase activity and cyclic GMP. We will test the integrity of NO mediated changes in CBF during delayed hypoperfusion by evaluating the CBF and pial vessel diameter effects of systemic administration of NO-synthase inhibitors and oxotremorine, a blood-brain barrier permeable muscarinic agonist that causes increased CBF via a NO mediated mechanism. In each of these protocols, we will measure pial vessel diameter to determine the exact time sequence of drug effects and to determine on which size vessel the majority of the vascular effect occurs. We will also investigate where abnormalities arise in the sequence of endothelial-smooth muscle coupling leading to impaired endothelial-dependent relaxation during delayed reperfusion. By using a variety of pharmacological probes, we will distinguish if impaired pial arteriolar responses are attributable to abnormalities in endothelial transduction to receptor activation, in NO synthesis, in smooth muscle response to NO, or in smooth muscle sensitivity to cyclic GNP. The hypothesis that superoxide anion inhibits NO dependent alterations in cerebrovascular tone will be tested by determining if liposomal-encapsulated superoxide dismutase improves reactivity to NO-mediated changes in CBF during reperfusion from ischemia. We will also determine if NO produced during ischemia and reperfusion is important in the mechanism of brain injury (histopathology and neurologic function) during transient global and focal ischemia since NO may react with superoxide anion and produce a toxic hydroxyl-like radical. The results of these studies will provide new, important information concerning the mechanisms of impaired vascular responses during reperfusion from ischemia and potentially offer ideas for therapeutic interventions.