Bepridil Reverses Atrial Electrical Remodeling and L-Type Calcium Channel Downregulation in a Canine Model of Persistent Atrial Tachycardia

Authors


  • This study was partially supported by Sankyo Co., Ltd., Tokyo, Japan. Part of this study was presented at the AHA Scientific Sessions 2006 and the symposium of the 23rd Annual Meeting of the International Society of Heart Research Japan Section. Sankyo Co., Ltd. provided bepridil used in this study.

  • Manuscript received 25 January 2007; Revised manuscript received 28 February 2007; Accepted for publication 5 March 2007.

Address for correspondence: Akira Fujiki, M.D., The Second Department of Internal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Fax: +81-76-434-5026; E-mail: fujiki@med.u-toyama.ac.jp

Abstract

Introduction: This study tested whether bepridil, a multichannel blocker, would reverse electrical remodeling induced by persistent atrial tachycardia.

Methods and Results: Fourteen dogs were subjected to rapid atrial pacing at 400 bpm for 6 weeks after atrioventricular block was created to control the ventricular rate. During the study period, seven dogs were given placebo for 6 weeks (Control group), and seven were given placebo for 3 weeks, followed by 3 weeks of bepridil (10 mg/kg/day, Bepridil group). The atrial effective refractory period (ERP) and the inducibility and duration of atrial fibrillation (AF) were determined on a weekly basis. After 6 weeks, expression of L-type calcium channel α1C messenger ribonucleic acid (mRNA) was quantified by real-time reverse transcription-polymerase chain reaction. In the Control group, ERP was shortened and the inducibility and duration of AF increased through the 6-week period. In the Bepridil group, the same changes occurred during the first 3 weeks, but were gradually reversed with bepridil. After 6 weeks, ERP was longer, AF inducibility was lower, and AF duration was shorter in Bepridil group than in the Control group. Expression of α1C mRNA was decreased by 64% in the Control group (P < 0.05 vs sham), but in the Bepridil group, it was not different compared with the sham dogs. As a whole group of dogs, ERP was positively correlated with α1C mRNA expression.

Conclusion: Bepridil reverses the electrophysiological consequences of atrial remodeling to some extent and L-type calcium channel downregulation in a canine model of atrial tachycardia.

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