Adenosine triphosphate (ATP)-sensitive potassium channel openers as a class exert cardioprotective effects, and we can separate vasodilator from glyburide-reversible cardioprotective activity in cromakalim analogs (e.g., BMS-180448). The purpose of this study was to determine the relation between cardiac function, energy status, and cardioprotective effects for BMS-180448 in isolated rat hearts compared with diltiazem. BMS-180448 (1-30 microM) or 0.1-1 microM diltiazem were given 10 min before 25-min global ischemia in rat hearts followed by 30 min of reperfusion. Both compounds significantly increased time to the onset of contracture during ischemia and improved postischemic recovery of contractile function in a concentration-dependent manner. At equivalent cardioprotective concentrations, BMS-180448 depressed preischemic cardiac function significantly less than did diltiazem. During ischemia, diltiazem significantly accelerated the functional decline observed in vehicle-treated hearts, whereas BMS-180448 attenuated the net rate of decline of function. Despite these different effects on preischemic and ischemic cardiac function, diltiazem and BMS-180448 conserved cardiac ATP during ischemia to a similar degree. BMS-180448 enhanced the recovery of ATP (also seen for diltiazem, but not to the same magnitude) and creatine phosphate during reperfusion compared with vehicle-treated hearts. For BMS-180448, this enhanced ATP recovery was accompanied by a significant improvement in the efficiency of oxygen use, which was profoundly reduced in reperfused vehicle-treated hearts. BMS-180448 also significantly enhanced the functional reserve after the 25-min period of global ischemia. Thus BMS-180448 protects ischemic myocardium and conserves ATP with less reduction in cardiac function compared with diltiazem.