Cardiac Efficiency Is Improved After Ischemia by Altering Both the Source and Fate of Protons

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Abstract
Cardiac efficiency is decreased in hearts after severe ischemia. We determined whether reducing the production of H + from glucose metabolism or inhibiting the clearance of H + via Na + -H + exchange could increase cardiac efficiency during reperfusion. This was achieved using dichloroacetate (DCA) to stimulate glucose oxidation and 5-( N , N -dimethyl)-amiloride (DMA) to inhibit Na + -H + exchange, respectively. Isolated working rat hearts were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Glycolysis and oxidation rates of glucose, lactate, and palmitate were measured. Recovery of cardiac work, O 2 consumption (MV˙O 2 ), and rates of acetyl-coenzyme A and ATP production during reperfusion were determined. After ischemia, cardiac work recovered to 35±5% of preischemic values in control hearts (n=23), although MV˙O 2 , tricarboxylic acid (TCA) cycle activity, and ATP production from glycolysis and oxidative metabolism rapidly recovered to preischemic levels. This decrease in cardiac efficiency was accompanied by a substantial production of H + from glucose metabolism. DCA caused a 2.2-fold increase in glucose oxidation, a 46±17% decrease in H + production, a 1.6-fold increase in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion (n=17). Inhibition of Na + -H + exchange with DMA did not alter TCA cycle activity and ATP production rates but did result in a 1.8-fold increase in cardiac efficiency and a 1.7-fold increase in cardiac work (n=12). These data show that cardiac efficiency and the contractile function after ischemia can be improved by either reducing the rate of H + production from glucose metabolism during reperfusion or inhibiting the clearance of H + via Na + -H + exchange. Our data suggest that an increased requirement for ATP to restore ischemia-reperfusion–induced alterations in ion homeostasis contributes to the decrease in cardiac efficiency and contractile function after ischemia.