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

可逆性全脑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， 一氧化氮（NO）对正常人脑血流量（CBF）的调节作用 和病理情况。 本项目的主要目标是测试 假设NO的产生有助于缺血后充血， 在延迟性低灌注期间， 并且NO合成的抑制导致改善的神经功能， 短暂性全脑和局灶性缺血的组织学恢复。 我们将 通过测定NO是否在缺血后充血中起作用， 抑制NO合酶对脑血流的影响， CBF与脑NO合酶活性和环GMP的变化。 我们将 测试延迟性脑缺血期间脑血流中NO介导的变化的完整性。 通过评估CBF和软脑膜血管直径的影响， 一氧化氮合酶抑制剂和氧化震颤素的全身给药， 血脑屏障可渗透性毒蕈碱激动剂， CBF通过NO介导的机制。 在这些协议中，我们将 测量软脑膜血管直径以确定药物的确切时间顺序 影响，并确定哪些大小的船只，大多数 血管效应发生。 我们还将调查 出现在内皮-平滑肌偶联的序列中，导致 延迟再灌注期间内皮依赖性舒张受损。 通过 使用各种药理学探针，我们将区分是否 软脑膜小动脉反应受损可归因于 内皮转导受体活化，在NO合成，在 平滑肌对NO的反应，或平滑肌对周期性 国民生产总值。 超氧阴离子抑制NO依赖性假说 脑血管张力的改变将通过确定是否 脂质体包封的超氧化物歧化酶提高了对 脑缺血再灌注过程中NO介导的CBF变化 我们将 还确定缺血和再灌注期间产生的NO是否 在脑损伤的机制（组织病理学和神经学）中起重要作用 功能），因为NO可能与 与超氧阴离子结合并产生有毒的羟基样自由基。 的 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，并可能提供治疗思路， 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.