Combined Na+/Ca2+ exchanger and l-type calcium channel block as a potential strategy to suppress arrhythmias and maintain ventricular function

Vincent J.A. Bourgonje, Marc A. Vos, Semir Ozdemir, Nicolas Doisne, Karoly Acsai, Andras Varro, Anita Sztojkov-Ivanov, Istvan Zupko, Erik Rauch, Lars Kattner, Virginie Bito, Marien Houtman, Roel Van Der Nagel, Jet D. Beekman, Toon A.B. Van Veen, Karin R. Sipido, Gudrun Antoons

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34 Citations (Scopus)

Abstract

Background-L-type calcium channel (LTCC) and Na+/Ca2+ exchanger (NCX) have been implicated in repolarizationdependent arrhythmias, but also modulate calcium and contractility. Although LTCC inhibition is negative inotropic, NCX inhibition has the opposite effect. Combined block may, therefore, offer an advantage for hemodynamics and antiarrhythmic efficiency, particularly in diseased hearts. In a model of proarrhythmia, the dog with chronic atrioventricular block, we investigated whether combined inhibition of NCX and LTCC with SEA-0400 is effective against dofetilide-induced torsade de pointes arrhythmias (TdP), while maintaining calcium homeostasis and hemodynamics. Methods and Results-Left ventricular pressure (LVP) and ECG were monitored during infusion of SEA-0400 and verapamil in anesthetized dogs. Different doses were tested against dofetilide-induced TdP in chronic atrioventricular block dogs. In ventricular myocytes, effects of SEA-0400 were tested on action potentials, calcium transients, and early afterdepolarizations. In cardiomyocytes, SEA-0400 (1 μmol/L) blocked 66±3% of outward NCX, 50±2% of inward NCX, and 33±9% of LTCC current. SEA-0400 had no effect on systolic calcium, but slowed relaxation, despite action potential shortening, and increased diastolic calcium. SEA-0400 stabilized dofetilide-induced lability of repolarization and suppressed early afterdepolarizations. In vivo, SEA-0400 (0.4 and 0.8 mg/kg) had no effect on left ventricular pressure and suppressed dofetilide-induced TdPs dose dependently. Verapamil (0.3 mg/kg) also inhibited TdP, but caused a 15±8% drop of left ventricular pressure. A lower dose of verapamil without effects on left ventricular pressure (0.06 mg/kg) was not antiarrhythmic. Conclusions-In chronic atrioventricular block dogs, SEA-0400 treatment is effective against TdP. Unlike specific inhibition of LTCC, combined NCX and LTCC inhibition has no negative effects on cardiac hemodynamics.

Original languageEnglish
Pages (from-to)371-379
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume6
Issue number2
DOIs
Publication statusPublished - Apr 2013

Keywords

  • Antiarrhythmic drug
  • Calcium channel
  • Heart failure
  • Long QT syndrome
  • Na /Ca exchange
  • Torsade de Pointes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Bourgonje, V. J. A., Vos, M. A., Ozdemir, S., Doisne, N., Acsai, K., Varro, A., Sztojkov-Ivanov, A., Zupko, I., Rauch, E., Kattner, L., Bito, V., Houtman, M., Van Der Nagel, R., Beekman, J. D., Van Veen, T. A. B., Sipido, K. R., & Antoons, G. (2013). Combined Na+/Ca2+ exchanger and l-type calcium channel block as a potential strategy to suppress arrhythmias and maintain ventricular function. Circulation: Arrhythmia and Electrophysiology, 6(2), 371-379. https://doi.org/10.1161/CIRCEP.113.000322