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

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.

Galectin‐3 enhances atrial remodelling and arrhythmogenesis through CD98 signalling

“…21 Moreover, the activation of NCX activity is vital for AF arrhythmogenesis. 22 The changes in calcium homeostasis in patients with AF or in AF animal models are similar to the changes in calcium dysregulation in Gal-3treated HL-1 cells; this finding suggests that Gal-3 takes part in inflammation-induced AF genesis. As shown in Figure 8, Gal-3-mediated Ca 2+ dyshomeostasis might be caused by the activation of CaMKII/RyR2 signalling, resulting in enhanced Nav1.…”

“…The dysregulation of ion channels, which either reduces I Ca‐L or increases I kur and I to , may accelerate repolarization, thereby shortening atrial APD and atrial refractoriness and promoting reentry 21 . Moreover, the activation of NCX activity is vital for AF arrhythmogenesis 22 . The changes in calcium homeostasis in patients with AF or in AF animal models are similar to the changes in calcium dysregulation in Gal‐3‐treated HL‐1 cells; this finding suggests that Gal‐3 takes part in inflammation‐induced AF genesis.…”

New Strategies for the Treatment of Atrial Fibrillation

“…AF was induced by isoproterenol and acetylcholine. Combined ranolazine and NCX blocker experiments showed that the inducibility of AF was reduced in both groups by the additional perfusion with ranolazine and the selective NCX-inhibitors [ 134 ].…”

Through the heart and beyond: a review on ranolazine

“…The perfusion with ranolazine and ORM-10103 by significantly prolonging the refractory periods and monophasic action potential, was able to reduce the episodes of AF. On the other side, the association between ranolazine and SEA0400 determined a slight decreasing in aAPD90 and a prolonging in aERP and aPRR so that the occurrence of AF episodes was consecutively reduced [60]. Functionally the ranolazine can be compared to the class Ia or III of antiarrhithmic drugs, since, just like them, it acts blocking the rapid component of the delayed rectifier potassium current (IKr).…”