title: Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.
abstract: Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.
authors.affiliation: Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Nakakoma-gun, Yamanashi 409-3898, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Satoh
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000818:Animals; D001283:Atrioventricular Node / Q000601:surgery; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology*; D017115:Catheter Ablation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006327:Heart Block / Q000150:complications / Q000503:physiopathology*; D006634:Histamine H1 Antagonists / Q000009:adverse effects*; D008133:Long QT Syndrome / Q000209:etiology / Q000503:physiopathology; D023421:Models, Animal; D016593:Terfenadine / Q000009:adverse effects*; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D006634:Histamine H1 Antagonists; D016593:Terfenadine