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.
Lodge
N J
NJ
Cardiovascular Pharmacology, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Smith
M A
MA
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D011817:Rabbits; D012414:Rubidium Radioisotopes
D001578:Benzopyrans; D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D006146:Guanidines; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; C084684:BMS 180448; C022192:alinidine; D003000:Clonidine; D005905:Glyburide