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），每年大约有30,000名北美人。一个重要的 动脉瘤破裂患者中风和死亡的原因是 大脑动脉变窄的脑血管痉挛 动脉瘤破裂后4天到14天。血管痉挛引起 大约15％的SAH患者的发病率和死亡率 在血管痉挛时期拍摄的血管造影将披露其 大约三分之二的病例存在。血管痉挛的治疗 包括钙通道拮抗剂，血液动力学疗法和组织 纤溶酶原激活剂，解释了 与 那些从中发展中风的人。我们的长期目标 实验室是（1）确定蛛网膜下腔血液中的化合物 这会导致血管痉挛，（2）确定它们所做的机制 因此，（3）为血管痉挛开发有效的治疗方法。具体 这笔赠款的目的是（1）确定时间课程如何 猴子的血管痉挛取决于亚蛛网膜下腔的血液和分析 痉挛的血液，（2）确定成分 引起大鼠血管痉挛的红细胞，（3）表征 脑脊液（CSF）和蛛网膜下腔血液中的血管活性化合物 从SAH患者中删除（4），以确定腺苷是否是否 三磷酸（ATP）和纯血红蛋白会在猴子中引起血管痉挛， （5）确定CSF更改的浓度和时间过程 SAH后人类中人类中腺嘌呤核苷酸和血红蛋白的水平，（6） 确定P2-Purinoceptor拮抗剂对 猴子中的血管痉挛，（7）确定内皮素（ET）的合成是否合成 ET受体信使核糖核酸（mRNA）和ET的分泌 ET受体蛋白在培养的大脑光滑中增加 暴露于红细胞血压素或 纯化的血红蛋白，（8）确定ET变化的时间过程 ET受体mRNA和蛋白质在SAH之后在大鼠中，（9）至 确定ET拮抗剂对猴子血管痉挛的影响。