Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

Morten Bækgaard Thomsen, Paul G A Volders, Milan Stengl, Roel L H M G Spätjens, Jet D M Beekman, Ulrike Bischoff, Morten A Kall, Kristen Frederiksen, Jørgen Matz, Marc A Vos

Research output: Contribution to journalJournal articleResearchpeer-review

58 Citations (Scopus)

Abstract

Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.
Original languageEnglish
JournalJournal of Pharmacology and Experimental Therapeutics
Volume307
Issue number2
Pages (from-to)776-84
Number of pages9
ISSN0022-3565
DOIs
Publication statusPublished - Nov 2003

Keywords

  • Action Potentials
  • Animals
  • Antipsychotic Agents
  • Arrhythmias, Cardiac
  • Dogs
  • Electrophysiology
  • Heart
  • Imidazoles
  • Indoles
  • Myocytes, Cardiac
  • Phenethylamines
  • Sulfonamides

Cite this