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