HEMODYNAMIC AND CARDIAC EFFECTS OF BMS-180448, A NOVEL K(+)ATP OPENER, IN ANESTHETIZED DOGS AND ISOLATED RAT HEARTS

Hemodynamic and cardiac effects of BMS-180448 (0.3-10 mg/kg i.v.) or c romakalim (0.01-0.3 mg/kg i.v.) were evaluated in anesthetized open-ch est dogs and isolated perfused rat hearts. In the canine studies, hear t rate (HR), mean arterial pressure and left ventricular pressure were measured as well as electromagnetic blood flows recorded from the aor tic, renal, coronary and femoral vascular beds. BMS-180448 was 187-fol d less potent than cromakalim in lowering blood pressure (ED(-20) valu es of 7.84, and 0.042 mg/kg for BMS-180448 and cromakalim, respectivel y). Both compounds increased HR. Effects of BMS-180448 occurred at dos es higher than those of cromakalim but at doses slightly lower than th ose needed to cause hypotension (ED((HR)))/ED((MABP)) ratio of 0.18 fo r BMS-180448). BMS-180448 had no effect on myocardial contractility or relaxation over the doses studied, whereas cromakalim significantly i ncreased +dP/dt and lowered -dP/dt. Effects on +dP/dt were associated with a decrease in blood pressure. Although BMS-180448 reduced total p eripheral resistance (ED(-25) = 5.75 mg/kg), it had little effect on s pecific vascular beds, with the exception of the coronary bed. BMS-180 448, unlike cromakalim which caused more general vasodilating effects, appeared to be relatively selective in dilating the coronary vascular bed. In isolated perfused rat hearts, BMS-180448, 10-fold more potent as a cardioprotectant (EC(25) = 2.7 mu M) than as a cardiodepressant (ED(-25) = 27.8 mu M), had no effect on HR, suggesting a lack of effec t of BMS-180448 on myocardial conduction. In conclusion, BMS-180448, a recently developed K-ATP(+) opener, exerted less hypotensive and more selective vascular effects than did cromakalim. These results suggest that BMS-180448, at doses previously reported to give cardioprotectio n, should have a safe hemodynamic profile.