The aim of this study is to determine the role of leukocytes, oxygen radicals, and leukotrienes in myocardial ischemia and infarction by assessing the effects of several interventions in a canine model involving occlusion-reperfusion of the left circumflex coronary artery. The interventions to be studied include neutrophil depletion by anti-neutrophil antibodies, enzymatic degradation of oxygen radicals by superoxide dismutase and catalase, and leukotriene inhibition by specific pharmacologic antagonists. Several durations of coronary occlusion will be studied for each intervention. The effects of intervention will be assessed in terms of infarct size, neutrophil infiltration of ischemic myocardium, functional integrity of ischemic microvasculature, regional blood flow and ventricular function, and ultimate healing. Infarct size and anatomic area at risk will be determined by a dual staining technique. Neutrophil infiltration will be assessed using autologous indium-111 labeled leukocytes. The microvasculature will be evaluated by permeability to iodine-125 labeled albumin. Myocardial blood flow will be measured using radiolabeled microspheres. Left ventricular function will be analyzed using two-dimensional echocardiography. Infarct healing will be graded by scar thickness and histology. The results will be analyzed to determine whether interference with leukocyte function, free radical activity, or leukotriene action affects tissue damage or healing after reperfusion of ischemic myocardium. The proposed project should substantially augment current knowledge of the role leukocytes play in mediating the effects of myocardial ischemia and reperfusion. It should also extend current concepts of leukotriene participation in the inflammatory response to ischemic myocardium. The results of this study will be important because the increasing use of thrombolytic therapy in patients with myocardial infarction may be exposing them to the untoward effects of reperfusion observed in experimental animals. Ultimately, this study may suggest more effective approaches to the management of patients with acute myocardial infarction.
