Vol. 291, Issue 2, 562-568, November 1999

Bepridil Blunts the Shortening of Action Potential Duration Caused by Metabolic Inhibition via Blockade of ATP-Sensitive K⁺ Channels and Na⁺-Activated K⁺ Channels

Yulong Li, Toshiaki Sato and Makoto Arita

Department of Physiology, Oita Medical University, Hasama, Oita, Japan

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.