INTRINSIC MYOCARDIAL DYSFUNCTION IN CIRCULATORY SHOCK

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Cardiac contractile status in circulatory shock is difficult to directly evaluate in the patient or intact animal where the presence of indirect factors may secondarily influence myocardial function. Accordingly, the applicant has characterized a reliable isolated heart muscle model of primary cardiac depression in shock, using atrial and ventricular muscle harvested from guinea pigs experiencing endotoxin shock. The objective of the current study is to utilize this model to evaluate the cardiac effects of putative therapeutic agents in shock, as well as use 45Ca and selected shock-drug interactions to provide insight into potential cellular mechanisms involved in producing shock-induced cardiac dysfunction. Isolated, perfused hearts and cardiac muscle (left atrial and ventricular papillary) preparations will be obtained from guinea pigs subjected to endotoxin shock. Myocardial contractility and reactivity to selected inotropic influences (e.g., Ca++, cAMP, catecholamines) and metabolic substrates (e.g., pyruvate, glucose-insulin) will be determined. Left ventricular function curves, compliance and coronary vascular responses will be contrasted with responses obtained in control hearts. Myocardial Ca++ fluxes in shock will be specifically assessed using cardiac tissue uptake and efflux of 45Ca. Subcellular membrane 45Ca fluxes and membrane phospholipid assays will be conducted and correlated with functional alterations. Effectiveness of selected putative chemotherapeutic agents (e.g., steroids, naloxone, free radical scavengers) in reducing or preventing shock-induced cardiac dysfunction will be evaluated. Assessment will involve dose regimens of in vivo administration of drugs to animals in shock as well as direct in vitro adminstration to heart muscle isolated from control and shocked animals. Shock induced cardiac depression will also be validated and compared in a hemorrhagic (hypovolemic) shock model, and in isolated cardiac preparations from other species. This project is designed to provide a correlative examination of functional and biochemical disturbances to the heart in shock, as well as suggest potential mechanisms whereby disorders of the shock state alter basic contractile processes of the myocardium. Importantly, new directions in chemotherapeutic management of shock will be evaluated. These studies will aid in predicting effects of shock on mechanical responsiveness of the heart to inotropic challenges that may be encountered by patients experiencing cardiovascular shock.