Yoshioki Satoh1, Atsushi Sugiyama2,*, Kohji Tamura1
and Keitaro Hashimoto2
1Secondﾊ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 purpose of this study was to test the potential
utility of mexiletine for the treatment of drug-induced long QT syndrome
in vivo. Beagle dogs were anesthetized with halothane inhalation (n=7).
Monophasic action potential (MAP) of the right ventricle, ECG, systemic
and left ventricular pressure, cardiac output and effective refractory period
(ERP) of the right ventricle were measured. The electrically vulnerable
period was estimated by the difference between MAP duration and ERP. An
intentionally high dose of 1ﾊmg/kg, i.v. of cisapride decreased the heart
rate, mean blood pressure, left ventricular contraction and cardiac output
and prolonged the ventricular repolarization phase and ERP, in which the
increment was greater in the former than in the latter, indicating the increase
of electrical vulnerability. The left ventricular end-diastolic pressure
and atrioventricular as well as intraventricular conduction were hardly
affected. Additional administration of an antiarrhythmic dose of 3ﾊmg/kg,
i.v. of mexiletine increased the heart rate, decreased the left ventricular
contraction and cardiac output, suppressed the atrioventricular as well
as intraventricular conduction, and prolonged the ERP, but shortened the
ventricular repolarization phase. There was no change in the afterload and
preload of the left ventricle. Thus, mexiletine decreased the electrical
vulnerability of the heart during cisapride overdose, suggesting that it
may become a potential pharmacological strategy for drug-induced long QT
syndrome.
Keywords: Mexiletine, Cisapride, Long QT syndrome, Monophasic action
potential, Effective refractory period
Copyrightｩ The Japanese Pharmacological Society 2000
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