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Cardiovascular effects of cisapride and prucalopride on human 5-HT4 receptors in transgenic mice

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Abstract

Cisapride and prucalopride act as 5-HT4 receptor agonists. As a part of our ongoing effort to study the utility of a transgenic (TG) mouse model overexpressing cardiac 5-HT4 receptors, we assessed the extent to which we could recapitulate cisapride and prucalopride agonists. Contractile studies were performed using isolated left and right atrial preparations of TG mice showing cardiac-specific human 5-HT4a receptor expression and those of their wild-type (WT) littermates. 5-Hydroxytryptamine (5-HT), cisapride, and prucalopride exerted concentration-dependent positive inotropic effects in the left atrial preparations of TG mice. Moreover, 5-HT induced concentration-dependent arrhythmias in the right atrial preparations of TG mice starting from 10-nM concentration. However, cisapride induced arrhythmias not only in the right atrial preparations of TG mice but also in the right atrial preparations of WT mice. For instance, 10 μM cisapride induced arrhythmias in the right atrial preparations of TG and WT mice to the same extent. Prucalopride did not exert concentration-dependent proarrhythmic effects in the isolated atrial preparations (left or right, WT or TG). Furthermore, cisapride and prucalopride increased the contractility and beating rate in vivo in TG mice, as assessed by performing echocardiography and surface electrocardiography. In summary, our results indicate that cisapride and prucalopride increase contractility and beating rate in the isolated atrial preparations of TG mice or in intact TG mice. Moreover, 5-HT induced arrhythmias in the isolated right atrial preparations of TG mice in a concentration-dependent manner. Furthermore, cisapride induced arrhythmias in the isolated right atrial preparations of both TG and WT mice. In contrast, prucalopride did not induce arrhythmias in the atrial preparations (left or right) of both WT and TG mice. We suggest that the present TG mouse model might be useful to predict at least some important cardiac effects of 5-HT4 receptor agonists in the human heart.

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Acknowledgements

The work contains parts of the medical thesis of Nicolas Keller.

Funding

This work was supported by the DFG (INST 109500/7-1 LAGG-KJPII).

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Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097, Halle, Germany

    Nicolas Keller, Joachim Neumann & Ulrich Gergs

  2. Klinik für Herzchirurgie, Herzzentrum der Universität Leipzig, 04289, Leipzig, Germany

    Stefan Dhein

  3. Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Str. 4, 06112, Halle, Germany

    Ulrich Gergs

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  1. Nicolas Keller
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  2. Stefan Dhein
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  3. Joachim Neumann
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  4. Ulrich Gergs
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Contributions

N.K. and S.D. have performed the experiments. S.D. and U.G. have evaluated the experiments. J.N. and U.G. wrote the manuscript.

Corresponding author

Correspondence to Ulrich Gergs.

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The study was approved by the animal welfare committee of the University of Halle-Wittenberg, Halle, Germany (approval reference number: 42502-02-691 MLU).

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The authors declare that they have no conflict of interest.

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Keller, N., Dhein, S., Neumann, J. et al. Cardiovascular effects of cisapride and prucalopride on human 5-HT4 receptors in transgenic mice. Naunyn-Schmiedeberg's Arch Pharmacol 391, 975–985 (2018). https://doi.org/10.1007/s00210-018-1519-z

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