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 journalArticle (Academic Journal)

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, 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 and
inactivated 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 INa
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 languageEnglish
JournalHeart Rhythm O2
DOIs
Publication statusAccepted/In press - 19 May 2020

Keywords

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

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