Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels

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 I Na and I Kr 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 (K 2P) 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 IC 50 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.

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

“…Homodimeric K 2P 2.1 (TREK-1) channels are inhibited by the anticonvulsant drugs valproate, gabapentin and carbamazepine [ 102 ] by the antidepressants like fluoxetine, paroxetine, citalopram or escitalopram ( Table 3 ) [ 96 , 102 ], and the antipsychotics haloperidol or clozapine [ 101 ]. While some of these interactions would only be relevant at supratherapeutic plasma levels, others already have an impact in the physiological range [ 141 ].…”

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

“…Ranolazine’s effect on the molecular electrophysiology has been investigated in previous studies. Ranolazine acts as a multi-ion-channel blocker, blocking late and peak I Na , I Kr [ 3 ], and as recently shown, the nearly atrial specific two-pore domain potassium channel TASK-1 [ 4 ]. Sossalla et al [ 19 ] demonstrated altered sodium channel kinetics with increased late I Na (I NaL ) in atrial appendages from patients with AF and furthermore showed the potency of ranolazine to suppress the altered late sodium influx.…”

“…Furthermore, the impact of each compound on the atrial electrophysiology cannot be dissected. However, the modes of action of ranolazine and NCX-inhibitors have been investigated before [ 3 , 4 , 13 , 14 ]. Of note, the induction of AF by perfusion with IsoACh does not represent the entire changes in atrial fibrillation and is likely to be associated with intracellular calcium overload [ 25 ], a situation in which NCX-inhibitors are expected to be very effective.…”

“…Consequently, 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 I Na , I NaL , I Kr [ 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 AF. While proving its antiarrhythmic effects in the treatment of AF after cardiac surgery [ 6 ], ranolazine has failed to terminate persisting forms of AF [ 7 ].…”

Calcium Signaling Silencing in Atrial Fibrillation: Implications for Atrial Sodium Homeostasis

“…Furthermore, experimental studies showed that the mechanism of action of ranolazine is not limited to I Na,L and in fact inhibits several key ionic currents (I Na , I Kr , I Ca , I NCX , and I KS ) without changes in I to and I K1 [ 97 ]. Ranolazine has also been found to inhibit TASK-1, an atrial specific potassium channel that is upregulated in AF [ 112 ]. Given that AF at the cellular level is defined by alteration in the expression and function of key ion currents, the observed effects of ranolazine can be mediated by its effects on other currents.…”