title: Bepridil blunts the shortening of action potential duration caused by metabolic inhibition via blockade of ATP-sensitive K(+) channels and Na(+)-activated K(+) channels.
abstract: 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 microM) inhibited the K(ATP) channel current in a concentration-dependent manner. The IC(50) value of bepridil was estimated to be 10.5 microM for outward K(ATP) channel currents (holding potential, +60 mV) and 6.6 microM for inward K(ATP) channel currents (holding potential, -60 mV). Bepridil (0.1-30 microM) also inhibited K(Na) channel currents measured at the holding potential of -60 mV, in a concentration-dependent manner with an IC(50) value of 2.2 microM. In coronary-perfused guinea pig right ventricular preparations, the metabolic inhibition (MI) achieved with the application of 0.1 microM carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone shortened the action potential duration (APD) in a time-dependent manner. When bepridil (10 microM) 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 microM) and a K(Na) channel antagonist (R56865, 10 microM) 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.
authors.affiliation: Department of Physiology, Oita Medical University, Hasama, Oita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Arita
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D015764:Bepridil / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D012964:Sodium / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D052160:Benzothiazoles; D002121:Calcium Channel Blockers; D010880:Piperidines; D015221:Potassium Channels; D013844:Thiazoles; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D015764:Bepridil; D000255:Adenosine Triphosphate; C054551:R 56865; D012964:Sodium; D005905:Glyburide