The oral hypoglycemic agent tolbutamide has been found to protect the ischemic myocardium against irreversible mechanical failure. The possibility that this salutary effect of tolbutamide was related to its ability to alter energy metabolism was examined in ischemic rat hearts perfused with 5 mM glucose, 5mM acetate and 2.5 units/l insulin. In the presence of 0.6 mM tolbutamide, coronary flow and oxygen consumption were unaltered; however, glucose utilization was stimulated by 30%, glycogenolysis was enhanced by 23%, and the drop in ATP content was reduced by 17% after 30 min, of low-flow perfusion. This elevation in glycolytic flux occurred without a parallel rise in the production of inhibitory metabolites; lactate production was unaltered and tissue lactate/pyruvate ratio decreased. Pyruvate dehydrogenase flux measurements reveal that the mechanism by which tolbutamide increases glycolysis without increasing lactate production is by promoting the entry of pyruvate into the mitochondria. The basis for the observed stimulation of anaerobic metabolism and pyruvate oxidation and how this contributes to the increase in ATP content and benefits the ischemic heart is discussed.