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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics November 1999, 291 (2) 562-568;
Yulong Li
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Toshiaki Sato
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Makoto Arita
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Abstract

The effects of bepridil, a potent antiarrhythmic drug, on the activity of ATP-sensitive K+ (KATP) channels and Na+-activated K+ (KNa) channels were examined in isolated patches from guinea pig ventricular myocytes. In inside-out membrane patches, KATP channel currents were recorded with 140 mM [K+]i and 140 mM [K+]o solutions, and KNa channel currents were recorded by increasing [Na+]ito 100 mM with 40 mM [K+]i, respectively. Bepridil (1–100 μM) inhibited the KATP channel current in a concentration-dependent manner. The IC50 value of bepridil was estimated to be 10.5 μM for outward KATPchannel currents (holding potential, +60 mV) and 6.6 μM for inward KATP channel currents (holding potential, −60 mV). Bepridil (0.1–30 μM) also inhibited KNa 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 KATP channel antagonist (glibenclamide, 1 μM) and a KNa 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 KATP channels and KNachannels 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.

Footnotes

  • Send reprint requests to: Makoto Arita, M.D., Ph.D., Department of Physiology, Oita Medical University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan. E-mail: arita{at}oita-med.ac.jp

  • Abbreviations:
    KATP
    ATP-sensitive K+
    APD
    action potential duration
    FCCP
    carbonyl cyanidep-(trifluoromethoxy)phenylhydrazone
    IC50
    concentration of half-maximum inhibition
    NPo
    open probability
    KNa
    Na+-activated K+
    MI
    metabolic inhibition
    R56865
    N[1-(4-(4-fluorophenoxy)butyl)-4-piperidinyl]-N-methyl-2-benzothiazolamine
    • Received March 18, 1999.
    • Accepted July 27, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 2
1 Nov 1999
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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 562-568;

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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics November 1, 1999, 291 (2) 562-568;
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