The mechanisms contributing to coronary artery occlusion and myocardial infarction remain unresolved. Various mechanical means have been used to produce partial or complete vascular occlusion in animal models of myocardial ischemia. These studies have provided significant information on the patho-physiological events associated with ischemia, but have not explored the role of thrombus formation per se in the evolution of ischemic heart disease. The majority of studies on thrombus formation have been conducted in in vitro systems. The primary goal of this study is to determine the role of platelet aggregation in contributing to coronary artery occlusion in an in vivo model of ischemia that more closely approximates the clinical situation. During platelet aggregation, serotonin is released into the plasma. This increase can be used as an index of platelet aggregation, if the reaccumulation of released serotonin by intact platelets is inhibited. Various pharmacological interventions will be utilized to selectively inhibit specific pathways involved in platelet aggregation and thrombus formation. The major aims of this study are directed to the role of platelet aggregation as a primary contributor to thrombus extension resulting in complete coronary artery occlusion. A partial coronary thrombus will be formed in instrumented dogs by application of current to the intraarterial lumen. In vivo platelet aggregation will be assessed by changes in plasma serotonin levels obtained via coronary sinus catheters. Plasma serotonin concentrations will be determined by a sensitive radioenzymatic method. Correlative measurements of myocardial function will be made using Doppler flow probes, length-segment gauges (left ventricular contractility), Millar pressure catheters (blood pressure) and epicardial ECGs. Selected agents (aspirin, Ketanserin, dazoxiben, diltiazem, aminophylline) will be used singly or in combination to block specific mechanisms associated with platelet aggregation. The thrust of these experiments is to gain a better understanding of the role of platelets in spontaneously extending an existing thrombus leading to coronary occlusion, not to the initial events associated with thrombogenesis. Preliminary studies in this laboratory have clearly demonstrated the feasibility of accomplishing these experiments in an in vivo model that can quantitatively assess both platelet aggregation and thrombus formation simultaneously with dynamic measurements of coronary blood flow and myocardial function.
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