Myocardial infarction remains a major cause of morbidity and mortality in the United States. Early reperfusion has been shown to reduce infarct size, improve ventricular function, and decrease mortality in the animal model and in man. The introduction of more effective and safer thrombolytic agents and percutaneous balloon angioplasty in evolving mycocardial infarction has resulted in increasing numbers of patients undergoing successful reperfusion. However, certain metabolic events and/or anatomic changes occur with reperfusion that may limit the amount of salvageable myocardium (""""""""reperfusion injury""""""""). Better understanding of the mechanism(s) and importance of reperfusion injury is essential in order to design appropriate therapeutic interventions. This proposal will attempt to identify structural and biochemical events which may be significant contributors to reperfusion injury, and explore the usefullness of various drugs in limiting these biochemical and structural changes. A canine reperfusion model which stimulates reperfusion with fibrinolytic therapy will be used. The structure and function of the endothelium will be assessed in vivo and in vitro using the artificial blood substance Fluosol-DA (FDA). Free radicals are cytotoxic substances which degrade proteins and cause lipid peroxidation of cellular membranes. In an attempt to identify the site and biochemical pathways involved in free radical production, drugs which act on specific free radical generating pathways or which replenish free radical scavenging enzymes will be investigated. Infarct size, ventricular function, regional myocardial blood flow, biochemical estimations, and ultrastructural changes will be assessed. Oxypurinol will define the role of xanthine oxidase in free radical mediated reperfusion injury, FDA and n-acetylcystein to determine whether restoration of scavenging enzymes will reduce reperfusion injury, and the iron chelator Deferoxamine to clarify whether iron is an essential contributor to lipid peroxidation in vivo. In addition, the role of neutrophil mediated injury and neutrophil-endothelial interaction will also be investigated. These studies will provide important information regarding the mechanisms of reperfusion injury in the canine model and the usefullness of various agents to limit this entity.
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