BackgroundThe antiarrhythmic or reverse remodeling effects of bepridil, a multi-ion channel blocker, have been recently reported, but inhomogeneity of the electrical remodeling and effects of bepridil have been observed in previous reports. In this study, the effect of long-term administration of bepridil on atrial electrical remodeling was evaluated in a comparison of the right and left atrium (RA and LA) in a canine rapid atrial stimulation model. Methods and ResultsIn 10 beagle dogs, rapid atrial pacing (400 beats/min) was delivered for 6 weeks and the atrial effective refractory period (AERP), conduction velocity (CV) and inducibility of atrial fibrillation (AF) were evaluated every week. In 5 of the pacing dogs, bepridil (10 mg·kg -1 ·day -1 ) was administered orally, starting 2 weeks after the initiation of the rapid pacing. At the end of the protocol, the hemodynamic parameters and extent of tissue fibrosis were evaluated and the mRNA of SCN5A, Kv4.3, the L-type Ca 2+ channel (LCC) and connexin (Cx) 40, 43, and 45 in both atria were examined by quantitative real-time reverse transcriptase-polymerase chain reaction. In the pacing control group, AERP shortening, decreased CV, increased AF inducibility and downregulation of the expression of SCN5A and LCC were observed. In the bepridil group, the AERP exhibited a relatively quick recovery after bepridil was started in the first week and continued to recover gradually until the end of the protocol, but that recovery was smaller in the LA than in the RA. The CV was not affected by bepridil administration. AF inducibility was well suppressed in the RA in the bepridil group, but the induction of short-duration AF could not be suppressed in the LA. The mRNA downregulation of the LCC and SCN5A was negated by bepridil administration in the RA; but not in the LA; however, the data showed similar tendencies. There were no significant differences in the hemodynamic parameters or tissue fibrosis and the mRNA expression of Kv4.3, Cx40, 43, and 45 between the pacing control and bepridil groups. Conclusion Bepridil exhibited an anti-electrical remodeling effect in this study as previously reported, but the effect was inhomogeneous between the RA and LA, with the LA appearing to be more resistant to the effect of bepridil. (Circ J 2008; 72: 318 -326)

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)

AimsRemodelling of the extracellular matrix (ECM) plays an important role in the production of arrhythmogenic substrate for atrial fibrillation (AF), and is considered to be promoted by the connective tissue growth factor (CTGF). Our objective was to assess the relationship between CTGF and ECM synthesis, and the effect of olmesartan on these processes.Methods and resultsFifteen canine AF models were produced by rapid atrial stimulation. They were divided into three groups: pacing control (n = 5): 6-week pacing, pacing + olmesartan (n = 5): pacing with olmesartan (2 mg/kg/day), and non-pacing group (n = 5). In the pacing control group, messenger ribonucleic acid expressions of CTGF and collagen types 1 and 3 were up-regulated in comparison with the non-pacing group (P < 0.05) while transforming growth factor-β (TGF-β) did not exhibit a significant difference. In the pacing + olmesartan group, these up-regulations were suppressed (P < 0.05). In fluorescent immunostaining, the expression of CTGF was localized in the cytoplasm. The protein level of collagen type 3 was increased in the pacing control and it was suppressed in the pacing + olmesartan group.ConclusionsCTGF and associated genes were up-regulated in the atria with the appearance of fibrosis. Because this up-regulation was independent of TGF-β and suppressed by olmesartan, CTGF up-regulation was considered to be mediated by angiotensin II.

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