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

一氧化氮在脑缺血时脑血流控制中的作用

• 批准号: 6243543
• 负责人: JEFFREY R KIRSCH
• 金额: $ 22.07万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243543
• 关键词: amine oxidoreductase; blood flow measurement; brain injury; cats; cerebral ischemia /hypoxia; cyclic GMP; enzyme inhibitors; free radicals; nitric oxide; reperfusion; superoxide dismutase; superoxides; vasomotion

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.

可逆的全球和局灶性缺血是重要的临床问题。 但是，引起脑损伤的精确途径和机制是 不清楚。 最近的兴趣集中在潜在的途径上 在正常情况下控制脑血流（CBF）的一氧化氮（NO） 和病理状况。 该项目的主要目标是测试 没有生产有助于缺血后血症的假设， 在延迟灌注期间，CBF的介导变化没有受损 并且抑制无合成导致神经系统的改善和 从瞬态全球和局灶性缺血中恢复组织学恢复。 我们将 测试NO​​是否通过确定是否在缺血后充血中起作用 无合酶抑制的CBF效应以及将变化的变化相关 CBF随着脑无合酶活性和环状GMP的变化。 我们将 测试延迟期间无介导的CBF变化的完整性 通过评估CBF和PIAL血管直径的灌注不足 全身施用无合子抑制剂和黄瓜，A 血脑屏障可渗透的毒蕈碱激动剂会导致增加 CBF通过无介导的机制。 在每个协议中，我们都会 测量伴侣直径以确定药物的确切时间序列 影响并确定大多数尺寸的容器 发生血管效应。 我们还将调查异常情况 以内皮平滑肌肉耦合的顺序出现 在延迟再灌注过程中，内皮依赖性放松受损。 经过 使用各种药理探针，我们将区分 pial小动脉反应受损归因于异常 内皮的内皮转导向受体激活，无合成，在 平滑肌肉对NO的反应，或者对循环的平滑肌敏感性 GNP。 超氧化阴离子不抑制依赖的假设 脑血管张力的改变将通过确定是否是否 脂质体封闭的超氧化物歧化酶改善了对 缺血再灌注过程中CBF的无介导的变化。 我们将 还确定在缺血期间没有产生的和再灌注是未产生的 在脑损伤机理中很重要（组织病理学和神经系统损伤 功能）在瞬时全局和局灶性缺血期间，因为没有可能反应 带有超氧化阴离子并产生有毒的羟基样的自由基。 这 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 缺血的再灌注，并有可能为治疗性提供想法 干预措施。