Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak

Dichloroacetate (DCA) is a pyruvate dehydrogenase activator that increases cardiac efficiency during reperfusion of ischemic hearts. We determined whe ther DCA increases efficiency of mitochondrial ATP production by measuring proton leak in mitochondria from isolated working rat hearts subjected to 3 0 min of ischemia and 60 min of reperfusion. In untreated hearts, cardiac w ork and efficiency decreased during reperfusion to 26% and 40% of preischem ic values, respectively. Membrane potential was significantly lower in mito chondria from reperfused (175.6 +/- 2.2 mV) versus aerobic (185.8 +/- 3.1 m V) hearts. DCA (1 mM added at reperfusion) improved recovery of cardiac wor k (1.9-fold) and efficiency (1.5-fold) but had no effect on mitochondrial m embrane potential (170.6 +/- 2.9 mV). At the maximal attainable membrane po tential, O-2 consumption (nmol O-2. mg(-1). min(-1)) did not differ between untreated or DCA-treated hearts (128.3 +/- 7.5 and 120.6 +/- 7.6, respecti vely) but was significantly greater than aerobic hearts (76.6 +/- 7.6). Dur ing reperfusion, DCA increased glucose oxidation 2.5-fold and decreased Hproduction from glucose metabolism to 53% of untreated hearts. Because H+ p roduction decreases cardiac efficiency, we suggest that DCA increases cardi ac efficiency during reperfusion of ischemic hearts by increasing the effic iency of ATP use and not by increasing the efficiency of ATP production.