Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle

A. S. Jensen, C. P. Pennisi, C. Sevcencu, J. B. Christensen, J. E. Kristiansen, J. J. Struijk

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (DeltaDelta-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent DeltaDelta-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% DeltaDelta-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P
Original languageEnglish
JournalEuropean Journal of Pharmacology
Volume747
Pages (from-to)7-12
ISSN0014-2999
DOIs
Publication statusPublished - 2015

Cite this

Jensen, A. S., Pennisi, C. P., Sevcencu, C., Christensen, J. B., Kristiansen, J. E., & Struijk, J. J. (2015). Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle. European Journal of Pharmacology, 747, 7-12. https://doi.org/10.1016/j.ejphar.2014.11.015
Jensen, A. S. ; Pennisi, C. P. ; Sevcencu, C. ; Christensen, J. B. ; Kristiansen, J. E. ; Struijk, J. J. / Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle. In: European Journal of Pharmacology. 2015 ; Vol. 747. pp. 7-12.
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abstract = "The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90{\%} APD in comparison with control (DeltaDelta-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent DeltaDelta-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5{\%} and 20.1{\%} DeltaDelta-APD90 prolongation, the racemate caused 8.0{\%} and 12.9{\%}, and (-)-thioridazine caused 1.5{\%} and 1.1{\%}. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P",
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Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle. / Jensen, A. S.; Pennisi, C. P.; Sevcencu, C.; Christensen, J. B.; Kristiansen, J. E.; Struijk, J. J.

In: European Journal of Pharmacology, Vol. 747, 2015, p. 7-12.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Jensen, A. S.

AU - Pennisi, C. P.

AU - Sevcencu, C.

AU - Christensen, J. B.

AU - Kristiansen, J. E.

AU - Struijk, J. J.

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AB - The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (DeltaDelta-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent DeltaDelta-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% DeltaDelta-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P

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DO - 10.1016/j.ejphar.2014.11.015

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JF - European Journal of Pharmacology

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