This investigator proposes a series of studies which will quantify substrate utilization in pathways designed to replete citric acid cycle intermediates lost during myocardial ischemia under conditions encountered during routine cardiac surgery. The proposed experiments will be conducted using an isolated perfused rat heart preparation and involve the use of labeled substrates and NMR spectroscopy. Oxidation of multiple citric acid substrates and anaplerosis will be studied under steady-state as well as during and after ischemia in the setting of various cardioplegic solutions. Specifically, the metabolic effects of cardioplegia will be studied, first in control hearts and then in hearts administered 1) warm continuous potassium cardioplegia, 2) an intracellular based cardioplegic solution, 3) low sodium and low potassium cardioplegia, 4) potassium cardioplegia with tetrodotoxin added to achieve polarized arrest, 5) the potassium channel opener pinacidil to achieve hyperpolarized arrest, and 6) washed and packed porcine erythrocytes to evaluate the effects of red blood cells on cellular metabolism. Once the metabolic effects of these interventions have been determined, the mechanisms by which potassium cardioplegia achieves suppression of fatty acid oxidation and stimulation of anaplerosis will be studied using substrates which cannot enter the TCA cycle via anaplerotic pathways. Studies will also be conducted in perfused hearts in which only pyruvate is labeled in order to detect the contribution of exogenous pyruvate. The next phase of the experiment includes evaluation of the metabolic effects of infusing potassium cardioplegia after ischemia. Finally, cardioplegic composition will be altered to include glutamate and aspartate. These studies will be designed to determine the linkage between metabolism and function and further eliminate mechanism of actions. It is anticipated that the findings will provide new information on the metabolic mechanisms that are important to preserving or enhancing cellular energy stores. This, in turn, should lead to improvements in cardioplegic solutions currently used.
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|Gilbert, Nathan F; Meyer, Paul E; Tauriainen, M Peter et al. (2002) Effects of hypothermia on myocardial substrate selection. Ann Thorac Surg 74:1208-12|