Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

Rachel E Caves; Alexander Carpenter; Stephanie C M Choisy; Ben Clennell; Hongwei Cheng; Cameron McNiff; Brendan Mann; James T Milnes; Jules C Hancox; Andrew F James

doi:10.1016/j.hroo.2020.05.006

Inhibition of voltage-gated Na⁺ currents by eleclazine in rat atrial and ventricular myocytes

Rachel E Caves, Alexander Carpenter, Stephanie C M Choisy, Ben Clennell, Hongwei Cheng, Cameron McNiff, Brendan Mann, James T Milnes, Jules C Hancox, Andrew F James^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

BACKGROUND Atrial-ventricular differences in voltage-gated Na⁺ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative anti-arrhythmic drug with properties similar to the prototypical atrial-selective Na⁺ channel blocker, ranolazine that has been shown to be safe and well-tolerated in patients.
OBJECTIVE The present study investigated atrial-ventricular differences in the
biophysical properties and inhibition by eleclazine of voltage-gated Na⁺ currents.

METHODS The fast and late components of whole-cell voltage-gated Na⁺ currents (respectively, I_Na & I_NaL) were recorded at room temperature (~22 °C) from rat isolated atrial and ventricular myocytes.

RESULTS Atrial I_Na activated at command potentials ~5.5 mV more negative and
inactivated at conditioning potentials ~7 mV more negative than ventricular I_Na. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of I_NaL activated by 3 nM ATX-II (IC₅₀s ~200 nM). 10 μM eleclazine inhibited I_Na in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of I_Na from inactivation in both cell types.

CONCLUSIONS Differences exist between rat atrial and ventricular myocytes in the biophysical properties of I_Na. The more negative voltage-dependence of I_Na
activation/inactivation in atrial myocytes underlies differences between the two cell types in the voltage-dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective anti-arrhythmic drug.

Original language	English
Pages (from-to)	206-214
Number of pages	9
Journal	Heart Rhythm O2
Volume	1
Issue number	3
Early online date	25 May 2020
DOIs	https://doi.org/10.1016/j.hroo.2020.05.006
Publication status	Published - 1 Aug 2020

Keywords

antiarrhythmic drug
atrial myocytes
cardiac regional heterogeneity
sodium current
late sodium current
Na+ channel blocker
ventricular myocytes

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Investigation of pharmacological modulators of TASK-1 K+ channels on electrophysiology of the atrioventricular node.
Hancox, J. C. (Principal Investigator)
1/02/17 → 31/01/20
Project: Research
Selective late sodium current blockers as antiarrhythmic drugs in atrial fibrillation
James, A. F. (Principal Investigator)
14/03/16 → 13/03/19
Project: Research

Cite this

@article{08672054fcdd4f82ad8771a09fa0e2f1,

title = "Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes",

abstract = "BACKGROUND Atrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative anti-arrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker, ranolazine that has been shown to be safe and well-tolerated in patients.OBJECTIVE The present study investigated atrial-ventricular differences in thebiophysical properties and inhibition by eleclazine of voltage-gated Na+ currents.METHODS The fast and late components of whole-cell voltage-gated Na+ currents (respectively, INa & INaL) were recorded at room temperature (~22 °C) from rat isolated atrial and ventricular myocytes.RESULTS Atrial INa activated at command potentials ~5.5 mV more negative andinactivated at conditioning potentials ~7 mV more negative than ventricular INa. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of INaL activated by 3 nM ATX-II (IC50s ~200 nM). 10 μM eleclazine inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of INa from inactivation in both cell types.CONCLUSIONS Differences exist between rat atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage-dependence of INaactivation/inactivation in atrial myocytes underlies differences between the two cell types in the voltage-dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective anti-arrhythmic drug.",

keywords = "antiarrhythmic drug, atrial myocytes, cardiac regional heterogeneity, sodium current, late sodium current, Na+ channel blocker, ventricular myocytes",

author = "Caves, {Rachel E} and Alexander Carpenter and Choisy, {Stephanie C M} and Ben Clennell and Hongwei Cheng and Cameron McNiff and Brendan Mann and Milnes, {James T} and Hancox, {Jules C} and James, {Andrew F}",

year = "2020",

month = aug,

day = "1",

doi = "10.1016/j.hroo.2020.05.006",

language = "English",

volume = "1",

pages = "206--214",

journal = "Heart Rhythm O2",

issn = "2666-5018",

publisher = "Elsevier Limited",

number = "3",

}

TY - JOUR

T1 - Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

AU - Caves, Rachel E

AU - Carpenter, Alexander

AU - Choisy, Stephanie C M

AU - Clennell, Ben

AU - Cheng, Hongwei

AU - McNiff, Cameron

AU - Mann, Brendan

AU - Milnes, James T

AU - Hancox, Jules C

AU - James, Andrew F

PY - 2020/8/1

Y1 - 2020/8/1

N2 - BACKGROUND Atrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative anti-arrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker, ranolazine that has been shown to be safe and well-tolerated in patients.OBJECTIVE The present study investigated atrial-ventricular differences in thebiophysical properties and inhibition by eleclazine of voltage-gated Na+ currents.METHODS The fast and late components of whole-cell voltage-gated Na+ currents (respectively, INa & INaL) were recorded at room temperature (~22 °C) from rat isolated atrial and ventricular myocytes.RESULTS Atrial INa activated at command potentials ~5.5 mV more negative andinactivated at conditioning potentials ~7 mV more negative than ventricular INa. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of INaL activated by 3 nM ATX-II (IC50s ~200 nM). 10 μM eleclazine inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of INa from inactivation in both cell types.CONCLUSIONS Differences exist between rat atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage-dependence of INaactivation/inactivation in atrial myocytes underlies differences between the two cell types in the voltage-dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective anti-arrhythmic drug.

AB - BACKGROUND Atrial-ventricular differences in voltage-gated Na+ currents might be exploited for atrial-selective antiarrhythmic drug action for the suppression of atrial fibrillation without risk of ventricular tachyarrhythmia. Eleclazine (GS-6615) is a putative anti-arrhythmic drug with properties similar to the prototypical atrial-selective Na+ channel blocker, ranolazine that has been shown to be safe and well-tolerated in patients.OBJECTIVE The present study investigated atrial-ventricular differences in thebiophysical properties and inhibition by eleclazine of voltage-gated Na+ currents.METHODS The fast and late components of whole-cell voltage-gated Na+ currents (respectively, INa & INaL) were recorded at room temperature (~22 °C) from rat isolated atrial and ventricular myocytes.RESULTS Atrial INa activated at command potentials ~5.5 mV more negative andinactivated at conditioning potentials ~7 mV more negative than ventricular INa. There was no difference between atrial and ventricular myocytes in the eleclazine inhibition of INaL activated by 3 nM ATX-II (IC50s ~200 nM). 10 μM eleclazine inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated state block. Eleclazine produced voltage-dependent instantaneous inhibition in atrial and ventricular myocytes; it caused a negative shift in voltage of half-maximal inactivation and slowed the recovery of INa from inactivation in both cell types.CONCLUSIONS Differences exist between rat atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage-dependence of INaactivation/inactivation in atrial myocytes underlies differences between the two cell types in the voltage-dependence of instantaneous inhibition by eleclazine. Eleclazine warrants further investigation as an atrial-selective anti-arrhythmic drug.

KW - antiarrhythmic drug

KW - atrial myocytes

KW - cardiac regional heterogeneity

KW - sodium current

KW - late sodium current

KW - Na+ channel blocker

KW - ventricular myocytes

U2 - 10.1016/j.hroo.2020.05.006

DO - 10.1016/j.hroo.2020.05.006

M3 - Article (Academic Journal)

C2 - 32864638

SN - 2666-5018

VL - 1

SP - 206

EP - 214

JO - Heart Rhythm O2

JF - Heart Rhythm O2

IS - 3

ER -

Inhibition of voltage-gated Na+ currents by eleclazine in rat atrial and ventricular myocytes

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Projects

Investigation of pharmacological modulators of TASK-1 K+ channels on electrophysiology of the atrioventricular node.

Selective late sodium current blockers as antiarrhythmic drugs in atrial fibrillation

Cite this

Inhibition of voltage-gated Na⁺ currents by eleclazine in rat atrial and ventricular myocytes