Effects of antiarrhythmic drugs on the hyperpolarization-activated cyclic nucleotide-gated channel current.
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 microM, 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 microM, 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.
Tamura
Atsushi
A
Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba, Japan.
Ogura
Takehiko
T
Uemura
Hiroko
H
Reien
Yoshie
Y
Kishimoto
Takashi
T
Nagai
Toshio
T
Komuro
Issei
I
Miyazaki
Masaru
M
Nakaya
Haruaki
H
D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000187:drug effects* / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques
D000889:Anti-Arrhythmia Agents; D054815:Cyclic Nucleotide-Gated Cation Channels