METABOLIC REGULATION OF MYOCARDIAL CONTRACTILITY

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The overall goal of this project is to determine the factors that regulate myocardial contractility during reductions of coronary flow. This goal will be accomplished by testing the following two-part hypothesis in isolated perfused rabbit hearts: .mild to moderate reductions of coronary flow. At coronary flow rates where oxygen availability is not rate-limiting for ATP synthesis, changes in the myocardial calcium transient primarily regulate myocardial contractility. .severe reductions of coronary flow. At coronary flow rates where oxygen availability is rate limiting for ATP synthesis, increases of inorganic phosphate (Pi) and/or H+ primarily regulate myocardial contractility by decreasing myofilament calcium sensitivity. To test this hypothesis, simultaneous measurements of the calcium transient, phosphates (ATP, phosphocreatine, Pi), intracellular pH, and myocardial contractility will be made during steady-state reductions of coronary flow and acute no-flow conditions. The calcium transient will be measured using indo-1, a fluorescent calcium indicator. Phosphates and intracellular pH will be measured using 31P NMR spectroscopy. The proposed experiments will provide new and important information regarding the mechanisms that regulate contractility during reductions of coronary flow.