The role of the Na +/Ca 2+ exchanger, I Na and I CaL in the genesis of dofetilide-induced torsades de pointes in isolated, AV-blocked rabbit hearts

Attila S. Farkas, Péter Makra, Norbert Csík, Szabolcs Orosz, Michael J. Shattock, Ferenc Fülöp, Tamás Forster, Miklós Csanády, Julius Gy Papp, András Varró, András Farkas

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Abstract

Background and purpose: The Na +/Ca 2+ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide-induced TdP. Experimental approach: Effects of SEA0400 (1 μmol·L -1) on dofetilide-induced TdP was studied in isolated, Langendorff-perfused, atrioventricular (AV)-blocked rabbit hearts. To verify the relevance of the model, lidocaine (30 μmol·L -1) and verapamil (750 nmol·L -1) were also tested against dofetilide-induced TdP. Key results: Acute AV block caused a chaotic idioventricular rhythm and strikingly increased beat-to-beat variability of the RR and QT intervals. SEA0400 exaggerated the dofetilide-induced increase in the heart rate-corrected QT interval (QTc) and did not reduce the incidence of dofetilide-induced TdP [100% in the SEA0400 + dofetilide group vs. 75% in the dofetilide (100 nmol·L -1) control]. In the second set of experiments, verapamil further increased the dofetilide-induced QTc prolongation and neither verapamil nor lidocaine reduced the dofetilide-induced increase in the beat-to-beat variability of the QT interval. However, lidocaine decreased and verapamil prevented the development of dofetilide-induced TdP as compared with the dofetilide control (TdP incidence: 13%, 0% and 88% respectively). Conclusions and implications: Na +/Ca 2+ exchanger does not contribute to dofetilide-induced TdP, whereas Na + and Ca 2+ channel activity is involved in TdP genesis in isolated, AV-blocked rabbit hearts. Neither QTc prolongation nor an increase in the beat-to-beat variability of the QT interval is a sufficient prerequisite of TdP genesis in rabbit hearts.

Original languageEnglish
Pages (from-to)920-932
Number of pages13
JournalBritish journal of pharmacology
Volume156
Issue number6
DOIs
Publication statusPublished - Mar 1 2009

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Keywords

  • Isolated heart
  • Lidocaine
  • NCX
  • QT variability
  • Rabbit
  • SEA0400
  • Torsades de pointes
  • Verapamil

ASJC Scopus subject areas

  • Pharmacology

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