The novel cardioprotective agent BMS-180448 activates a potassium conductance in cardiac and vascular smooth muscle

The goal of the present study was to further characterize the effects of the novel cardioprotective agent BMS-180448 on potassium fluxes in cardiac and vascular smooth muscle. Exposure of voltage-clamped guinea pig ventricular myocytes to BMS-180448 (300 microM) produced an inhibition of IK followed by the delayed (5.5 +/- 0.5 min) activation of a large time-independent potassium current. At 100 microM, BMS-180448 produced only inhibition of IK. The BMS-180448 activated current was refractory to block by 30 microM glyburide but was largely inhibited by 100 microM alinidine (84 +/- 6% inhibition at +40 mV). Cromakalim (100 microM)-activated currents were fully inhibited by 3 microM glyburide and 79 +/- 4% blocked by 100 microM alinidine. The current responses to BMS-180448 were unaffected by the inclusion of 10 mM UDP (100 microM ATP) in the pipette. BMS-180448 also produced a concentration-dependent increase in 86Rb efflux from aortic strips; efflux responses were increased in low calcium medium and fully antagonized by 3 microM glyburide. Thus, BMS-180448 activates a potassium conductance in both cardiac and smooth muscle. The glyburide sensitivity of the BMS-180448-induced increase in 86Rb efflux from the aortic preparations suggests that this drug activates IKATP in vascular smooth muscle. Moreover, the observation that BMS-180448 (100 microM) partially inhibits the effects of cromakalim in ventricular muscle cells suggests that these drugs interact, directly or indirectly, with a common site in cardiac muscle.