Pathophysiology of Chronic Cerebral Vasospasm

慢性脑血管痉挛的病理生理学

• 批准号: 6898183
• 负责人: Robert Loughlin Macdonald
• 金额: $ 65.33万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898183
• 关键词: Macaca fascicularis; cGMP dependent protein kinase; calcium flux; cerebral aneurysm; cerebral artery; cerebral hemorrhage; clinical research; disease /disorder model; electron spin resonance spectroscopy; hemoglobin; immunocytochemistry; laboratory rat; nitric oxide; pathologic process; polymerase chain reaction; potassium channel; thrombosis; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasodilation; vasospasm; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): We are investigating cerebral vasospasm which is an important cause of cerebral ischemia after subarachnoid hemorrhage (SAH). The long-term objective of this grant is to determine the mechanism of vasospasm after SAH and to thereby develop treatments that will prevent and/or reverse it. We have shown that hemoglobin causes vasospasm and that vasospasm is associated with impaired arterial relaxation. One mechanism of hemoglobin-induced vasospasm may be the binding and removal of nitric oxide (NO). We have used electron paramagnetic resonance (EPR) spectroscopy to detect nitrosyl hemoglobin in the subarachnoid space after SAH, proving that this mechanism occurs. We will therefore test the hypothesis that there is an NO-reversible component of vasospasm by: 1) defining the extent to which vasospasm is reversible with NO donors in a monkey model of SAH; 2) measuring heme-NO adducts (nitrosyl hemoglobin) by EPR spectroscopy in clots removed from the subarachnoid space of monkeys at different times after SAH; 3) quantifying NO in the perivascular space at different times after SAH in monkeys; and 4) defining the time course of changes in and the immunohistochemical locations of the 3 isoforms of NOS in cerebral arteries and perivascular blood clot after SAH in monkeys. Second, because vasospasm does not seem to be completely preventable by NO donors, we will investigate mechanisms of NO-independent vasospasm by: 1) measuring protein kinase G messenger ribonucleic acid, protein and activity during the time course of vasospasm in monkeys; and 2) assessing calcium sensitivity of monkey cerebral arteries during the time course of vasospasm. In a rat model, we will assess the contribution of other downstream effectors of NO-induced relaxation by: 1) assessing potassium channel function during vasospasm (calcium-activated potassium channel density, single channel conductance, and open probability will be assessed using whole cell and single channel patch clamp recordings of isolated vasospastic rat cerebrovascular smooth muscle cells); and 2) measuring whole cell calcium currents during vasospasm in rats because assessment of potassium channel function requires knowledge of intracellular calcium and because smooth muscle calcium homeostasis may be altered during vasospasm after SAH.

描述（由申请人提供）：我们正在研究脑血管痉挛，这是蛛网膜下腔出血（SAH）后脑缺血的重要原因。该赠款的长期目标是确定SAH后血管痉挛的机制，从而开发出可以预防和/或逆转其的治疗方法。我们已经表明，血红蛋白会导致血管痉挛，血管痉挛与动脉松弛受损有关。血红蛋白诱导的血管痉挛的一种机制可能是一氧化氮的结合和去除（NO）。我们已经使用了电子顺磁共振（EPR）光谱来检测SAH后蛛网膜下腔空间中的硝基血红蛋白，证明了这种机制发生。因此，我们将测试以下假设：血管痉挛的不可逆成分：1）定义在SAH猴子模型中没有供体的血管痉挛可逆的程度； 2）通过EPR光谱在SAH后不同时间从猴子的亚蛛网膜下腔空间中去除的凝块中，测量EPR光谱中的血红素 - 无内合物（亚硝基血红蛋白）； 3）在猴子在SAH之后的不同时间，在血管周空间中量化NO； 4）定义猴子在SAH后SAH后，NOS的3种NOS和血管周围血凝块的3个同工型的变化时间和免疫组织化学位置。其次，由于没有供体似乎无法完全预防血管痉挛，因此我们将通过以下方式研究无独立的血管痉挛的机制：1）测量猴子血管痉挛期间的蛋白激酶G信使核糖核酸，蛋白质和活性； 2）评估血管痉挛时间期间猴子脑动脉的钙敏感性。在大鼠模型中，我们将通过以下方式评估其他无诱导放松的下游效应子的贡献：1）评估血管痉挛过程中钾通道功能（钙激活的钾通道密度，单通道电导，单个通道电导和开放概率将使用全细胞和单个通道斑块斑块记录的隔离血管孔隙率夹层的隔离型血管骨膜骨膜腔平滑肌肉的录音来评估）； 2）在大鼠血管痉挛过程中测量整个细胞钙电流，因为对钾通道功能的评估需要了解细胞内钙，并且由于SAH后血管痉挛可能会改变平滑肌肉钙稳态。

项目成果

A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm.

21-氨基类固醇 U74006F 在灵长类动物慢性脑血管痉挛模型中的试验。

• DOI: 10.1227/00006123-198902000-00005
• 发表时间: 1989
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Steinke,DE;Weir,BK;Findlay,JM;Tanabe,T;Grace,M;Krushelnycky,BW
• 通讯作者: Krushelnycky,BW

Activation of protein kinase C inhibits potassium currents in cultured endothelial cells.

蛋白激酶 C 的激活会抑制培养的内皮细胞中的钾电流。

• DOI: 10.1159/000139289
• 发表时间: 1995
• 期刊: Pharmacology
• 影响因子: 3.1
• 作者: Zhang,H;Weir,B;Daniel,EE
• 通讯作者: Daniel,EE

U74389G prevents vasospasm after subarachnoid hemorrhage in dogs.

U74389G 可预防狗蛛网膜下腔出血后的血管痉挛。

• DOI: 10.1097/00006123-199806000-00089
• 发表时间: 1998
• 期刊: Neurosurgery
• 影响因子: 4.8
• 作者: Macdonald,RL;Bassiouny,M;Johns,L;Sajdak,M;Marton,LS;Weir,BK;Hall,ED;Andrus,PK
• 通讯作者: Andrus,PK

Immediate early gene expression in vascular smooth-muscle cells synergistically induced by hemolysate components.

溶血产物成分协同诱导血管平滑肌细胞中立即早期基因表达。

• DOI: 10.3171/jns.1999.90.6.1083
• 发表时间: 1999
• 期刊: Journal of neurosurgery.
• 作者: Wang,X;Marton,LS;Weir,BK;Macdonald,RL
• 通讯作者: Macdonald,RL

Antagonism of eicosanoid-induced contraction of rat aorta by sulphonylureas.

磺脲类药物对类花生酸诱导的大鼠主动脉收缩的拮抗作用。

• DOI: 10.1159/000139232
• 发表时间: 1994
• 期刊: Pharmacology
• 影响因子: 3.1
• 作者: Zhang,H;Cook,D
• 通讯作者: Cook,D