EFFECTS OF DICHLOROACETATE ON MECHANICAL RECOVERY AND OXIDATION OF PHYSIOLOGICAL SUBSTRATES AFTER ISCHEMIA AND REPERFUSION IN THE ISOLATED HEART

The effects of dichloroacetate (DCA) on fatty acid oxidation and flux through pyruvate dehydrogenase (PDH) were studied in ischemic, reperfu sed myocardium supplied with glucose, long-chain fatty acids, lactate, pyruvate, and acetoacetate. The oxidation rates of all substrates wer e determined by combined C-13 nuclear magnetic resonance (NMR) spectro scopy and oxygen-consumption measurements, and PDH flux was assessed b y lactate plus pyruvate oxidation. In nonischemic control hearts, DCA increased PDH flux more than eightfold (from 0.68 +/- 0.28 to 5.81 +/- 1.16 mu mol/min/g dry weight; n = 8 each group; p < 0.05) and signifi cantly inhibited the oxidation of acetoacetate and fatty acids. DCA al so improved mechanical recovery after 30 min of ischemia plus 30 min o f reperfusion bur did not significantly increase PDH flux measured at the end of the reperfusion period (1.35 +/- 0.42 mu mol/min/g dry weig ht) compared with untreated ischemic hearts (0.87 +/- 0.28 mu mol/min/ g dry weight; n = 8 each group; p = NS), Although DCA had a modest eff ect on functional recovery in the reperfused myocardium, this benefici al effect was not associated with either marked stimulation of PDH flu x or inhibition of fatty acid oxidation.