Atrial-ventricular differences in rabbit cardiac voltage-gated Na+ currents: basis for atrial-selective block by ranolazine

Rachel Caves, Hongwei Cheng, Stephanie Choisy, Hanne Gadeberg, Simon Bryant, Jules Hancox, Andrew James

Research output: Contribution to journalArticle (Academic Journal)

3 Citations (Scopus)
254 Downloads (Pure)

Abstract

BACKGROUND Class 1 antiarrhythmic drugs are highly effective in restoring and maintaining sinus rhythm in atrial fibrillation patients but carry a risk of ventricular tachyarrhythmia. The anti-anginal agent, ranolazine, is a prototypic atrial-selective voltage-gated Na+ channel blocker but the mechanisms underlying its atrial-selective action remain unclear. OBJECTIVE The present study examined the mechanisms underlying the atrial-selective action of ranolazine. METHODS Whole-cell voltage-gated Na+ currents (INa) were recorded at room temperature (~22 °C) from rabbit isolated left atrial and right ventricular myocytes. RESULTS INa conductance density was ~1.8-fold greater in atrial than in ventricular cells. Atrial INa was activated at command potentials ~7 mV more negative and inactivated at conditioning potentials ~11 mV more negative than ventricular INa. The onset of inactivation of INa was faster in atrial cells than in ventricular myocytes. Ranolazine (30 μM) inhibited INa in atrial and ventricular myocytes in a use-dependent manner consistent with preferential activated/inactivated state block. Ranolazine caused a significantly greater negative shift in voltage of half-maximal inactivation in atrial cells than in ventricular cells, the recovery from inactivation of INa was slowed by ranolazine to a greater extent in atrial myocytes than in ventricular cells and ranolazine produced an instantaneous block that showed marked voltage-dependence in atrial cells. CONCLUSIONS Differences exist between rabbit atrial and ventricular myocytes in the biophysical properties of INa. The more negative voltage-dependence of INa activation and inactivation, together with trapping of the drug in the inactivated channel, underlies an atrial-selective action of ranolazine.
Original languageEnglish
Pages (from-to)1657-1664
Number of pages8
JournalHeart Rhythm
Volume14
Issue number11
Early online date10 Jun 2017
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • antiarrhythmic drug
  • atrial myocytes
  • cardiac regional heterogeneity
  • Na+ channel blocker
  • ventricular myocytes
  • Physiology
  • Therapeutics
  • PHARMACOLOGY

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