The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2
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Author(s)
Type
Journal Article
Abstract
Rationale: Flecainide, a class 1c antiarrhythmic, has emerged as an effective therapy in preventing arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) refractory to β-adrenergic receptor blockade. It has been proposed that the clinical efficacy of flecainide in CPVT is because of 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 supraphysiological 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 charge-compensating counter current. Using permeabilized 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 sarcoplasmic reticulum 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.
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 supraphysiological 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 charge-compensating counter current. Using permeabilized 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 sarcoplasmic reticulum 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.
Date Issued
2015-02-03
Date Acceptance
2015-02-03
Citation
Circulation Research, 2015, 116 (8), pp.1324-1335
ISSN
1524-4571
Publisher
American Heart Association
Start Page
1324
End Page
1335
Journal / Book Title
Circulation Research
Volume
116
Issue
8
Copyright Statement
© 2015 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
License URL
Sponsor
British Heart Foundation
Identifier
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.116.305347
Grant Number
PG/09/032/27241
Subjects
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Hematology
Peripheral Vascular Disease
Cardiovascular System & Cardiology
antiarrhythmic drugs
cardiac arrhythmias
flecainide
polymorphic catecholergic ventricular tachycardia
ryanodine receptor calcium release channel
POLYMORPHIC VENTRICULAR-TACHYCARDIA
CARDIAC SARCOPLASMIC-RETICULUM
CATION-SELECTIVE CHANNEL
CALCIUM-RELEASE CHANNELS
RYANODINE RECEPTOR
POTASSIUM CHANNELS
CA2+ RELEASE
MOLECULAR-BASIS
NA+ CHANNELS
BLOCK
antiarrhythmic drugs
cardiac arrhythmias
flecainide
polymorphic catecholergic ventricular tachycardia
ryanodine receptor calcium release channel
Animals
Anti-Arrhythmia Agents
Calcium Signaling
Dose-Response Relationship, Drug
Flecainide
HEK293 Cells
Humans
Ion Channel Gating
Male
Membrane Potentials
Myocytes, Cardiac
Potassium Channels
Rats, Sprague-Dawley
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Tachycardia, Ventricular
Time Factors
Transfection
Voltage-Gated Sodium Channel Blockers
Sarcoplasmic Reticulum
Myocytes, Cardiac
Animals
Humans
Rats, Sprague-Dawley
Tachycardia, Ventricular
Flecainide
Ryanodine Receptor Calcium Release Channel
Potassium Channels
Anti-Arrhythmia Agents
Transfection
Ion Channel Gating
Calcium Signaling
Membrane Potentials
Dose-Response Relationship, Drug
Time Factors
Male
HEK293 Cells
Voltage-Gated Sodium Channel Blockers
Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status
Published
Date Publish Online
2015-02-03