Abstract 1083: Bepridil Reverses Established Atrial Electrical Remodeling and Prevents L-Type Calcium Channel Downregulation in a Canine Long-Term Atrial Tachycardia Model
Introduction: Bepridil is effective in restoring sinus rhythm in patients with long-lasting atrial fibrillation (AF), but the mechanism still remains to be elucidated. This study tested whether bepridil administered after the development of atrial remodeling can reverse the electrophysiological consequencies and whether it can suppress the L-type calcium (Ca2+) channel downregulation in a canine six-week atrial tachycardia model.
Methods: Fourteen dogs were subjected to rapid atrial pacing at 400 bpm for six weeks after an atrioventricular block was created to control ventricular rate. Seven dogs were paced for six weeks with placebo (Group I). The other seven dogs were paced for the first three weeks with placebo, and for the subsequent three weeks under bepridil administration (10 mg/kg/day, Group II). The atrial effective refractory period (ERP) and the inducibility and duration of AF were determined every week. The L-type Ca2+channel α1C mRNA expression was quantified by real time RT-PCR and compared with five sham dogs.
Results: In Group I, the ERP shortened and the inducibility and durations of AF increased during the six-week pacing period. In Group II, the same changes were promoted in the first three weeks but were gradually reversed during the subsequent three weeks after starting bepridil administration. After the six-week study period, ERP was longer, AF inducibility was lower, and mean AF duration was shorter in Group II as compared with Group I (ERP at basic cycle length 400 msec, 102.1±4.7 msec vs. 80.0±3.1 msec, p<0.01; AF inducibility, 40.0±10.7% vs. 82.9±6.4%, p<0.01; mean AF duration, 4.2±1.4 sec vs. 345.2±253.6 sec, p<0.05). The α1C mRNA expression (α1C mRNA/18S rRNA ratio) was decreased by 72% in Group I (p<0.05 vs. sham), but was not affected in Group II as compared with the sham dogs after the six-week pacing period.
Conclusions: Bepridil suppresses AF induced by tachycardia-induced remodeling, and prevents the electrophysiological and biochemical consequence of the remodeling.