Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Salvage, Samantha C.; Chandrasekharan, K.; Jeevaratnam, Kamalan; Dulhunty, Angela F.; Thompson, Andrew; Jackson, Antony P.; Huang, Christopher L.‐H.

doi:10.1111/bph.13807

Cited by 55 publications

(72 citation statements)

References 156 publications

(185 reference statements)

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“…In parallel with the present findings, RyR2 ‐P2328S cardiomyocytes also demonstrated acutely reduced Na v 1.5 function . This was partially rescued by pharmacological interventions reducing RyR2‐mediated Ca 2+ release . These findings together suggest direct effects of altered cytosolic [Ca 2+ ] upon Nav1.5 function .…”

Section: Discussionsupporting

confidence: 89%

“…This was partially rescued by pharmacological interventions reducing RyR2-mediated Ca 2+release [22][23][24][25]. These findings together suggest direct effects of altered cytosolic [Ca 2+ ] upon Nav1.5 function [49][50][51].…”

mentioning

confidence: 74%

“…21 Pharmacological inhibition of RyR2-mediated Ca 2+ release with flecainide partly rescued these effects. [22][23][24][25] Furthermore, selective, acute RyR2 activation through the Epac pathway produced parallel pro-arrhythmic effects. 18 It correspondingly produced decreases in AP conduction velocities that were partially reversed by the RyR2 antagonist dantrolene, with an absence of alterations in AP recovery characteristics.…”

Section: And Ventricular Conduction Velocities In Common Withmentioning

confidence: 99%

“…However, murine RyR2‐P2328S CPVT cardiac models showed reduced atrial and ventricular conduction velocities in common with Na v 1.5‐haploinsufficient Scn5a+/− hearts modelling the Brugada Syndrome . Pharmacological inhibition of RyR2‐mediated Ca 2+ release with flecainide partly rescued these effects . Furthermore, selective, acute RyR2 activation through the Epac pathway produced parallel pro‐arrhythmic effects .…”

Section: Introductionmentioning

confidence: 99%

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Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Valli

Ahmad

Sriharan

et al. 2017

Clin Exp Pharma Physio

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SummaryAcute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro‐arrhythmic effects. Loose patch‐clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage‐dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of −20.23 ± 1.48 (17) and −29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8‐CPT (1 μmol/L) reduced these currents to −11.21 ± 0.91 (12) (P < .004) and −19.3 ± 1.6 (11) pA/μm2 (P < .04) respectively. Currents following further addition of the RyR2 inhibitor dantrolene (10 μmol/L) (−19.91 ± 2.84 (13) and −26.6 ± 1.7 (17)), and dantrolene whether alone (−19.53 ± 1.97 (8) and −27.6 ± 1.9 (14)) or combined with 8‐CPT (−19.93 ± 2.59 (12) and −29.9 ± 2.5(11)), were indistinguishable from pretreatment values (all P >> .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half‐maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double‐pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff‐perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max. We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro‐arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically‐modified RyR2‐P2328S hearts.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 74%

Section: And Ventricular Conduction Velocities In Common Withmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Valli

Ahmad

Sriharan

et al. 2017

Clin Exp Pharma Physio

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“…Salvage et al . () identified multiple targets for the class Ic anti‐arrhythmic agent flecainide. The apparently complicated actions of flecainide on cardiac arrhythmias can be explained by its action on different membrane proteins and their role in cellular Na + and Ca 2+ homeostasis.…”

mentioning

confidence: 99%

Spotlight on small molecules in cardiovascular diseases

Wang

Huang

2018

British J Pharmacology

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Reduced cardiomyocyte Na⁺ current in the age‐dependent murine Pgc‐1β^−/− model of ventricular arrhythmia

Ahmad

Valli

Smyth

et al. 2018

Journal Cellular Physiology

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Peroxisome proliferator-activated receptor-γ coactivator-1 deficient (Pgc-1β ) murine hearts model the increased, age-dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na current in these electrophysiological phenotypes by applying loose patch-clamp techniques in intact young and aged, wild-type (WT) and Pgc-1β , ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage-dependent activating and inactivating inward Na currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two-way analysis of variance associated Pgc-1β genotype with independent reductions in maximum peak ventricular Na currents from -36.63 ± 2.14 (n = 20) and -35.43 ± 1.96 (n = 18; young and aged WT, respectively), to -29.06 ± 1.65 (n = 23) and -27.93 ± 1.63 (n = 20; young and aged Pgc-1β , respectively) pA/μm (p < 0.0001), without independent effects of, or interactions with age. Voltages at half-maximal current V*, and steepness factors k in plots of voltage dependences of both Na current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K ) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current-voltage properties directly implicate decreases specifically in maximum available Na current with unchanged voltage dependences and unaltered K current properties, in proarrhythmic reductions in AP conduction velocity in Pgc-1β ventricles.

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Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 55 publications

References 156 publications

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Spotlight on small molecules in cardiovascular diseases

Reduced cardiomyocyte Na⁺ current in the age‐dependent murine Pgc‐1β^−/− model of ventricular arrhythmia

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Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

Abstract: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Cited by 55 publications

References 156 publications

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Epac‐induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Spotlight on small molecules in cardiovascular diseases

Reduced cardiomyocyte Na+ current in the age‐dependent murine Pgc‐1β−/− model of ventricular arrhythmia

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Product

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Reduced cardiomyocyte Na⁺ current in the age‐dependent murine Pgc‐1β^−/− model of ventricular arrhythmia