The primary focus of this proposal is to extend our current studies designed to examine the role of the polymorphonuclear leukocytes (PMN), oxygen radicals and metabolites of arachidonic acid as mediators of cell injury associated with myocardial ischemia and/or myocardial reperfusion. Studies will be conducted in the anesthetized dog subjected to temporary left circumflex coronary artery occlusion followed by reperfusion and the heart later subjected to a quantitative assessment of irreversible ischemic myocardial damage. The interventions to be examined include depletion of PMN's by anti-neutrophil antibodies, enzymatic degradation of oxygen radicals by superoxide dismutase and catalase, and pharmacologic inhibitors of phospholipase and of lipoxygenase and/or cyclooxygenase. The effects of selected interventions will be assessed in terms of infarct size, neutrophil infiltration of ischemic myocardium, functional integrity of ischemic microvasculature, regional blood flow, ventricular function and ultimate healing. Infarct size and the anatomic area a risk will be determined by a dual staining technique. PMN infiltration will be assessed using autologous 111-indium labeled leukocytes. Permeability changes within the microvasculature will be assessed with the use of 125-iodine labeled albumin. Regional myocardial blood flow will be determined with the use of radiolabeled microspheres. Segmental contractile function will be assessed with the use of intramyocardial ultrasonic crystals, both acutely and chronically. Infarct healing will be graded by determination of scar thickness and histological evaluation. The object of these studies will be to determine whether modification of leukocyte function, scavaging of free radicals or alterations of arachidonic acid metabolism will favorably alter the effects of reperfusion upon ischemic myocardium, thus, reducing that component of myocardial injury associated with coronary reperfusion. The results of this study should enhance our understanding of the cytotoxic role of the leukocyte in myocardial ischemia and/or reperfusion injury. The outcome could lead to the development of improved pharmacologic interventions to protect the heart subject to reperfusion as with thrombolytic therapy or after the termination of global-ischemic arrest during cardiopulmonary by-pass.
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