Abstract
Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and one of the major causes of cardiovascular morbidity and mortality. Despite good progress within the past years, safe and effective treatment of AF remains an unmet clinical need. The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties via mainly late INa and IKr blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. Furthermore, ranolazine has been shown to be effective in the treatment of AF. TASK-1 is a two-pore domain potassium (K2P) channel that shows nearly atrial specific expression within the human heart and has been found to be upregulated in AF, resulting in shortening the atrial APD in patients suffering from AF. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine. Methods: We used Xenopus laevis oocytes and CHO-cells as heterologous expression systems for the study of TASK-1 inhibition by ranolazine and molecular drug docking simulations to investigate the ranolazine binding site and binding characteristics. Results: Ranolazine acts as an inhibitor of TASK-1 potassium channels that inhibits TASK-1 currents with an IC50 of 30.6 ± 3.7 µM in mammalian cells and 198.4 ± 1.1 µM in X. laevis oocytes. TASK-1 inhibition by ranolazine is not frequency dependent but shows voltage dependency with a higher inhibitory potency at more depolarized membrane potentials. Ranolazine binds within the central cavity of the TASK-1 inner pore, at the bottom of the selectivity filter. Conclusions: In this study, we show that ranolazine inhibits TASK-1 channels. We suggest that inhibition of TASK-1 may contribute to the observed antiarrhythmic effects of Ranolazine. This puts forward ranolazine as a prototype drug for the treatment of atrial arrhythmia because of its combined efficacy on atrial electrophysiology and lower risk for ventricular side effects.
Highlights
Atrial fibrillation (AF) is a common cardiac rhythm disorder and one of the major causes of stroke, acute heart failure, sudden death, and cardiovascular morbidity (January et al, 2014)
TASK-1 channels were blocked with an IC50 of 30.6 ± 3.7 μM in Chinese Hamster Ovary (CHO) cells, and 198.4 ± 1.1 μM in oocytes, analyzed at +20 mV (Figures 1C, D)
The maximum inhibition of 67.3 ± 4.5% in oocytes and 58.5 ± 6.9% in CHO cells was achieved with ranolazine concentrations of 1 mM and 100 μM, FIGURE 1 | Effect of ranolazine on TASK-1 current. (A) Time course of TASK-1 current reduction during ranolazine application (n = 6); currents are normalized to their respective value before ranolazine application after a stabilization period with no significant amplitude changes. (B) Representative TASK-1 current recordings evoked by applying a test pulse from −80 mV to +20 mV under control conditions and after 30 min incubation with 300 μM and 1 mM ranolazine. (C) Dose– response curve of TASK-1 inhibition by ranolazine in X. laevis oocytes
Summary
Atrial fibrillation (AF) is a common cardiac rhythm disorder and one of the major causes of stroke, acute heart failure, sudden death, and cardiovascular morbidity (January et al, 2014). Drug treatment with antiarrhythmic drugs (AADs) is often discontinued because of poor tolerability or adverse effects (Lafuente-Lafuente et al, 2015). Because ranolazine predominantly prolongs atrial rather than ventricular action potential duration (APD) and effective refractory period (ERP) (Burashnikov et al, 2007; Antzelevitch and Burashnikov 2009), it appears to be effective in AF (Guerra et al, 2017), far attributed to an atrial-selective sodium channel block (Sossalla et al, 2010; Antzelevitch et al, 2011). The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties via mainly late INa and IKr blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
