GLYBURIDE-REVERSIBLE CARDIOPROTECTIVE EFFECT OF BMS-180448 IS INDEPENDENT OF ACTION-POTENTIAL SHORTENING

Objective: We determined if action potential duration (APD) shortening and cardioprotection are separable phenomena in ATP-sensitive potassi um channel (K-ATP) openers which protect ischemic myocardium via a gly buride-reversible mechanism. Methods: We determined the effect of the weakly vasodilating K-ATP opener, BMS-180448, and the less cardiac-sel ective cromakalim, on APD in normal, hypoxic or ischemic guinea pig pa pillary muscles or isolated hearts and compared their APD effects with their cardioprotective activity in isolated guinea pig hearts. Result s: In isolated ischemic guinea pig hearts, cromakalim and BMS-180448 h ad similar cardioprotective potencies (EC(25) of 3.2 and 3.3 mu M, res pectively, for increasing time to the onset of contracture). At 10 mu M, BMS-180448 produced no APD shortening, yet was equally protective a t this concentration compared to cromakalim, which produced profound A PD shortening under either hypoxic or ischemic conditions. The cardiop rotective effects of both compounds at 10 mu M were abolished by 0.3 m u M glyburide. Conclusions: APD shortening is not correlated with card ioprotective activity for BMS-180448 and cromakalim while their cardio protective effects are abolished by glyburide. These results suggest t he possibility of reduced proarrhythmic activity in some K-ATP openers and that their cardioprotective activity is not associated with sarco lemmal K-ATP opening.