The principle objective of this research is to learn how myocardial cells react to ischemic injury and to reperfusion following periods of ischemia which cause reversible or irreversible cell injury. We have previously shown that reperfusion of canine myocardium which has been severely ischemic for 40 minutes, in vivo, is associated with explosive cell swelling, sarcolemmal disruption and development of contraction bands, i.e., so-called contraction band necrosis. These changes develop within two minutes of reperfusion. Reperfusion of reversibly injured (""""""""stunned"""""""") myocardium results in none of these changes but full recovery of adenine nucleotides and contractile function may require several days. 1. We plan to study other aspects of post-ischemic recovery of reversibly injured (""""""""stunned"""""""") myocardium including ultrastructural changes, cell swelling and electrolyte changes. Also we will study the effects of repeated brief coronary occlusions on myocyte metabolite content, ultrastructure and viability. 2. We will examine the cause(s) of events associated with reperfusion of irreversibily injured myocardium. In particular, the role of calcium overload or of reoxygenation, per se, will be assessed by manipulating the constituents of blood or electrolyte media used for reperfusion. Tissue damage will be evaluated from ultrastructural observations and from measurement of tissue electrolyte and water content. Also the possible role of free radicals in ischemic injury will be studied by testing superoxide dismutase in a reperfusion model of myocardial infarction. The late effects of reperfusion on the healing process and the ultimate character and size of myocardial scars, and on arrhythmogenesis also will be studied, in dogs reperfused three hours after coronary occlusion. 3. We will compare the cellular effects of moderate vs. severe ischemia by comparing metabolite and ultrastructural changes in relation to local collateral blood flow. Severe vs. moderate ischemia in the subendocardial region will be compared by subgrouping dogs with naturally differing degrees of collateral flow. Transmural differences in the rate of metabolite depletion and ultrastructural features of injury also will be correlated with collateral flow. We also will compare the response of moderately and severely ischemic myocardium to therapeutic intervention, e.g. with verapamil and with glucose-insulin-potassium. These studies will contribute to our understanding of the pathogenesis of ischemic cell death and may have clinical applications 1) for cardiac preservation during cardiac surgery and 2) for the rational development of the means to delay myocyte death and/or to limit myocardial infarct size.
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