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Human 5-HT4 receptor stimulation in atria of transgenic mice

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Abstract

In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT4 receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT4(a) receptor under control of the heart-specific α-myosin heavy chain promoter in the atria (and ventricles). Contractile studies were performed in isolated electrically driven left atrial preparations and spontaneously beating right atrial preparation of TG and littermate control mice (wild type (WT)). 5-HT increased force of contraction and phospholamban phosphorylation on serine 16 only in left atrial preparations from TG but not from WT. In contrast, β-adrenoceptor stimulation of left atrial preparations by isoprenaline increased force of contraction with similar pEC50 values and to a similar maximum extent in both TG and WT. The contractile effects of 5-HT in left atrial preparations from TG could be blocked by the 5-HT4 receptor-specific antagonists GR125487 or GR113808. In right atrial preparations from WT and TG, the β-adrenoceptor agonist isoprenaline exerted a positive chronotropic effect with similar pEC50 values and similar maximum effects. Only in right atrial preparations from TG but not WT, 5-HT exerted a positive chronotropic effect that could be attenuated by 5-HT4 receptor-specific antagonists. Finally, in left atrial preparations of TG, a higher incidence of arrhythmias was noted compared to WT. The present data indicate that the human 5-HT4 receptors expressed in mouse atria are functional. This is the first transgenic model to study this human receptor in the atrium ex vivo or in vivo.

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Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG). The work was part of the medical thesis of Anne Böckler.

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Authors and Affiliations

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

    Ulrich Gergs, Anne Böckler, Nicolas Keller, Klaus Pönicke & Joachim Neumann

  2. Zentrum für Innere Medizin, Universitätsklinik und Poliklinik für Innere Medizin III, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097, Halle, Germany

    Henning Ebelt & Volker Otto

  3. Institut für Pathologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097, Halle, Germany

    Steffen Hauptmann

  4. Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, 48149, Münster, Germany

    Wilhelm Schmitz

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  1. Ulrich Gergs
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  2. Anne Böckler
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  7. Klaus Pönicke
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Correspondence to Ulrich Gergs.

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Gergs, U., Böckler, A., Ebelt, H. et al. Human 5-HT4 receptor stimulation in atria of transgenic mice. Naunyn-Schmiedeberg's Arch Pharmacol 386, 357–367 (2013). https://doi.org/10.1007/s00210-013-0831-x

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  • DOI: https://doi.org/10.1007/s00210-013-0831-x

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