Analysis of Arrhythmogenic Profile in a Canine Model of Chronic Atrioventricular Block by Comparing In Vitro Effects of the Class III Antiarrhythmic Drug Nifekalant on the Ventricular Action Potential Indices Between Normal Heart and Atrioventricular Block Heart

• Published in: Journal of Pharmacological Sciences Vol. 103; no. 2; pp. 181 - 188
• Main Authors: Takahara, Akira, Nakamura, Hideki, Nouchi, Hideaki, Tamura, Takeshi, Tanaka, Toshikazu, Shimada, Hideaki, Tamura, Miku, Tsuruoka, Noriko, Takeda, Kentaro, Tanaka, Hikaru, Shigenobu, Koki, Hashimoto, Keitaro, Sugiyama, Atsushi
• Format: Journal Article
• Language: English; Japanese
• Published: Japan Elsevier B.V 2007; The Japanese Pharmacological Society; Elsevier
• Subjects: action potential; Action Potentials - drug effects; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - physiopathology; chronic atrioventricular block dog; Dogs; Dose-Response Relationship, Drug; Heart Block - physiopathology; Heart Ventricles - drug effects; Microelectrodes; nifekalant; Purkinje Fibers - drug effects; Pyrimidinones - pharmacology; action potential; nifekalant; chronic atrioventricular block dog
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.FP0061077

The chronic atrioventricular block dog is a useful model for predicting the future onset of drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III antiarrhythmic drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 µM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.