This grant proposes to determine the mechanism by which myocardial function is altered during the hyperdynamic stage of sepsis. Rats show an elevated whole body oxygen consumption and cardiac output 2 days after inoculation with an aliquot of fecal homogenate. This elevation indicates a hypermetabolic and hyperdynamic phase which is characteristic of the early stages of clinical sepsis. Hearts removed at this stage and studied as working heart preparations show a depressed Starling curve. To determine the mechanism by which function is depressed, myocardial tissue will be studied at three levels of organization: 1) isolated perfused working hearts; 2) subcellular fractions involved in energy production and calcium homeostasis; and 3) structural (particularly fatty acid) composition of organelles with an altered function. The study of isolated hearts will involve determining the ability of inotropic agents such as ouabain and catecholamines to improve contractile function. On mitochondria, respiratory control and calcium binding capacity will be measured. On sarcoplasmic reticula, the calcium ATPase activity, calcium binding and uptake will be determined. Myofibrillar Ca-Mg ATPase will be measured. On plasma membranes indices of membrane function such as the Na+, K+ ATPase, Ca++ ATPase activity and Ca++ binding will be studied. On organelles demonstrating altered function, individual phospholipid moieties and fatty acid composition of these moieties will be determined. The results of these studies should help clarify the cause of the myocardial dysfunction in hyperdynamic sepsis and lead to improved treatment of this dysfunction in a clinical situation.
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