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

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 (V_max) 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 V_max 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 V_max 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 I_Na with class I/B antiarrhythmic characteristics. Although peak I_Na 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 I_Na (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 (I_Na), rapid delayed rectifier potassium current (I_Kr) and calcium current (I_Ca) (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 I_Kr 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.