During myocardial ischemia, the extracellular potassium concentration increases in a triphasic pattern, an initial early increase, a constant phase, and a late increasing phase. The aim of this study was to determine whether diltiazem inhibits the late increasing phase by maintaining glycolytic adenosine triphosphate (ATP) synthesis in ischemic myocardium. The extracellular potassium concentration and pH were measured simultaneously with ion-sensitive electrodes during 30 min of global ischemia in isolated guinea-pig hearts. In the control hearts, the late increasing phase occurred 13 min after the onset of ischemia when the change in extracellular pH had reached a plateau. There was a sharp increase in the myocardial lactate level in the control hearts, which was maintained for approximately 8 min after the onset of ischemia. Iodoacetate (1 mM) led to a ATP depletion and rapid accumulation in extracellular potassium shortly after the onset of ischemia without a decrease in extracellular pH. The preischemic treatment with diltiazem (3 microM) reduced cardiac function both before ischemia and during the early period of ischemia. Diltiazem almost completely abolished the late increasing phase with a continuous decrease in extracellular pH throughout the ischemic period. The myocardial lactate level in the diltiazem-treated group increased sharply between 2 and 15 min after the onset of ischemia. The myocardial ATP level was preserved throughout the ischemic period. This study shows that diltiazem inhibits the late increasing phase in extracellular potassium by maintaining glycolytic ATP synthesis during ischemia.