Myocardial infarction remains a major cause of morbidity and mortality in the United States. One important determinant of early and late mortality is the degree of left ventricular dysfunction. Early reperfusion remains the most effective way of reducing infarct size and improving ventricular function in the animal model. The introduction of new thrombolytic agents and percutaneous balloon angioplasty has resulted in increasing numbers of patients undergoing successful reperfusion. The results of reperfusion therapy on ventricular function in man have shown disappointing results with either no or minimal improvement. Certain deleterious metabolic and anatomic events occur with reperfusion which may limit the amount of potentially salvageable myocardium (""""""""REPERFUSION INJURY""""""""). The extent of Reperfusion INJURY may be an important determinant of myocardial damage after the first few hours of reperfusion. ADENOSINE is a endogenous substance which has numerous pharmacologic effects including coronary arteriolar smooth muscle dilatation, anti-platelet and neutrophil effects and reduction of sympathetic neuronal discharges. Since all of these mechanisms have been postulated to be involved in REPERFUSION INJURY, intracoronary infusion of ADENOSINE should be a highly effective agent in reducing infarct size and improving ventricular function after reperfusion. This proposal will attempt to identify the role and mechanism(s) of action of ADENOSINE in reducing REPERFUSION INJURY. A canine model which simulates reperfusion with fibrinolytic therapy will be used. Initial studies will assess the time course of ADENOSINE in protecting against ischemic/REPERFUSION INJURY and its effect on infarct morphology. The role of ADENOSINE as an endogenous natural occurring protector against REPERFUSION INJURY will be determined using receptor and uptake blockers. Since caffeine is a potent receptor blocker and widely consumed in beverages, its role in altering the response to infarction and reperfusion will also be examined. Since reperfusion results in microvascular damage associated with progressive decrease in flow, the effect of ADENOSINE on the structure and function of the endothelium and the no-reflow phenomenon will be determined. The effect of ADENOSINE on neutrophil function in vivo will also be examined. Finally the mechanisms of protection by ADENOSINE will be examined utilizing cultured canine coronary endothelial cells. These studies will provide important information regarding the efficacy and mechanism(s) of actions of ADENOSINE in protecting against REPERFUSION INJURY and would be an important advance in the treatment of evolving myocardial infarction.
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