The effect of tolbutamide on carbohydrate and energy metabolism of an isolated working rat heart preparation will be examined. The hearts will be perfused with Krebs Henseleit buffer containing an appropriate substrate. To test the effect of tolbutamide on particular metabolic pathways, various substrates will be used to perfuse hearts and glycolytic flux, glucose oxidation rate, oxygen consumption and ATP synthesis will be measured. A series of hearts will be frozen and the tissue concentration of several key intermediates will be determined. These data will provide the basis for establishing the site of tolbutamide action. We have found that short-term tolbutamide treatment protects the ischemic myocardium against damage. Associated with this protection is an inhibition by tolbutamide of lactate accumulation and adenine nucleotide loss from the heart. The mechanism for these changes will be investigated.