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 μg/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 μg/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 μg/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