BRAIN MICROCIRCULATION AND ENDOTHELIAL INJURY

脑微循环和内皮损伤

• 批准号: 3350403
• 负责人: WILLIAM I ROSENBLUM
• 金额: $ 23.18万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350403
• 关键词: acetylcholine; arterioles; bradykinin; brain circulation; calcium channel blockers; calcium transporting ATPase; cardiovascular pharmacology; cerebrovascular occlusions; eicosanoid metabolism; electron microscopy; free radicals; histamine; laboratory mouse; lipoxygenase; microcirculation; phorbols; platelet aggregation; prostacyclins; prostaglandin inhibitors; protein kinase C; serotonin inhibitor; thromboxanes; vascular endothelium; vasoconstriction; vasoconstrictors; vasodilators

Our long term goals are to expand our knowledge concerning mechanisms regulating brain microcirculation. These mechanisms are vitally important in providing appropriate flow to the brain, whose function is especially sensitive to impaired delivery of oxygen and nutrients. Present studies focus on the role of endothelium in controlling diameter of arterioles, and on the ways in which endothelial damage can derange flow. Two groups of studies are planned. All are relatively unique because they are conducted on microcirculation in vivo. Surface arterioles on the mouse brain are observed by intravital microscopy. The first group of studies investigates the role of endothelium in producing relaxing or constricting factors (EDRFs, EDCFs) when stimulated by selective vasoactive agonists or during autoregulation to an increase in blood pressure. Endothelial injury, produced in situ by helium neon laser/Evans blue causes a focus of lost capacity to produce EDRFs or EDCFs and provides a method for testing which agonists are dependent upon such an endothelial mechanism for their action. Pharmacologic probes, followed by chemical measurements will be used to determine the chemical nature of the endothelium derived mediators (e.g. prostanoids, other eicosanoids). We will also use pharmacologic probes to determine the role of protein kinase C, and of guanylate or adenylate cyclase and of L-arginine in mediating the synthesis, release or effects of the endothelium derived mediators. The second group of studies concerns the production of platelet aggregation by endothelial injury in the arterioles. Pharmacologic probes will be used to study the role of altered synthesis/release of an antiaggregant endothelium derived relaxing factor in promoting local platelet adhesion/aggregation at a site injured by light/dye. The capture of embolizing platelets at such a site will be studied for its relevance to repetitive symptoms of transient ischemic attacks. Pharmacologic probes will be used to assess the role of increased release of such an EDRF in decreasing platelet aggregation when flow and shear are increased. The role of L-arginine in regulating the antiaggregating and antiadhesive properties of this EDRF will be investigated.

我们的长期目标是扩展我们有关机制的知识 调节大脑微循环。 这些机制至关重要 为大脑提供适当的流量，其功能尤其重要 对氧气和营养物质输送受损敏感。 目前的研究 重点关注内皮细胞在控制小动脉直径方面的作用，以及 内皮损伤如何扰乱血流。 两组 研究已计划进行。 所有这些都相对独特，因为它们是在 对体内微循环的影响。 小鼠大脑的表面小动脉是 通过活体显微镜观察。 第一组研究调查 内皮细胞在产生松弛或收缩因子中的作用 （EDRF、EDCF）当受到选择性血管活性激动剂刺激或在 自我调节导致血压升高。 内皮损伤， 由氦氖激光/埃文斯蓝原位产生的导致焦点丢失 生产 EDRF 或 EDCF 的能力，并提供一种测试方法 激动剂的作用依赖于这种内皮机制。 药理学探针，然后是化学测量将用于 确定内皮衍生介质的化学性质（例如 前列腺素、其他类二十烷酸）。 我们还将使用药理学探针 确定蛋白激酶 C 以及鸟苷酸或腺苷酸的作用 环化酶和L-精氨酸在介导合成、释放或作用中的作用 内皮衍生的介质。 第二组研究涉及 内皮损伤导致血小板聚集 小动脉。 药理学探针将用于研究改变的作用 抗聚集内皮衍生舒张因子的合成/释放 促进受损伤部位的局部血小板粘附/聚集 光/染料。 在这样的部位捕获栓塞血小板将是 研究其与短暂性脑缺血的重复症状的相关性 攻击。药理学探针将用于评估增加的作用 当流动和流动时，释放这种 EDRF 可减少血小板聚集 剪切力增加。 L-精氨酸的调节作用 该 EDRF 的抗聚集和抗粘附特性将是 调查了。