AUTONOMIC RECEPTOR FUNCTION IN MYOCARDIAL ISCHEMIA

心肌缺血中的自主受体功能

• 批准号: 3364331
• 负责人: Dorothy Eileen Vatner
• 金额: $ 24.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3364331
• 关键词: G protein; adenylate cyclase; adrenergic agents; beta adrenergic receptor; coronary occlusion /thrombosis; dogs; guanosine triphosphate; heart motion; heart pharmacology; isoproterenol; myocardial ischemia /hypoxia; normetanephrine; radioactive microsphere technique; reperfusion; sarcolemma; swine

One hour of myocardial ischemia results in increased beta-adrenergic receptor density but uncoupling of the beta-adrenergic receptor from adenylate cyclase associated with decreases in the GTP regulatory protein, G(s-alpha). The goals of this research proposal are directed at examining the mechanism and time course of these changes as well as whether the changes are reversible with coronary artery reperfusion. One major feature is the combined study of physiology in the conscious animal instrumented for measurement of subendocardial and subepicardial wall motion in ischemic and nonischemic zones with biochemical measurements from the same hearts. Coronary artery occlusion and reperfusion will be verified by direct measurement of coronary blood flow (Doppler technique) and regional myocardial blood flow (radioactive microsphere technique). The second critical feature of the experimental design is the study of the changes in subendocardial and subepicardial regions of the ischemic zone compared with respective control values in the subendocardium and subepicardium in the non-ischemic zone from the same hearts. Specifically ,beta-adrenergic receptor agonist and antagonist binding, adenylate cyclase activity, cyclic AMP, and GTP regulatory proteins will be examined in models of acute myocardial ischemia. After determining the time course of changes in autonomic receptors and coupling to adenylate cyclase, it will be determined whether the changes are reversible by coronary artery reperfusion.Another major goal is to determine whether changes are transmural or affected regionally across the myocardial wall varying with the level of ischemia across the myocardial wall. These experiments will be compared where ischemia is more intense subendocardially and where ischemia is equally intense in subepi- and subendocardium. In addition to examining the responsiveness of in vivo myocardial wall motion and cellular changes to beta-adrenergic stimulation with isoproterenol, mechanisms will be addressed by examining the effects of coronary artery occlusion and reperfusion in the presence and absence of alpha- and beta-adrenergic receptor blockades and also in the desensitized heart, induced by chronically elevated norepinephrine levels.

心肌缺血一小时会导致β-肾上腺素能增加 受体密度，但β-​​肾上腺素能受体从 与 GTP 调节蛋白减少相关的腺苷酸环化酶， G(s-α)。本研究计划的目标旨在检查 这些变化的机制和时间进程以及是否 随着冠状动脉再灌注，变化是可逆的。一大特色 是对有意识的动物的生理学的综合研究 用于测量缺血性心内膜下和心外膜下室壁运动 和非缺血区，对同一心脏进行生化测量。 冠状动脉闭塞和再灌注将通过直接验证 冠状动脉血流测量（多普勒技术）和局部 心肌血流量（放射性微球技术）。第二个 实验设计的关键特征是研究 缺血区的心内膜下和心外膜下区域与 心内膜下和心外膜下各自的控制值 来自同一心脏的非缺血区。具体来说，β-肾上腺素能 受体激动剂和拮抗剂结合、腺苷酸环化酶活性、循环 AMP 和 GTP 调节蛋白将在急性模型中进行检查 心肌缺血。确定变化的时间过程后 自主受体并与腺苷酸环化酶偶联，它将 确定冠状动脉的变化是否可逆 再灌注。另一个主要目标是确定变化是否是 跨壁或跨心肌壁的区域性影响随 心肌壁缺血的程度。这些实验将 比较心内膜下缺血更严重的地方和缺血更严重的地方 在心外膜下和心内膜下同样强烈。除了检查之外 体内心肌壁运动和细胞变化的反应性 用异丙肾上腺素刺激β-肾上腺素，其机制是 通过检查冠状动脉闭塞的影响来解决 在存在和不存在α-和β-肾上腺素能的情况下再灌注 受体阻滞以及在脱敏心脏中，由 去甲肾上腺素水平长期升高。