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

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Abstract

K201 (JTV519) is a 1,4-benzothiazepine derivative that exhibits a strong cardioprotective action and acts as a multiple-channel blocker, including as a K+ channel blocker. An experimental model of prolongation of the QT interval and torsades de pointes can be induced in rabbits by treatment with clofilium in the presence of the α1-adrenoreceptor agonist methoxamine. In this study we examined the effects of K201 with and without methoxamine on the QT and QTc intervals, and determined whether K201 inhibits clofilium-induced torsades de pointes in the presence of methoxamine (15 μg/kg/min) in rabbits (n = 74). Administration of K201 (0, 40, 100, 200 and 400 μg/kg/min) with and without methoxamine prolonged the QT interval in a dose-dependent manner, and torsades de pointes did not occur in any animals. However, clofilium (50 μg/kg/min) with methoxamine induced torsades de pointes in all animals (6/6). Torsades de pointes occurred at rates of 100%, 67%, 40% and 0% at K201 concentrations of 0, 50, 200 and 400 μg/kg/min, respectively, in the clofilium-infused torsades de pointes model. Therefore, 400 μg/kg/min of K201 completely inhibited clofilium-induced torsades de pointes and attenuated the increase of repolarization caused by clofilium; the inhibitory effects of K201 may be related to its pharmacological properties as an α1-adrenoceptor blocker. Overall, our results show that K201 causes prolongation of the QT and QTc intervals, but does not induce torsades de pointes, with and without α1-adrenoceptor stimulation. Furthermore, K201 inhibits clofilium-induced torsades de pointes, despite QT prolongation, suggesting that QT prolongation alone is not a proarrhythmic signal.

Introduction

K2011 (JTV-519), 4-[3-(4-benzylpiperidin-1-yl}propionyl)-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride, was originally discovered as an agent for prevention of sudden cardiac death and myocardial infarction (Kaneko, 1994). K201 has several effects, including α1-adrenergic blocking activity, an intracellular Ca2+ blocking action (Kaneko, 1994), and strong cardioprotective effects against ischemia-reperfusion-induced myocardial injury (Inagaki et al., 2000, Ito et al., 2000, Kawabata et al., 2000). K201 also exhibits multi-channel blocking effects: inhibition of the fast sodium current (INa) and L-type calcium current (ICa,L), and blocking of the delayed rectifier potassium current (IK) have been shown in atrial and ventricular cardiomyocytes from rabbits, rats and guinea pigs (Kimura et al., 1999, Kiriyama et al., 2000, Nakaya et al., 2000). K201 is also effective for prevention of atrial fibrillation (Kumagai et al., 2003).

Class I and III antiarrhythmic agents and non-cardiac drugs are well known to prolong the QT interval and induce torsades de pointes (Thibault and Nattel, 1999, Bednar et al., 2001, De Ponti et al., 2002, Haddad and Anderson, 2002, Roden, 2004). Amiodarone and bepridil are antiarrhythmic agents that have complex multi-channel blocking effects (Hollingshead et al., 1992, Nobe et al., 1993, Singh, 1996, Antzelevitch, 2004); these agents induce torsades de pointes and are known to cause lengthening of the action potential duration. Prolongation of the QT interval is sometimes, but not always, associated with the occurrence of torsades de pointes and ventricular fibrillation (Zipes and Wellens, 1998, Straus et al., 2006). An experimental model of torsades de pointes can be prepared using a relatively low dose of the class III antiarrhythmic agent, clofilium, together with the α1-adrenoreceptor agonist, methoxamine, and marked prolongation of the QT interval and torsades de pointes has been demonstrated in chloralose-anaesthetized rabbits (Carlsson et al., 1990). However, recent studies have shown that prolongation of the QT interval is not the sole determinant of the potential of a drug to cause torsades de pointes (Antzelevitch, 2004).

In this study, we investigated the effects of K201 with and without α1-adrenoreceptor stimulation on QT and corrected QT (QTc) intervals, and determined whether K201 decreases or increases torsades de pointes, and attenuates or accelerates prolongation of the QT interval in a clofilium-induced torsades de pointes model in rabbits.

Section snippets

Animal preparation

Seventy-four male New Zealand white rabbits (2.5 to 3.5 kg) were used in the study. The animals were allowed free access to standard feed and water, and the experiments were performed in accordance with the guidelines for animal experimentation established by the ethics committee of Dokkyo Medical University School of Medicine and Environmental Biological Life Sciences. Anesthesia was induced using thiopental sodium (20 mg/kg, one bolus administration) followed by α-chloralose (90 mg/kg/20 min,

Results

Administration of K201 without α1-adrenoceptor stimulation by methoxamine caused dose-dependent prolongation of the QT and QTc intervals (Fig. 2). Administration of K201 at concentrations of 200 and 400 μg/kg/min for 30 min significantly prolonged the QT interval by 186.4 ± 31.3% and 252.5 ±37.2%, respectively, compared to the control group (P < 0.05 and P < 0.05, respectively, vs. control). Administration of K201 at 400 μg/kg/min also prolonged the QTc interval by 144.5 ±23.0%. Infusion of K201 at

Discussion

Drugs that prolong the QT interval sometimes induce torsades de pointes and ventricular fibrillation, with an accompanying risk of sudden death (Zipes and Wellens, 1998, Straus et al., 2006). Drugs that prolong the action potential duration by blocking potassium currents are referred to as class III antiarrhythmics (Nobe et al., 1993), and infusion of a low dose of class III antiarrhythmic agents and non-cardiac drugs can prolong the QT interval and induce torsades de pointes (Thibault and

Acknowledgments

The technical assistance of Makoto Shinozaki and Rie Asaishi is greatly appreciated. We also thank Aetas Pharma (Tokyo, Japan) for manufacturing of K201 and permission to use this agent.

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