CALCIUM BLOCKER & RELATED THERAPY FOR CEREBRAL ISCHEMIA

钙阻滞剂

• 批准号: 3408179
• 负责人: JAMES C GROTTA
• 金额: $ 16.24万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3408179
• 关键词: adenosine triphosphate; calcium channel blockers; calcium flux; cerebral ischemia /hypoxia; chromatography; combination chemotherapy; drug metabolism; electroencephalography; evoked potentials; glutamates; hippocampus; histology; human therapy evaluation; laboratory rat; learning; lipid metabolism; microscopy; nicardipine; phospholipids; somesthetic sensory cortex; thromboxanes

Calcium flux into neurons and consequent production of phospholipid metabolites such as thromboxane A2 may cause permanent cellular injury after cerebral ischemia. Furthermore, the release of excitatory neurotransmitters such as glutamate may be the trigger causing opening of calcium channels. In this study, the effect on neuronal histology, electrophysiology, metabolism, learning ability, and CBF of nicardipine (Ni), a dihydropyridine calcium entry blocker, will be studied in male wistar rats rendered ischemic by 30 minutes of 4-vessel occlusion. Additional studies will evaluate Baclofen (Ba), an inhibitor of glutamate release, and 1 benzylimidazole (1-Bi), a thromboxane synthase inhibitor in combination with Ni. The hypothesis to be tested in this project is that Ni alone or augmented by Ba or 1-Bi will improve outcome following ischemia, and that this is associated with inhibition of calcium activated phospholipid metabolism. All animals will undergo vertebral artery cautery followed 24 hours later by carotid artery and collateral vessel occlusion for 30 minutes. Loss of righting reflex and EEG activity will be documented. Animals will be divided into 4 groups; normals, shams, untreated ischemic controls, and treatment with systemic Ni, Ba, 1-Bi, or combination therapy. Histologic damage in hippocampi, SEP amplitude and latency, and enzymatic quantitation of ATP, ATP turnover, and phosphocreatine in dissected hippocampal regions will be determined during 72 hours of reperfusion. Reference and working memory will be tested in an 8-arm radial maze over a 3 month period. Thromboxane B2 and 6-keto-PGF1a, indicators of phospholipid breakdown in this model, will be assayed during 72 hours of reperfusion. Finally, the effects of treatment on these measures of calcium activated neuronal dysruption will be compared to changes in regional cerebral blood flow measured by the 14C-butanol indicator fractionation technique.

钙流进入神经元和随之产生的 磷脂代谢物如血栓素A2可能导致 脑缺血后的永久性细胞损伤。 此外，委员会认为， 兴奋性神经递质如谷氨酸的释放 可能是导致钙通道开放的触发器。在这 研究，对神经元组织学，电生理学， 尼卡地平（Ni）的代谢、学习能力和CBF， 二氢吡啶类钙通道阻滞剂，将在男性中进行研究 Wistar大鼠通过30分钟的4-血管闭塞而呈现缺血。 其他研究将评估巴氯芬（Ba），一种抑制剂， 谷氨酸盐释放和1-苄基咪唑（1-Bi），一种血栓烷 合成酶抑制剂与Ni的组合。 假设是 在这个项目中测试的是Ni单独或添加Ba或1-Bi 将改善缺血后的结果，这是 与抑制钙激活磷脂有关 新陈代谢. 所有动物将接受椎动脉烧灼术， 缺血30 h后行颈动脉及侧支血管阻断 分钟 翻正反射和脑电图活动的丧失 记录在案。 将动物分为4组：正常组， 假手术、未治疗的缺血对照和全身性 Ni、Ba、1-Bi或联合治疗。 组织学损伤 SEP振幅和潜伏期，以及酶 ATP、ATP周转率和磷酸肌酸的定量 将在72小时内确定解剖的海马区域 再灌注。 参考记忆和工作记忆将在 8臂放射状迷宫中进行了3个月的实验。 血栓素B2 和6-keto-PGF 1a，磷脂分解的指标， 模型，将在再灌注72小时期间进行测定。 最后 治疗对这些钙激活措施的影响 神经元破裂将与区域性的变化进行比较。 通过14 C-丁醇指示剂测量脑血流量 分馏技术