Effects of Antiarrhythmic Drugs on the Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Current

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  • Tamura Atsushi
    Department of Pharmacology, Chiba University Graduate School of Medicine, Japan Department of General Surgery, Chiba University Graduate School of Medicine, Japan
  • Ogura Takehiko
    Department of Pharmacology, Chiba University Graduate School of Medicine, Japan
  • Uemura Hiroko
    Department of Pharmacology, Chiba University Graduate School of Medicine, Japan
  • Reien Yoshie
    Department of Pharmacology, Chiba University Graduate School of Medicine, Japan
  • Kishimoto Takashi
    Department of Molecular Pathology, Chiba University Graduate School of Medicine, Japan
  • Nagai Toshio
    Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan
  • Komuro Issei
    Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan
  • Miyazaki Masaru
    Department of General Surgery, Chiba University Graduate School of Medicine, Japan
  • Nakaya Haruaki
    Department of Pharmacology, Chiba University Graduate School of Medicine, Japan

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Abstract

After the report of the Cardiac Arrhythmia Suppression Trial, a tabular framework of the Sicilian Gambit has been proposed to display actions of antiarrhythmic drugs on ion channels and receptors and to provide more rational pharmacotherapy of arrhythmias. However, because effects of antiarrhythmic drugs on If have not been thoroughly examined, we used patch clamp techniques to determine the effects of various antiarrhythmic drugs on the HCN (hyperpolarization-activated cyclic nucleotide–gated) channel currents. HCN4 channels, a dominant isoform of HCN channels in the heart, were expressed in HEK293 cells. Amiodarone and bepridil potently inhibited the HCN4 channel current with IC50 values of 4.5 and 4.9 μM, respectively, which were close to their therapeutic concentrations. The inhibitory effects of quinidine, disopyramide, cibenzoline, lidocaine, mexiletine, aprindine, propafenone, flecainide, propranolol, and verapamil on the HCN4 channel current were weak in their therapeutic concentrations, with IC50 values of 78.3, 249, 46.8, 276, 309, 43.7, 14.3, 1700, 50.5, and 44.9 μM, respectively, suggesting that the inhibitory effects on If would be clinically small. d,l-Sotalol hardly affected the HCN4 channel current. Information about the HCN4-channel effects of many antiarrhythmic drugs may be useful for determining the appropriate drug for treatment of various arrhythmias while minimizing adverse effects.<br>

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