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Open Access 01-11-2014 | Original Contribution

Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue

Authors: Alexandra Eder, Arne Hansen, June Uebeler, Thomas Schulze, Christiane Neuber, Sebastian Schaaf, Lei Yuan, Torsten Christ, Marc A. Vos, Thomas Eschenhagen

Published in: Basic Research in Cardiology | Issue 6/2014

Abstract

The assessment of proarrhythmic risks of drugs remains challenging. To evaluate the suitability of rat engineered heart tissue (EHT) for detecting proarrhythmic effects. We monitored drug effects on spontaneous contractile activity and, in selected cases, on action potentials (sharp microelectrode) and Ca²⁺ transients (Fura-2) and contraction under electrical pacing. The I_to-blocker inhibitor 4-aminopyridine increased action potential duration and T2 and caused aftercontractions, which were abolished by inhibitors of ryanodine receptors (RyR2; JTV-519) or sodium calcium exchanger (NCX; SEA0400). 77 Drugs were then tested at 1-10-100× free therapeutic plasma concentrations (FTPC): Inhibitors of I_Kr, I_Ks, I_to, antiarrhythmics (8), drugs withdrawn from market for torsades des pointes arrhythmias (TdP, 5), drugs with measurable (7) or isolated TdP incidence (13), drugs considered safe (14), 28 new chemical entities (NCE). Inhibitors of I_Kr or I_Ks had no effect alone, but substantially prolonged relaxation time (T2) when combined at high concentration. 15/33 drugs associated with TdP and 6/14 drugs considered non-torsadogenic (cibenzoline, diltiazem, ebastine, ketoconazole, moxifloxacin, and phenytoin) induced concentration-dependent T2 prolongations (10-100× FTPC). Bepridil, desipramine, imipramine, thioridazine, and erythromycin induced irregular beating. Three NCE prolonged T2, one reduced force. Drugs inhibiting repolarization prolong relaxation in rat EHTs and cause aftercontractions involving RyR2 and NCX. Insensitivity to I_Kr inhibitors makes rat EHTs unsuitable as general proarrhythmia screen, but favors detection of effects on I_to, I_Ks + I_to or I_Ks + I_Kr. Screening a large panel of drugs suggests that effects on these currents, in addition to I_Kr, are more common than anticipated.

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Title: Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue
Authors: Alexandra Eder
Arne Hansen
June Uebeler
Thomas Schulze
Christiane Neuber
Sebastian Schaaf
Lei Yuan
Torsten Christ
Marc A. Vos
Thomas Eschenhagen
Publication date: 01-11-2014
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 6/2014
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-014-0436-7

2024 ASCO Annual Meeting

Springer Medicine

Effects of proarrhythmic drugs on relaxation time and beating pattern in rat engineered heart tissue

Abstract

2024 ASCO Annual Meeting

Springer Medicine

Abstract

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