Antiarrhythmic Effect of Ranolazine in Combination with Selective NCX-Inhibition in an Experimental Model of Atrial Fibrillation

Julian Wolfes,Benjamin Rath,Patrick Leitz,Niklas Broer,Philipp Lange,Kevin Willy,Lars Eckardt,Christian Ellermann,Gerrit Frommeyer

doi:10.3390/ph13100321

Julian Wolfes, Benjamin Rath + Show 7 more

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https://doi.org/10.3390/ph13100321

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Journal: Pharmaceuticals	Publication Date: Oct 20, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: University Hospital Münster

Abstract

The aim of this study was to investigate the effects of a combination of ranolazine with different selective inhibitors of the Na+/Ca2+-exchanger (NCX) in an established experimental model of atrial fibrillation (AF). Eighteen hearts of New Zealand white rabbits were retrogradely perfused. Atrial catheters were used to record monophasic action potentials (aPRR). Hearts were paced at three different cycle lengths. Thereby, atrial action potential durations (aAPD90), atrial effective refractory periods (aERP) and atrial post-repolarization refractoriness were obtained. Isoproterenol and acetylcholine were employed to increase the occurrence of AF. Thereafter, the hearts were assigned to two groups (n = 9 each group) and additionally perfused with a combination of 10 µM ranolazine and 1 µM of the selective NCX-inhibitor ORM-10103 (group A: Rano-ORM) or 10 µM ranolazine and 1 µM of another NCX-inhibitor, SEA0400 (group B: Rano-SEA). The infusion of Iso/ACh led to a shortening of aAPD90, aERP, aPRR and the occurrence of AF episodes was significantly increased. Additional perfusion with ranolazine and ORM-10103 (group A) significantly prolonged the refractory periods and aPRR and AF episodes were effectively reduced. In group B, Rano-SEA led to a slight decrease in aAPD90 while aERP and aPRR were prolonged. The occurrence of AF episodes was consecutively reduced. To our knowledge, this is the first study investigating the effect of ranolazine combined with different selective NCX-inhibitors in an isolated whole-heart model of AF. Both combinations prolonged aERP and aPRR and thereby suppressed the induction of AF.

Highlights

Treatment of atrial fibrillation (AF) remains challenging and the results of antiarrhythmic drugs (AADs) in atrial fibrillation are often unsatisfactory for both patients and doctors [1]
The aim of this study was to investigate the effects of a combination of ranolazine with different selective inhibitors of the Na+/Ca2+-exchanger (NCX) in an established experimental model of atrial fibrillation (AF)
The infusion of Iso/ACh led to a shortening of aAPD90, atrial effective refractory periods (aERP), atrial post repolarization refractoriness (aPRR) and the occurrence of AF episodes was significantly increased

Summary

Introduction

Treatment of atrial fibrillation (AF) remains challenging and the results of antiarrhythmic drugs (AADs) in atrial fibrillation are often unsatisfactory for both patients and doctors [1]. The few AADs available are often limited to narrow indications. Most AADs come with severe side effects including the risk of proarrhythmia. AF is the most common sustained arrhythmia, the development of new antiarrhythmic drugs proceeds only slowly and the common AADs are often in the market for multiple decades [2]. The development of new AADs or the use of drugs, approved for different indications, have great clinical relevance. Ranolazine, an FDA-approved antianginal agent which influences cardiac electrophysiology by inhibiting INa, INaL, IKr [3] and TASK-1 [4] with a certain degree of atrial selectivity and a low risk of proarrhythmia [5], is a potential new compound to treat

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