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Electrophysiological profile of propiverine – relationship to cardiac risk

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Abstract

Drugs that prolong the QT interval by blocking human ether-a-go-go (HERG) channels may enhance the risk of ventricular arrhythmia. The spasmolytic drug propiverine is widely used for the therapy of overactive bladder (OAB). Here, we have investigated the effects of propiverine on cardiac ion channels and action potentials as well as on contractile properties of cardiac tissue, in order to estimate its cardiac safety profile, because other drugs used in this indication had to be withdrawn due to safety reasons. Whole-cell patch clamp technique was used to record the following cardiac ion currents: rapidly and slowly activating delayed rectifier K+ current (IKr, IKs), ultra rapidly activating delayed rectifier K+ current (IKur), inwardly rectifying K+ current IK1, transient outward K+ current (Ito), and L-type Ca2+ current (ICa,L). Action potentials in cardiac tissue biopsies were recorded with conventional microelectrodes. The torsade de pointes screening assay (TDPScreenTM) was used for drug scoring. Propiverine blocked in a concentration-dependent manner HERG channels expressed in HEK293 cells, as well as native IKr current in ventricular myocytes of guinea pig (IC50 values: 10 μM and 1.8 μM respectively). At high concentrations (100 μM), propiverine suppressed IKs. IK1 and the transient outward current Ito and IKur were not affected. In guinea-pig ventricular and human atrial myocytes, propiverine also blocked ICa,L (IC50 values: 34.7 μM and 41.7 μM, respectively) and reduced force of contraction. Despite block of IKr, action potential duration was not prolonged in guinea-pig and human ventricular tissue, but decreased progressively until excitation failed altogether. Similar effects were observed in dog Purkinje fibers. Propiverine obtained a low score in the TDPScreenTM. In conclusion, in vitro and in vivo studies of propiverine do not provide evidence for an enhanced cardiovascular safety risk. We propose that lack of torsadogenic risk of propiverine is related to enhancement of repolarization reserve by block of ICa,L.

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Acknowledgements

The authors gratefully acknowledge the skillful technical assistance of Annegret Häntzschel, Ulrike Heinrich, Trautlinde Thurm and Sabine Kirsch. We thank the cardiovascular surgeons of the Heart Center Dresden for careful supply of human cardiac tissue.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Medical Faculty, Dresden University of Technology, Fetscherstrasse 74, 01307, Dresden, Germany

    Torsten Christ, Erich Wettwer, Melinda Wuest & Ursula Ravens

  2. APOGEPHA Arzneimittel GmbH, Kyffhäuser Strasse 27, 01309, Dresden, Germany

    Manfred Braeter & Frank Donath

  3. Centre de Recherches Biologiques, Chemin Montifault, 18800, Baugy, France

    Pascal Champeroux & Serge Richard

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  1. Torsten Christ
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  2. Erich Wettwer
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  3. Melinda Wuest
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  5. Frank Donath
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  6. Pascal Champeroux
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  7. Serge Richard
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  8. Ursula Ravens
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Correspondence to Ursula Ravens.

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Christ, T., Wettwer, E., Wuest, M. et al. Electrophysiological profile of propiverine – relationship to cardiac risk. Naunyn-Schmied Arch Pharmacol 376, 431–440 (2008). https://doi.org/10.1007/s00210-007-0231-1

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  • DOI: https://doi.org/10.1007/s00210-007-0231-1

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