The effects of bepridil, a potent antiarrhythmic drug, on the activity of ATP-sensitive K+ (K(ATP)) channels and Na+-activated K+ (K(Na)) channels were examined in isolated patches from guinea pig ventricular myocytes. In inside-out membrane patches, K(ATP) channel currents were recorded with 140 mM [K+](i) and 140 mM [K+](o) solutions, and K(Na) channel currents were recorded by increasing [Na+](i) to 100 mM with 40 mM [K+](i), respectively. Bepridil (1-100 μM) inhibited the K(ATP) channel current in a concentration-dependent manner. The IC50 value of bepridil was estimated to be 10.5 μM for outward K(ATP) channel currents (holding potential, +60 mV) and 6.6 μM for inward K(ATP) channel currents (holding potential, -60 mV). Bepridil (0.1-30 μM) also inhibited K(Na) channel currents measured at the holding potential of -60 mV, in a concentration- dependent manner with an IC50 value of 2.2 μM. In coronary-perfused guinea pig right ventricular preparations, the metabolic inhibition (MI) achieved with the application of 0.1 μM carbonyl cyanide p- (trifluoromethoxy)phenylhydrazone shortened the action potential duration (APD) in a time-dependent manner. When bepridil (10 μM) was applied 5 min after the introduction of MI, the APD shortening was significantly blunted. The concomitant application of a K(ATP) channel antagonist (glibenclamide, 1 μM) and a K(Na) channel antagonist (R56865, 10 μM) could mimic the effect of bepridil and attenuated the shortening otherwise produced by MI. These results suggest that bepridil inhibits both K(ATP) channels and K(Na) channels and blunts the shortening of APD during MI. These effects of bepridil may partly account for the alleged antiarrhythmic action of this drug during ischemia.
|Original language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Nov 1 1999|
ASJC Scopus subject areas
- Molecular Medicine