AUTONOMIC RECEPTOR FUNCTION IN MYOCARDIAL ISCHEMIA

心肌缺血一小时导致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-alpha）。本研究计划的目的是研究 这些变化的机制和时间过程，以及 冠状动脉再灌注的变化是可逆的。一个主要特点 是对有意识的动物生理学的综合研究， 用于测量缺血性心脏病患者的心内膜下和心外膜下壁运动 和非缺血区的生化指标。 冠状动脉闭塞和再灌注将通过直接 测量冠状动脉血流（多普勒技术）和局部 心肌血流量（放射性微球技术）。第二 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的相应对照值 非缺血区。特别是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，环 AMP和GTP调节蛋白将在急性胰腺炎模型中进行检查。 心肌缺血在确定了变化的时间过程之后， 自主神经受体和腺苷酸环化酶的耦合，它将是 确定这些变化是否是可逆的冠状动脉 再灌注。另一个主要目标是确定变化是否是 跨壁或跨心肌壁局部受影响， 整个心肌壁的缺血程度这些实验将 比较心内膜下缺血更严重和 在皮下和皮下同样强烈。除了审查 在体心肌室壁运动和细胞变化反应性 β-肾上腺素能刺激与异丙肾上腺素，机制将是 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的再灌注 受体阻滞，也在脱敏的心脏，诱导 去甲肾上腺素水平长期升高

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.