We have previously shown that high concentrations of fatty acids depress reperfusion recovery of ischemic rat hearts as a result of a fatty acid inhibition of glucose oxidation. In this study, we determined whether dichloroacetate, an activator of pyruvate dehydrogenase, could overcome fatty acid inhibition of glucose oxidation and thereby improve mechanical recovery of hearts reperfused after a period of transient global ischemia. Isolated working rat hearts, perfused with 11 mM glucose, 1.2 mM palmitate, and 500 microU/ml insulin, were subjected to a 30-min period of no flow ischemia, followed by a 30-min period of reperfusion. Under these conditions, control hearts recovered 37% of preischemic function. The addition of 1 mM dichloroacetate to the perfusate at reperfusion resulted in a significant improvement in recovery of mechanical function (to 73% of preischemic function). When dichloroacetate was added before the onset of ischemia, however, this protective effect was lost, and a significant increase in myocardial lactate accumulation during ischemia was observed. The effects of dichloroacetate on glucose oxidation rates in both nonischemic and reperfused ischemic hearts was determined by perfusing hearts with 11 mM [U-14C]glucose and 1.2 mM palmitate and quantitatively collecting 14CO2 produced by the heart. In nonischemic hearts, 1 mM dichloroacetate increased steady-state glucose oxidation rates from 298 +/- 69 to 1,223 +/- 135 nmol.g dry wt-1.min-1. The addition of dichloroacetate to hearts reperfused after a 25-min period of ischemia also increased glucose oxidation rates from (112 +/- 25 to 561 +/- 83 nmol.g dry wt-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)