Effects of Flecainide and Ranolazine on Intracellular Calcium Handling and Sarcolemmal Sodium Current

Flecainide has received considerable interest due to its antiarrhythmic efficacy. However, more detailed analyses of calcium (Ca2+)-dependent processes are required to demonstrate a conclusive mechanism of action. We characterise flecainide's ability to suppress arrhythmogenic Ca2+-waves and examine the involvement of ryanodine receptors in flecainide's antiarrhythmic efficacy, Further, we evaluate the native cardiac sodium channel contribution to flecainide¯s pharmacological profile and compare its actions with a late sodium current inhibitor, ranolazine.Extracellular drug effects on Ca2+-sparks and Ca2+-waves were measured in field-stimulated Fluo-4AM loaded human and rat ventricular cardiomyocytes. Whole-cell sodium currents (INa) were measured before and after a series of high-frequency depolarizing pulses, establishing acute- and use-dependent inhibition, respectively.A therapeutic dose of flecainide (5μM) significantly decreased spark-mediated Ca2+ leak, primarily as a result of reduced Ca2+-spark amplitude (P < 0.001). Following flecainide perfusion spontaneous wave frequency was significantly reduced (P < 0.001), whilst wave-free survival and inter-wave interval were significantly increased (P < 0.01 and P < 0.05, respectively).The late INa blocker ranolazine (10-50μM) was evaluated against flecainide for its potential to inhibit sarcolemmal INa and Ca2+-waves. Under acute application, 5μM flecainide reduced peak INa to 49 ± 7% of control compared to 75 ± 9% and 66 ± 10% with 10μM and 50μM ranolazine respectively. Flecainide showed increased use-dependency, causing 35 ± 5% peak INa inhibition compared to control, while 10μM and 50μM ranolazine resulted in 73 ± 7% and 60 ± 7% reduction, respectively. Furthermore, flecainide's effect on Ca2+-wave frequency show correspondingly higher efficacy (P < 0.001) versus increasing concentrations of ranolazine (P < 0.01).Our results suggest that flecainide normalizes arrythmogenic Ca2+-waves by selectively reducing spark mass and a corresponding wave initiation. Additionally, we draw parallel between the ability of flecainide and ranolazine to suppress arrhythmogenic Ca2+-waves, and establish correlation with membrane sodium influx.