Effects of amiodarone on electrical and structural remodeling induced in a canine rapid pacing-induced persistent atrial fibrillation model

Ashikaga, Keiichi; Kobayashi, Takao; Kimura, Masaomi; Owada, Shigeki; Sasaki, Satoshi; Iwasa, Atsushi; Furukawa, Ken‐Ichi; Motomura, Shigeru; Okumura, Ken

doi:10.1016/j.ejphar.2006.02.023

Cited by 26 publications

(42 citation statements)

References 22 publications

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“…Several clinical reports have shown the possibility of using bepridil as a "reverse remodeling" agent, so this effect should be tested in clinical cases. It has been shown that amiodarone, another multi-ion channel blocker, might have a "reverse remodeling effect" in short-and long-term experimental studies; 19,24 however, the use of amiodarone is limited by its various side-effects. Therefore, bepridil is potentially a more useful antiarrhythmic drug, especially for treating long-lasting AF, without inducing severe side-effects.…”

Section: Circulation Journal Vol72 February 2008mentioning

confidence: 99%

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 2008mentioning

confidence: 99%

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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“…Also, amiodarone inhibits sodium and calcium channels, and has a noncompetitive anti-sympathetic effect (12,15,17). In addition, amiodarone was reported to reverse the mechanical stretch induced-remodeling process of atria by blocking T-type calcium channels, scavenging oxygen free radicals, and suppressing inflammatory cytokines, including tumor necrosis factor-α and interleukin-6 (3,12,17,18). Long-term effects of amiodarone may be modulated by the direct action of the parent drug and its active metabolite desethylamiodarone in plasma and tissue (16).…”

Section: Electropharmacological Effects Of Amiodaronementioning

confidence: 99%

In Vivo Electropharmacological Effects of Amiodarone and Candesartan on Atria of Chronic Atrioventricular Block Dogs

Wang

Takahara²,

Nakamura³

et al. 2007

J Pharmacol Sci

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Abstract. Electropharmacological effects of chronically administered amiodarone and candesartan on atria that had been remodeled against congestive heart failure were assessed using dogs (about 10 kg in weight) with chronic atrioventricular block. Amiodarone was administered orally in a dose of 200 mg / body per day for the initial 7 days followed by 100 mg for the following 21 days (n = 7). Candesartan was administered in a dose of 12 mg / body per day for 28 days (n = 7). All animals survived the 4-week experimental period, indicating the lack of risks for inducing cardiohemodynamic collapse or torsade de pointes by these drugs. The plasma amiodarone concentration was 353 ng / ml at 4 weeks of treatment. Before candesartan treatment (control), intravenous administration of 30 ng / kg of angiotensin II increased the mean blood pressure by 18 mmHg, which was significantly decreased to 1 mmHg by 4 weeks of treatment. Amiodarone prolonged the atrial effective refractory period without affecting inter-atrial conduction time and decreased the duration of the burst pacing-induced atrial fibrillation, whereas candesartan hardly affected these variables. These results indicate that amiodarone should become a pragmatic pharmacological strategy against atrial fibrillation in patients with chronically compensated heart failure and suggest that a much higher dose of candesartan may be needed to exert its efficacy in this model.

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“…It has been suggested that prevention of L-type Ca 2+ current α 1C -subunit downregulation contributes to these anti-remodeling properties (Shinagawa et al 2003). Similarly, amiodarone prevented both electrical and structural remodeling in the ventricles of canines with heart failure (Ashikaga et al 2006) and in a rat model of inflammatory cardiomyopathy (Tachikawa et al 2005). Of note, in the latter study, inflammatory markers IL-6 and TNF-α were unchanged in myocardial tissue by treatment with 50 mg/kg amiodarone for 6 weeks (Tachikawa et al 2005), in contrast to short-term treatment in the sepsis model (Polat et al 2013), further highlighting the complex actions of amiodarone and the importance of differences in treatment duration and/or pathology.…”

mentioning

confidence: 99%

Pleiotropic actions of amiodarone: still puzzling after half a century

Heijman

Dobrev

2013

Naunyn-Schmiedeberg's Arch Pharmacol

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Effects of amiodarone on electrical and structural remodeling induced in a canine rapid pacing-induced persistent atrial fibrillation model

Cited by 26 publications

References 22 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

In Vivo Electropharmacological Effects of Amiodarone and Candesartan on Atria of Chronic Atrioventricular Block Dogs

Pleiotropic actions of amiodarone: still puzzling after half a century

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