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

Nishida, Keiya; Fujiki, Akira; Sakamoto, Tamotsu; Iwamoto, Jotaro; Mizumaki, Koichi; Hashimoto, Norio; Inoue, Hiroshi

doi:10.1111/j.1540-8167.2007.00833.x

Cited by 44 publications

(46 citation statements)

References 37 publications

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“…In the LA site, SCN5A and Cx43 were also downregulated in the pacing control group, but the changes in the LCC and Kv4.3 did not show any statistical significance, but they showed similar tendencies as in the RA site. In the bepridil group, the downregulation of the LCC and SCN5A was suppressed in the RA, similar to a previous report, 10 but not in the LA. The downregulation of Kv4.3 and Cx43 was not affected by bepridil administration.…”

Section: Circulation Journal Vol72 February 2008supporting

confidence: 90%

“…Most recently,(LCC), but they did not document any difference between the right and left atrium (RA and LA). 10 Because we have demonstrated an inhomogeneity of electrical remodeling in the RA and LA, at least in our canine rapid atrial stimulation model without atrioventricular block, 11,12 in the present study we focused on the effect of bepridil on atrial electrical remodeling and the difference between the RA and LA in using a new protocol in which we started administering the drug in the later phase of the pacing protocol.…”

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confidence: 98%

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

Fukaya

Niwano

Satoh

et al. 2008

Circ J

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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)

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Section: Circulation Journal Vol72 February 2008supporting

confidence: 90%

mentioning

confidence: 98%

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

Fukaya

Niwano

Satoh

et al. 2008

Circ J

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“…Especially, bepridil has a concentration-dependent strong I CaL blocking effect. [16][17][18][19] Nishida et al reported the efficacy of bepridil against the expression of L-type calcium channel 1c messenger ribonucleic acid (mRNA) after 6 weeks of rapid atrial pacing. 16) 1c mRNA expression was decreased in only the rapid pacing group.…”

Section: Mechanisms Of Atrial Electrical Remodeling In the Acute Phasementioning

confidence: 99%

“…[16][17][18][19] Nishida et al reported the efficacy of bepridil against the expression of L-type calcium channel 1c messenger ribonucleic acid (mRNA) after 6 weeks of rapid atrial pacing. 16) 1c mRNA expression was decreased in only the rapid pacing group. By using bepridil, it was maintained signifi- Rapid pacing decreased atrial ERPs in all regions significantly (P < 0:05).…”

Section: Mechanisms Of Atrial Electrical Remodeling In the Acute Phasementioning

confidence: 99%

Effects of Bepridil on Atrial Electrical Remodeling in Short-Term Rapid Pacing

et al. 2009

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Introduction: Bepridil is a multi-ion channel blocker similar to amiodarone. Recent clinical studies have indicated that bepridil shows a favorable efficacy for the treatment of atrial fibrillation (AF). The purpose of this study is to evaluate the effectiveness of bepridil for electrical remodeling induced by rapid atrial stimulation particularly in the acute-phase.Methods and Results: We studied 18 pigs subjected to right atrial appendage rapid pacing at 500 beats/min for 3 hours that were randomly assigned to the absence or presence of bepridil administration for 14 days. They were divided into 2 groups, an atrial pacing only group (PG; n ¼ 10) and an atrial pacing plus bepridil group (PBG; n ¼ 8). We measured the effective refractory period (ERP) at the right atrial free wall (RAFW), the right atrial appendage (RAA) and the left atrial free wall (LAFW), as well as the monophasic action potential duration at 90% (MAPD 90 ) in RAA during the rapid pacing phase and recovery phase.In the PG, the ERP decreased gradually at all atrial sites during the 3 hour phase of rapid pacing. In contrast, the shortening of the ERP was suppressed significantly at the RAFW and LAFW in the PBG. The MAPD 90 was also shortened by rapid atrial pacing in the PG. This shortening was suppressed significantly in the PBG.We evaluated the effect of bepridil on the inducibility of AF during all time spans. The mean number of AF occurrences in the PBG was significantly fewer than in the PG. (2:1 AE 2:4 vs. 8:5 AE 7:0, p < 0:05) Conclusions: Bepridil prevented the shortening of the ERP and MAPD 90 induced by rapid atrial pacing in the acute phase. The results of this study might explain the efficacy of bepridil for preventing the recurrence of paroxysmal AF. (J Arrhythmia 2009; 25: 89-94)

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“…8) In addition to these electrophysiological actions, it has been speculated in a few reports that bepridil might affect the myocardial remodeling that would promote the arrhythmogenic substrates in a condition of long-lasting AF, and the recovery of down-regulated ion channels was induced by bepridil treatment at least in several experimental studies. 9,10) Regardless of the validity of the proposed anti-remodeling effect of bepridil, several reports have confirmed that it sometimes takes a relatively long time for bepridil to interrupt long-lasting AF even in effective cases. Additionally, bepridil therapy could be associated with risk of adverse effects such as torsades de pointes, QT prolongation, or bradycardia.…”

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confidence: 99%

Repetitive Evaluation of Fibrillation Cycle Length Predicts the Efficacy of Bepridil for Interruption of Long-Lasting Persistent Atrial Fibrillation

Aoyama

Niwano

et al. 2011

Int. Heart J.

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SummaryAlthough bepridil is effective for conversion of long-lasting persistent atrial fibrillation (AF) to sinus rhythm, it sometimes takes a long time to interrupt AF and there is no feasible index to predict its efficacy.In 60 patients with long-lasting persistent AF, bepridil (100-200 mg/day) was administered and continued for 8 weeks while body surface ECG was recorded every 2 weeks. The fibrillation cycle length (FCL) was evaluated using the spectral analysis of the fibrillation waves in each ECG. AF was interrupted in 32 patients receiving bepridil. The conversion was observed at 2 weeks in 4, at 4 weeks in 7, at 6 weeks in 7, and at 8 weeks in 14 patients. When comparing these responders and nonresponders, clinical background characteristics other than the dosage of bepridil did not show any difference and neither did temporal changes in QT parameters and heart rate. In contrast, the FCL and ∆FCL (prolongation in FCL from baseline) became significantly larger in responders than in nonresponders at later observation points (FCL: 177 ± 17 versus 164 ± 19 ms, P = 0.018, and ∆FCL: 38 ± 16 versus 22 ± 12 ms, P < 0.001, at 4-week point; FCL: 188 ± 17 versus 169 ± 19 ms, P = 0.004, and ∆FCL: 49 ± 18 versus 27 ± 14 ms, P < 0.001, at 6-week point).Repetitive evaluation of FCL using spectral analysis of fibrillation waves can be a feasible index to predict the efficacy of bepridil therapy. (Int Heart J 2011; 52: 353-358)

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

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

Cited by 44 publications

References 37 publications

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

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

Effects of Bepridil on Atrial Electrical Remodeling in Short-Term Rapid Pacing

Repetitive Evaluation of Fibrillation Cycle Length Predicts the Efficacy of Bepridil for Interruption of Long-Lasting Persistent Atrial Fibrillation

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