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, Makoto Arita

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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 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 languageEnglish (US)
Pages (from-to)562-568
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume291
Issue number2
StatePublished - Nov 1 1999

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Bepridil
Action Potentials
Adenosine Triphosphate
Anti-Arrhythmia Agents
R 56865
Inhibitory Concentration 50
Guinea Pigs
Glyburide
Muscle Cells
Ischemia

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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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 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.",
author = "Yulong Li and Toshiaki Sato and Makoto Arita",
year = "1999",
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T1 - Bepridil blunts the shortening of action potential duration caused by metabolic inhibition via blockade of ATP-sensitive K+ channels and Na+- activated K+ channels

AU - Li, Yulong

AU - Sato, Toshiaki

AU - Arita, Makoto

PY - 1999/11/1

Y1 - 1999/11/1

N2 - 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.

AB - 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.

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