Anti-atrial Fibrillatory Versus Proarrhythmic Potentials of Amiodarone: A New Protocol for Safety Evaluation In Vivo
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Anti-atrial fibrillatory and proarrhythmic potentials of amiodarone were simultaneously analyzed by using the halothane-anesthetized beagle dogs (n = 4) in order to begin to prepare standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of 0.3 mg/kg of amiodarone hydrochloride decreased the heart rate and mean blood pressure. Additional administration of 3 mg/kg of amiodarone hydrochloride prolonged the QT interval besides the effects observed by the low dose, whereas it showed 1.6 times larger prolongation in the effective refractory period of the atrium than that of the ventricle, which may explain its clinical efficacy against atrial arrhythmias. However, no significant change was detected by either dose in the early repolarization assessed by corrected J–T peak or the late repolarization done by T peak–T end in the electrocardiogram, although the former tended to be shortened and the reverse was true for the latter. Lack of prolongation in the early repolarization will make it feasible to better understand why amiodarone lacks proarrhythmic potential in spite of the QT-interval prolongation. Thus, these results of amiodarone obtained by current protocol may become a guidance on assessing efficacy and adverse effects of new anti-atrial fibrillatory drugs in vivo.
KeywordsAmiodarone Atrial fibrillation Bepridil Early repolarization Effective refractory period QT interval dl-Sotalol Torsade de pointes
This study was supported in part by JSPS KAKENHI (#25460344), MEXT KAKENHI (#S1101016), and AMED Grant (#AS2116907E). We thank Drs. Ken Kitahara, Yukiko Yamazaki, Ms. Misako Nakatani, and Mrs. Yuri Ichikawa for their technical assistances.
Compliance with Ethical Standards
Conflict of Interest
The authors indicated no potential conflict of interests.
- 1.Kaufman, E. S., Zimmermann, P. A., Wang, T., Dennish, G. W. I. I. I., Barrell, P. D., Chandler, M. L., & Greene, H. L. (2004). Risk of proarrhythmic events in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study: A multivariate analysis. Journal of the American College of Cardiology, 44, 1276–1282.PubMedGoogle Scholar
- 5.Yoshida, H., Sugiyama, A., Satoh, Y., Ishida, Y., Yoneyama, M., Kugiyama, K., & Hashimoto, K. (2002). Comparison of the in vivo electrophysiological and proarrhythmic effects of amiodarone with those of a selective class III drug, sematilide, using a canine chronic atrioventricular block model. Circulation Journal, 66, 758–762.CrossRefPubMedGoogle Scholar
- 6.van Opstal, J. M., Schoenmakers, M., Verduyn, S. C., de Groot, S. H., Leunissen, J. D., van Der Hulst, F. F., et al. (2001). Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome. Circulation, 104, 2722–2727.CrossRefPubMedGoogle Scholar
- 10.Johannesen, L., Vicente, J., Mason, J. W., Sanabria, C., Waite-Labott, K., Hong, M., et al. (2014). Differentiating drug-induced multichannel block on the electrocardiogram: Randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clinical Pharmacology and Therapeutics, 96, 549–558.CrossRefPubMedGoogle Scholar
- 19.Yoshida, H., Sugiyama, A., Satoh, Y., Ishida, Y., Kugiyama, K., & Hashimoto, K. (2002). Effects of disopyramide and mexiletine on the terminal repolarization process of the in situ heart assessed using the halothane-anesthetized in vivo canine model. Circulation Journal, 66, 857–862.CrossRefPubMedGoogle Scholar