Bepridil Inhibits Sub-Acute Phase of Atrial Electrical Remodeling in Canine Rapid Atrial Stimulation Model

Abstract

Evaluation of Electrophysiological PropertiesTo achieve a stable condition, each dog was allowed to recover for 7 days after the initial surgical procedure without any pacing. Then, rapid atrial pacing (400 beats/min) was initiated and continued for 2 weeks (rapid pacing phase). This pacing was performed at an output of 4-fold the diastolic threshold and a pulse width of 2 ms. After this continuous rapid pacing, the pacing was ceased, and each dog was allowed to recover for 1 week (recovery phase). On days 0, 3, 7, 10 and 14 during the rapid pacing phase, the rapid pacing was stopped temporarily to evaluate the atrial Background The effect of bepridil, a multichannel blocker, on atrial electrical remodeling was evaluated in a canine rapid atrial stimulation model. Methods and ResultsIn 10 beagle dogs, the right atrial appendage (RAA) was paced at 400 beats/min for 2 weeks. The atrial electrophysiological parameters, including effective refractory period (AERP), were evaluated at three atrial sites: RAA, the right atrium close to the inferior vena cava (IVC) and the left atrium (LA), during the time course of rapid pacing. Five of the dogs were given bepridil (10 mg·kg -1 ·day -1 po). In the control group, AERP was significantly shortened at all atrial sites and the AERP shortening (∆AERP) was larger for the RAA and LA than at the IVC site (p<0.05). In the bepridil group, ∆AERP was smaller than that of the controls at all atrial sites, and the AERP started to return slowly to the pre-pacing level in the second week, regardless of the continuation of rapid pacing. Conclusions In a canine rapid atrial stimulation model, bepridil suppressed AERP shortening. Bepridil might have a reverse electrical remodeling effect, at least for AERP shortening, because it showed slow recovery of AERP in the subacute phase of rapid atrial pacing. (Circ J 2006; 70: 206 -213)

Inhomogenic Effect of Bepridil on Atrial Electrical Remodeling in a Canine Rapid Atrial Stimulation Model

“…Previously, we reported the nominative effect of bepridil in a canine 2-week atrial stimulation model; 9 namely, that bepridil suppressed AERP shortening in the first week and further restored the AERP to the pre-pacing level in the second week. As this type of "late recovery" effect on the AERP was not observed when other drugs were subjected to the same evaluation, 14,15 we also suspected the existence of a "reverse remodeling effect" of bepridil.…”

“…The CV was calculated as the reciprocal of this conduction time, and the values were expressed in percentages as the %CV by dividing each piece of data by the data for day 0 to exclude the influence of the difference in the actual distance of the electrodes in each dog. 9 AF Inducibility and the Longest Duration of AF To evaluate AF inducibility, the incidence of AF induction was evaluated with atrial burst pacing for 3 s at the minimal pacing cycle length that achieved 1:1 atrial capture at each pacing site. This pacing was delivered at 4-fold the diastolic threshold with a pulse width of 2 ms.…”

“…7,8 Because there have been cases in which bepridil interrupted persistent AF after being administered for 1-2 months, a type of "reverse remodeling effect" has been speculated regarding the action of bepridil. In our previous experimental studies, 9 we demonstrated that bepridil suppressed the shortening of the atrial effective refractory period (AERP) in the first week and continued to prolong it in the second week of a 2-week rapid pacing model, but the study design was not appropriate for documenting such a "reverse remodeling effect". Most recently,(LCC), but they did not document any difference between the right and left atrium (RA and LA).…”

Arrhythmogenic Difference Between the Left and Right Atria During Rapid Atrial Activation in a Canine Model of Atrial Fibrillation

“…For continuous atrial rapid pacing, a unipolar screw-in pacing lead (CapSureFix 5568, Medtronic Inc, Minneapolis, MN, USA) was inserted through the right external jugular vein, and the distal end of the lead was screwed into the endocardial surface of the RAA in 7 dogs (RA stimulation group). 18 In the remaining 7 dogs, a screw-in lead was fixed to the epicardial surface of the left atrial appendage (LAA, LA stimulation group, Fig 1). The distal end of the pacing electrode for rapid pacing was connected to a rapid pulse generator (Soletra ® , Medtronic), which was implanted into a subcutaneous pocket in the neck.…”

“…The distal end of the pacing electrode for rapid pacing was connected to a rapid pulse generator (Soletra ® , Medtronic), which was implanted into a subcutaneous pocket in the neck. 18 All studies were performed in accordance with the guidelines specified by the Animal Experimentation and Ethics Committee of the Kitasato University School of Medicine.…”