GLYBURIDE-REVERSIBLE CARDIOPROTECTIVE EFFECTS OF BMS-180448 - FUNCTIONAL AND ENERGETIC CONSIDERATIONS

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 anal ogs (e.g., BMS-180448). The purpose of this study was to determine the relation between cardiac function, energy status, and cardioprotectiv e effects for BMS-180448 in isolated rat hearts compared with diltiaze m. BMS-180448 (1-30 mu M) or 0.1-1 mu M diltiazem were given 10 min be fore 25-min global ischemia in rat hearts followed by 30 min of reperf usion. Both compounds significantly increased time to the onset of con tracture during ischemia and improved postischemic recovery of contrac tile function in a concentration-dependent manner. At equivalent cardi oprotective concentrations, BMS-180448 depressed preischemic cardiac f unction significantly less than did diltiazem. During ischemia, diltia zem significantly accelerated the functional decline observed in vehic le-treated hearts, whereas BMS-180448 attenuated the net rate of decli ne of function Despite these different effects on preischemic and isch emic 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 cr eatine phosphate during reperfusion compared with vehicle-treated hear ts. For BMS-280448, this enhanced ATP recovery was accompanied by a si gnificant improvement in the efficiency of oxygen use, which was profo undly reduced in reperfused vehicle-treated hearts. BMS-180448 also si gnificantly enhanced the functional reserve after the 25-min period of global ischemia. Thus BMS-180448 protects ischemic myocardium and con serves ATP with less reduction in cardiac function compared with dilti azem.