Yoshioki Satoh1, Atsushi Sugiyama2,*, Kohji Tamura1
and Keitaro Hashimoto2
1Second Department of Internal Medicine and 2Department of Pharmacology, Yamanashi Medical University, Tamaho-cho, Nakakoma-gun, Yamanashi 409 - 3898, Japan
* To whom correspondence should be addressed.
Abstract: The cardiovascular profile of dofetilide was examined using halothane-anesthetized, closed-chest in vivo canine model (n=6). Dofetilide was administered at the dose of 1, 10 or 100 É g/kg, i.v. over 10 min with a pause of 20 min. After the lowest infusion rate, no significant change was detected in any of the cardiovascular parameters. Infusion of 10 É g/kg dofetilide, which was close to the submaximal clinically effective antiarrhythmic dose, decreased the heart rate and prolonged the ventricular repolarization phase and refractory period. After the highest dose of dofetilide, the cardiac output and left ventricular contraction decreased during sinus rhythm, the latter of which was not changed during the constant heart rate of 150 beats/min, while the dose-related effects were observed on the heart rate, repolarization phase and refractory period. The afterload and preload to the left ventricle and AV nodal as well as intraventricular conductions were hardly affected even at 100 É g/kg, i.v. These results obtained in the in vivo canine model support the previous reports describing that dofetilide possesses a highly selective blocking property for IKr. Moreover, the absence of effects on the afterload and preload to the left ventricle and the cardiac conduction makes dofetilide favorable as an antiarrhythmic drug because it is often used for patients with moderate to severe left ventricular dysfunction.
Keywords: Dofetilide, Monophasic action potential, Long QT syndrome, IKr blocker,
Post repolarization refractoriness