The novel cardioprotective agent BMS-180448 activates a potassium conductance in cardiac and vascular smooth muscle |
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Authors: | Nicholas J. Lodge Mark A. Smith |
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Affiliation: | (1) Cardiovascular Pharmacology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 4000, 08543-4000 Princeton, NJ, USA |
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Abstract: | 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 M) produced an inhibition of IK followed by the delayed (5.5 ± 0.5 min) activation of a large time-independent potassium current. At 100 M, BMS-180448 produced only inhibition of IK. The BMS-180448 activated current was refractory to block by 30 M, glyburide but was largely inhibited by 100 M alinidine (84 ± 6% inhibition at + 40 mV). Cromakalim (100 M)-activated currents were fully inhibited by 3 M, glyburide and 79 ± 4% blocked by 100 M alinidine. The current responses to BMS-180448 were unaffected by the inclusion of 10 mM UDP (100 M, ATP) in the pipette. BMS-180448 also produced a concentrationdependent increase in 86Rb efflux from aortic strips; efflux responses were increased in low calcium medium and fully antagonized by 3 M, 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 M) 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. |
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Keywords: | BMS-180448 Cardiac muscle Smooth muscle Electrophysiology 86Rb fluxes Potassium channel activators Glyburide Alinidine Alinidine |
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