The objective of this research proposal is to examine the effects of coronary artery occlusion and reperfusion on measurements of regional myocardial function, wall thickness and segment shortening, regional blood flow (radioactive microspheres), electrograms and adrenergic and cholinergic receptors and adenylate cyclase activity and calculations of myocardial stiffness, in chronically instrumented, conscious dogs. In addition, new methodology developed in the principal investigator's laboratory, permits the assessment of coronary artery occlusion and reperfusion on direct and continuous measurements of coronary arterial diameter in the conscious dog with the aim of determining whether the vasoactivity of these large coronary arteries is modified by coronary artery occlusion and reperfusion. The major aim of this proposal is to determine whether the critical time period of coronary artery occlusion, after which coronary artery reperfusion is no longer beneficial, can be extended by a) i.c. administration of Alpha and Beta adrenergic blockers, or b) regional or total cardiac denervation. The underlying hypothesis is that activation of the Alpha- and Beta-adrenergic sympathetic system is deleterious during coronary artery occlusion and reperfusion. By eliminating these adverse effects a more beneficial response to coronary artery reperfusion will be evident. Potential mechanisms responsible for salvage of myocardial function by cardiac denervation or i.c. administration of Alpha or Beta adrenergic blockers include a) enhanced regional blood flow to ischemic myocardium, b) reduction of reperfusion arrhythmias, c) preventing increases in Alpha or Beta adrenergic receptors, d) prolonging the time required for myocardial stiffness to increase. The goal of this proposal is to examine these hypotheses in the same chronically, instrumented, conscious animals utilizing the techniques developed in the principal investigator's laboratory and utilizing the collaborative efforts of Drs. C. Homcy, D. Vatner and I. Mirsky to examine the biochemical and myocardial stiffness mechanisms, respectively. The results of these studies will have significance for understanding myocardial ischemia in general and coronary artery reperfusion in particular. In addition, the studies on the denervated hearts will be relevant to the clinical situation of cardiac transplantation, since the transplanted heart is denervated.
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