Cardiovascular Pharmacology
Class I/B antiarrhythmic property of ranolazine, a novel antianginal agent, in dog and human cardiac preparations

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Abstract

The aim of this study was to investigate the cellular electrophysiological effects of ranolazine on action potential characteristics. The experiments were carried out in dog and human cardiac preparations using the conventional microelectrode technique. In dog Purkinje fibres ranolazine produced a concentration- and frequency-dependent depression of the maximum rate of depolarization (Vmax) while action potential duration (APD) was shortened. In dog and human right ventricular papillary muscle ranolazine exerted no significant effect on APD, while it produced, like mexiletine, use-dependent depression of Vmax with relatively fast onset and offset kinetics. In dog midmyocardial preparations the drug did not exert statistically significant effect on repolarization at 10 μM, although a tendency toward prolongation was observed at 20 μM. A moderate lengthening of APD90 by ranolazine was noticed in canine atrial preparations obtained from dogs in sinus rhythm and in tachypacing induced remodelled preparations. Use-dependent depression of Vmax was more pronounced in atria from dogs in sinus rhythm than those in remodelled atria or in the ventricle. These findings indicate that ranolazine, in addition to its known late sodium current blocking effect, also depresses peak INa with class I/B antiarrhythmic characteristics. Although peak INa inhibition by ranolazine is stronger in the atria, it is also substantial (at fast stimulation frequencies) in ventricular preparations. Ranolazine also decreased the dispersion of ventricular repolarization (the difference in APD90 values between Purkinje fibres and papillary muscles), which can contribute to the antiarrhythmic property of the drug.

Introduction

Ranolazine (Ranexa®) is a novel antianginal agent shown to exert anti-ischemic effects without causing significant bradycardia or hypotension (Chaitman et al., 2004a, Louis et al., 2002, Pepine and Wolff, 1999). It was found that the drug decreased the late INa (Antzelevitch et al., 2004b) which could contribute to its therapeutic effect. In addition, ranolazine has been proposed to possess atrial-predominant antiarrhythmic properties (Antzelevitch et al., 2004a, Antzelevitch et al., 2004b, Antzelevitch and Burashnikov, 2009, Burashnikov et al., 2007, Kumar et al., 2009, Sicouri et al., 2008, Wu et al., 2004) which were principally related to the inhibition of sodium current (INa), rapid delayed rectifier potassium current (IKr) and calcium current (ICa) (Allen and Chapman, 1996, Antzelevitch et al., 2004a, Rajamani et al., 2008, Rajamani et al., 2009, Schram et al., 2004, Song et al., 2004). The drug was reported to produce atrial-predominant use dependent block of sodium channels and postrepolarization refractoriness which was postulated in the mechanism of suppressing atrial fibrillation (Antzelevitch and Burashnikov, 2009, Burashnikov et al., 2007, Kumar et al., 2009). Due to its IKr blocking effect ranolazine has been shown to cause a slight prolongation of the QT interval on the ECG (Chaitman et al., 2004a, Chaitman et al., 2004b, Schram et al., 2004). The drug proved to be effective in suppressing arrhythmogenesis in models of Long QT syndromes in guinea pig, rabbit and dog (Antoons et al., 2010, Fredj et al., 2006, Song et al., 2004, Moss et al., 2008, Sicouri et al., 2007, Wu et al., 2004, Wu et al., 2006, Wu et al., 2008). The aim of our present work was to further characterise the cellular electrophysiological effects of ranolazine in dog and human heart preparations. The effects of ranolazine were mainly investigated in dog, a species resembling human in heart size, spontaneous frequency and repolarization.

Section snippets

Dog cardiac tissues

All experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animals (USA NIH publication No 85–23, revised 1985). The protocols were approved by the Department of Animal Health and Food Control of the Ministry of Agriculture and Rural Development, Hungary (15.1/01031/006/2008).

Adult mongrel dogs (8–16 kg) of either sex were used. Following anaesthesia (sodium pentobarbital, 30 mg kg−1 administered intravenously), the heart of each animal was rapidly removed

Dog Purkinje fibre

Ranolazine (dose- and rate-dependently) decreased the maximum rate of rise of the action potential upstroke (Vmax) in isolated dog cardiac Purkinje fibres (Fig. 1B). Action potential duration measured at 50% and 90% of repolarization (APD50, APD90) was shortened in a concentration-dependent manner at pacing with a constant cycle length of 500 ms (Fig. 1A and Table 1). The reduction of APD50 was more pronounced than that of APD90 which resulted in an action potential with a triangular shape (

Discussion

The main new finding of the present study is that ranolazine at relatively high concentrations (5–20 μM) in dog and human cardiac preparations – in addition to its well-known late INa and IKr blocking effects – produces a concentration- and frequency-dependent depression of Vmax with rather fast onset and offset kinetics, i.e. exerts mexiletine-like Class IB antiarrhythmic action not only in normal and remodelled atria, but also in the ventricle. The other important finding is that due to its

Conflicts of interest

None.

Acknowledgements

This work was supported by grants from the Hungarian Scientific Research Fund (OTKA CNK-77855, OTKA K-82079); Hungarian Ministry of Health (ETT 302-03/2009 and ETT 306-03/2009); the Hungarian National Office for Research and Technology — Hungarian National Technology Programme (TECH_08_A1_CARDIO08); National Development Agency (TÁMOP-4.2.2-08/1-2008-0013); European Community (EU FP7 grant ICT-2008-224381, preDiCT); the Hungarian Academy of Sciences and by the János Bolyai Research Scholarship

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