Cibenzoline attenuates upregulation of Kv1.5 channel gene expression by experimental paroxysmal atrial fibrillation.
Antiarrhythmic drugs exert their effects by inhibiting the ion channels of cardiomyocytes. However, these effects could also modify the ionic environment around them, and thereby affect the expression of ion channels, leading to biochemical enhancement or attenuation of the antiarrhythmic effects. To test this hypothesis, the physiological and biochemical effects of cibenzoline were evaluated in a rapid atrial pacing model in rats. In rats with rapid atrial pacing, pretreatment with cibenzoline significantly inhibited the increases in Kv1.5 mRNA at 2 hours and immunoreactive protein at 4 hours by 35 +/- 15% and 30 +/- 10%, respectively. These effects were observed only in the rapid atrial pacing group, not in the sham-operated group. With cibenzoline pretreatment, 4-hour rapid atrial pacing resulted in significant prolongation of the atrial refractory period compared to the untreated group even after removal of cibenzoline. In contrast, the sham and rapid atrial pacing model with and without cibenzoline pretreatment showed similar acute physiological responses to cibenzoline. In conclusion, in addition to the acute physiological effects, pretreatment with cibenzoline exerted pleiotropic effects of inhibition of Kv1.5 channel upregulation by rapid pacing, implying differences in the cibenzoline effects when administered before and after onset of paroxysmal atrial fibrillation.
Yamashita
Takeshi
T
The Cardiovascular Institute, Roppongi, Tokyo, Japan.
Sekiguchi
Akiko
A
Iwasaki
Yu-Ki
YK
Sagara
Kouichi
K
Hatano
Seiji
S
Iinuma
Hiroyuki
H
Aizawa
Tadanori
T
Fu
Long-Tai
LT
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004594:Electrophysiology; D006325:Heart Atria / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel; D010138:Pacemaker, Artificial; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological; D015854:Up-Regulation / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D007093:Imidazoles; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; C032151:cifenline