Imperial College London
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Emeritus ProfessorKenMacLeod

Faculty of Medicine, National Heart & Lung Institute

Emeritus Professor of Cardiac Physiology
 
 
 
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Contact

 

+44 (0)20 7594 2734k.t.macleod

 
 
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Assistant

 

Miss Natasha Richmond +44 (0)20 7594 6457

 
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Location

 

336ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Bannister:2015:10.1161/CIRCRESAHA.116.305347,
author = {Bannister, ML and Thomas, NL and Sikkel, MB and Mukherjee, S and Maxwell, C and MacLeod, KT and George, CH and Williams, AJ},
doi = {10.1161/CIRCRESAHA.116.305347},
journal = {Circulation Research},
pages = {1324--1335},
title = {The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2},
url = {http://dx.doi.org/10.1161/CIRCRESAHA.116.305347},
volume = {116},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Bannister,ML
AU  - Thomas,NL
AU  - Sikkel,MB
AU  - Mukherjee,S
AU  - Maxwell,C
AU  - MacLeod,KT
AU  - George,CH
AU  - Williams,AJ
DO  - 10.1161/CIRCRESAHA.116.305347
EP  - 1335
PY  - 2015///
SN  - 1524-4571
SP  - 1324
TI  - The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2
T2  - Circulation Research
UR  - http://dx.doi.org/10.1161/CIRCRESAHA.116.305347
UR  - https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.116.305347
UR  - http://hdl.handle.net/10044/1/34238
VL  - 116
ER  -
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