MYCOCARDIAL DYSFUNCTION AND CA++ FLUXES IN SHOCK

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Intrinsic cardiac contractile status in shock and sepsis is difficult to directly evaluate in the patient or intact animal where the presence of indirect factors secondarily influences myocardial function. Accordingly, the applicant has characterized reliable isolated heart muscle models of primary cardiac depression in shock, using cardiac preparations harvested from animals experiencing experimental shock. The current project is based on our hypothesis that intrinsic myocardial dysfunction occurs as a progressive participant of both early and subsequent shock states, and importantly, is associated with specific alterations in Ca++ transport and excitation-contraction coupling processes of the heart cell in shock. Susceptibility of the shock-induced cardiac alterations to therapeutic intervention will also be examined. Isolated, perfused hearts and cardiac muscle (left atrial and ventricular papillary) preparations will be obtained from guinea pigs subjected to endotoxin shock. In vitro myocardial contractile responses will be compared with in vivo hemodynamic parameters during both early non-hypotensive endotoxicosis and subsequent hypotensive shock. 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 in cardiac tissue and sarcolemmal and sarcoplasmic reticulum membrane fractions. Subcellular membrane Na+-Ca++ exchange (activity, stoichiometry), passive Ca++ binding, active Ca++ transport, Ca++ efflux, and membrane phospholipid assays will be correlated with functional analyses. Selected Ca++-dependent inotropic interventions (Ca++, cAMP, Ca++-channel agonists-antagonists) will be used as pharrmacologic probes to delineate functional and biochemical alterations and sites of dysfunction. Shock induced cardiac depression and altered Ca++ regulation will be validated and compared in sepsis and hemorrhagic (hypovolemic) shock models. Effectiveness of selected chemotherapeutic agents (Ca++ channel antagonists, oxygen radical scavengers) in reducing myocardial depression and altered Ca++ fluxes will be determined. This project is designed to provide a correlative examination of functional and biochemical disturbances to the heart in shock and sepsis, as well as suggest Ca++-related cellular mechanisms whereby disorders of the shock state alter basic excitation-contraction coupling processes of the myocardium.