Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine

Jingjing Wu, Longxian Cheng, Wim J. Lammers, Lin Wu, Xin Wang, John C. Shryock, Luiz Belardinelli, Ming Lei

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

The aim of this study was to characterize the role of the late Na+ current (INa,L) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, INa,L. In sixteen hearts studied, exposure to 1-10 nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early afterdepolarisations, delayed afterdepolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n = 5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 μM ranolazine in intact hearts (n = 11) and isolated sino-atrial preparations (n = 5). In conclusion, the INa,L enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the INa,L blocker, ranolazine (10 μM). The results suggest that INa,L blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.

Original languageEnglish
Pages (from-to)198-207
Number of pages10
JournalProgress in Biophysics and Molecular Biology
Volume98
Issue number2-3
DOIs
Publication statusPublished - Oct 2008
Externally publishedYes

Keywords

  • ATX-II
  • I
  • LQT3
  • Late Na current
  • SCN5A
  • Sinus node dysfunction

ASJC Scopus subject areas

  • Biophysics
  • Molecular Biology

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