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

Tamás Szél, István Koncz, N. Jost, I. Baczkó, Zoltán Husti, L. Virág, Alexandra Bussek, Erich Wettwer, Ursula Ravens, J. Papp, A. Varró

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)31-39
Number of pages9
JournalEuropean Journal of Pharmacology
Volume662
Issue number1-3
DOIs
Publication statusPublished - Jul 15 2011

Fingerprint

Dogs
Action Potentials
Purkinje Fibers
Papillary Muscles
Mexiletine
Drug Compounding
Anti-Arrhythmia Agents
Microelectrodes
Ranolazine
Canidae
Sodium

Keywords

  • Action potential
  • Dog and human cardiac preparations
  • Electrophysiology
  • M-cell
  • Ranolazine
  • Sodium channel

ASJC Scopus subject areas

  • Pharmacology

Cite this

Class I/B antiarrhythmic property of ranolazine, a novel antianginal agent, in dog and human cardiac preparations. / Szél, Tamás; Koncz, István; Jost, N.; Baczkó, I.; Husti, Zoltán; Virág, L.; Bussek, Alexandra; Wettwer, Erich; Ravens, Ursula; Papp, J.; Varró, A.

In: European Journal of Pharmacology, Vol. 662, No. 1-3, 15.07.2011, p. 31-39.

Research output: Contribution to journalArticle

Szél, Tamás ; Koncz, István ; Jost, N. ; Baczkó, I. ; Husti, Zoltán ; Virág, L. ; Bussek, Alexandra ; Wettwer, Erich ; Ravens, Ursula ; Papp, J. ; Varró, A. / Class I/B antiarrhythmic property of ranolazine, a novel antianginal agent, in dog and human cardiac preparations. In: European Journal of Pharmacology. 2011 ; Vol. 662, No. 1-3. pp. 31-39.
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AU - Baczkó, I.

AU - Husti, Zoltán

AU - Virág, L.

AU - Bussek, Alexandra

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AU - Ravens, Ursula

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N2 - 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.

AB - 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.

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