The Mechanism of Flecainide Action in CPVT Does Not Involve a Direct Effect on RyR2
Rationale: Flecainide, a class Ic anti-arrhythmic, has emerged as an effective therapy in preventing arrhythmias in catecholaminergic polymorphic ventricular tachycardia (CPVT) patients refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is due to the combined actions of direct blockade of ryanodine receptors (RyR2) and Na+ channel inhibition. However, there is presently no direct evidence to support the notion that flecainide blocks RyR2 Ca2+ flux in the physiologically-relevant (luminal-to-cytoplasmic) direction. The mechanism of flecainide action remains controversial.
Objective: To examine in detail the effect of flecainide on the human RyR2 channel and to establish whether the direct blockade of physiologically-relevant RyR2 ion flow by the drug contributes to its therapeutic efficacy in the clinical management of CPVT.
Methods and Results: Using single channel analysis we show that, even at supra-physiological concentrations, flecainide did not inhibit the physiologically relevant, luminal-to-cytosolic flux of cations through the channel. Moreover, flecainide did not alter RyR2 channel gating and had negligible effect on the mechanisms responsible for the sarcoplasmic reticulum (SR) charge-compensating counter current. Using permeabilised cardiac myocytes to eliminate any contribution of plasmalemmal Na+ channels to the observed actions of the drug at the cellular level, flecainide did not inhibit RyR2-dependent SR Ca2+ release.
Conclusions: The principal action of flecainide in CPVT is not via a direct interaction with RyR2. Our data support a model of flecainide action in which Na+-dependent modulation of intracellular Ca2+ handling attenuates RyR2 dysfunction in CPVT.
- ryanodine receptor
- antiarrhythmic drug
- catecholaminergic polymorphic ventricular tachycardia
- Received September 26, 2014.
- Revision received February 2, 2015.
- Accepted February 3, 2015.
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