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K201, a multi-channel blocker, inhibits clofilium-induced torsades de pointes and attenuates an increase in

Hisashi Hasumi1, Ryuko Matsuda, Ken Shimamoto

  • 1Department of Cardiology and Pneumology, Dokkyo Medical University School of Medicine 880 Kitakobayashi, Mibu, Tochigi, Japan.

European Journal of Pharmacology
|November 23, 2006
PubMed

Insights

K201 (JTV519) prolongs the QT interval but does not induce torsades de pointes. This drug effectively inhibits clofilium-induced torsades de pointes, suggesting QT prolongation alone isn't always proarrhythmic.

Area of Science:

  • Pharmacology
  • Cardiology
  • Electrophysiology

Background:

  • K201 (JTV519) is a 1,4-benzothiazepine derivative with cardioprotective properties.
  • K201 acts as a multiple-channel blocker, including potassium (K+) channels.
  • An established rabbit model using clofilium and methoxamine can induce QT interval prolongation and torsades de pointes.

Purpose of the Study:

  • To investigate the effects of K201 on QT and QTc intervals.
  • To determine if K201 inhibits methoxamine-potentiated clofilium-induced torsades de pointes in rabbits.
  • To explore the proarrhythmic potential of K201 in the presence of alpha1-adrenoceptor stimulation.

Main Methods:

  • Rabbits (n=74) were treated with varying doses of K201 (0-400 microg/kg/min) with or without methoxamine.
  • The clofilium-induced torsades de pointes model was used to assess K201's inhibitory effects.
  • Electrocardiographic parameters (QT and QTc intervals) were monitored throughout the study.

Main Results:

  • K201 administration, with or without methoxamine, dose-dependently prolonged the QT interval without inducing torsades de pointes.
  • Clofilium combined with methoxamine induced torsades de pointes in all control animals (100%).
  • K201 demonstrated dose-dependent inhibition of torsades de pointes, with 400 microg/kg/min completely preventing it.

Conclusions:

  • K201 prolongs QT and QTc intervals but does not induce torsades de pointes, even with alpha1-adrenoceptor stimulation.
  • K201 inhibits clofilium-induced torsades de pointes, indicating that QT prolongation may not always be a proarrhythmic indicator.
  • The anti-torsadogenic effect of K201 might be linked to its alpha1-adrenoceptor blocking activity.

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