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.
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