PATHOPHYSIOLOGY OF CHRONIC CEREBRAL VASOSPASM

慢性脑血管痉挛的病理生理学

• 批准号: 6187194
• 负责人: Robert Loughlin Macdonald
• 金额: $ 45.16万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187194
• 关键词: Primates; adenine nucleotides; adenosine triphosphate; calcium flux; cerebral aneurysm; cerebral hemorrhage; cerebrospinal fluid; clinical research; disease /disorder model; endothelin; erythrocytes; hemoglobin; human subject; laboratory rat; pathologic process; polymerase chain reaction; protein biosynthesis; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasodilators; vasospasm

Rupture of an intracranial aneurysm, causing subarachnoid hemorrhage (SAH), afflicts about 30,000 North Americans per year. An important cause of stroke and death in patients with ruptured aneurysms is cerebral vasospasm which is narrowing of the major cerebral arteries developing from 4 to 14 days after aneurysm rupture. Vasospasm causes morbidity and mortality in about 15% of patients with SAH although angiograms taken during the time of vasospasm will disclose its presence in about two-thirds of cases. Treatment of vasospasm, that includes calcium-channel antagonists, hemodynamic therapy and tissue plasminogen activator, accounts for some of the discrepancy between the number of patients with vasospasm seen angiographically compared to those who develop stroke from it. The long-term objectives of our laboratory are (1) to determine the compound(s) in subarachnoid blood that cause vasospasm, (2) to determine the mechanisms by which they do so, and (3) to develop effective treatments for vasospasm. The specific aims of this grant are (1) to determine how the time course and degree of vasospasm in monkeys depends on subarachnoid blood and to analyze the blood for spasmogens, (2) to determine the component(s) of erythrocytes that cause vasospasm in rats, (3) to characterize the vasoactive compound in cerebrospinal fluid (CSF) and subarachnoid blood removed from patients with SAH, (4) to determine whether adenosine triphosphate (ATP) and pure hemoglobin can cause vasospasm in monkeys, (5) to determine the concentrations and time course of changes-in CSF levels of adenine nucleotides and hemoglobins in humans after SAH, (6) to determine the effects of P2-purinoceptor antagonists against vasospasm in monkeys, (7) to determine if synthesis of endothelin (ET) and ET receptor messenger ribonucleic acids (mRNAs) and secretion of ET and ET receptor proteins are increased in cultured cerebral smooth muscle and endothelial cells exposed to erythrocyte hemolysate or purified hemoglobin, (8) to determine the time course of changes in ET and ET receptor mRNAs and proteins following SAH in rats and (9) to determine the effects of an ET antagonist on vasospasm in monkeys.

颅内动脉瘤破裂，导致蛛网膜下腔出血 (SAH)，每年困扰着大约30,000名北美人。一个重要的 破裂动脉瘤患者中风和死亡的原因是 脑血管痉挛，即大脑主要动脉变窄 发病时间为动脉瘤破裂后4~14天。血管痉挛的原因 约15%的SAH患者的发病率和死亡率 在血管痉挛期间进行的血管造影将揭示其 出现在大约三分之二的案例中。治疗血管痉挛，即 包括钙通道拮抗剂、血流动力学疗法和组织 纤溶酶原激活剂，解释了一些差异 血管造影显示的血管痉挛患者的数量与 那些因此而患中风的人。我们的长期目标是 实验室：(1)蛛网膜下腔血中化合物(S)的测定 导致血管痉挛，(2)确定它们的作用机制 因此，(3)开发治疗血管痉挛的有效方法。具体的 这项资助的目的是(1)确定时间进程和学位如何 猕猴脑血管痉挛的蛛网膜下腔血运分析 用于痉挛的血液，(2)测定成分(S) 引起大鼠血管痉挛的红细胞，(3)表征 脑脊液和蛛网膜下腔血中的血管活性物质 从SAH患者中取出，(4)确定腺苷是否 三磷酸(ATP)和纯血红蛋白会导致猴子的血管痉挛， (5)测定脑脊液中的浓度和变化的时程 蛛网膜下腔出血后腺嘌呤核苷酸和血红蛋白水平，(6) 检测P2-嘌呤受体拮抗剂对小鼠肺泡灌洗液的影响 猴血管痉挛，(7)测定内皮素(ET)的合成 和ET受体信使核糖核酸与ET的分泌 培养的大鼠脑血管内皮细胞ET受体蛋白增加 肌肉和内皮细胞暴露于红细胞溶血物或 纯化的血红蛋白，(8)测定ET变化的时间进程 和ET受体mRNAs和蛋白在大鼠蛛网膜下腔出血后和(9)至 确定一种ET拮抗剂对猴子血管痉挛的影响。