The general objective are to learn the mechanism(s) through which myocardial cells react to ischemic injury, followed by reperfusion. After a brief episode of ischemia which causes no necrosis, myocardium does have persistent alterations of metabolism and post-ischemic contractile dysfunction (""""""""stunning""""""""). Such myocardium also has increased resistance against injury may be caused by events in ischemia or, hypothetically, by effects of reperfusion, per se (non-lethal or lethal """"""""reperfusion injury""""""""). It is postulated that reperfusion injury may be caused by 1) excess free radicals, perhaps produced by neutrophils (PMNs) accumulating in the injured tissue, 2) excess intracellular Ca++ (calcium overload), or 3) cellular swelling due to an increased intracellular osmotic load. The proposed studies will address the importance of free radical and of calcium overload in their pathogenesis of preconditioning (PC), stunning, and lethal myocyte injury. Anti-free radical therapies will be used to determine whether PC is a manifestation of free radical """"""""injury"""""""". Studies also will address whether PC depends on the rapid synthesis of stress proteins and whether stunning must be present for PC to occur. Protection against lethal myocyte injury will be assessed by measuring myocardial infarct size. Corresponding changes in energy metabolism after PC will be assessed by measuring adenine nucleotides and intermediates of anaerobic glycolysis. To assess the potential importance of PMN accumulation in reperfusion injury, the number of tissue PMNs vs. time of reperfusion will be assessed, the effect of antibodies to PMN adhesion proteins on PMN accumulation and myocardial infarct size will be determined. The importance of calcium overload (mediated by Na+/H+ exchange and Na+/Ca++ exchange) will be studied by testing the effect of transient hypocalcemic reperfusion or of analogs of amiloride on myocardial segmental shortening or myocardial infarct size. Since patients often have brief episodes of ischemia (angina) preceding infarction, it seems likely that PC occurs in patients; elucidation of the mechanism(s) of this phenomenon may have clinically important implications. In addition, although early reperfusion is generally accepted to limit myocardial infarct size and reduce morbidity and mortality, it may become possible to achieve further benefit with adjuvant therapy which could attenuate lethal or non-lethal reperfusion injury.
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