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Cisapride and a structural analogue, R 76186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens

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Summary

The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors.

Both cisapride and R 76186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 × 10−7 M, maximum effect = 40.3% of methacholine induced (3 × 10−7 M) contractions; R 76186: EC5o = 2.4 × 10−8 M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205–557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R76186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76186. The contractions to cisapride and R76186 were sensitive to mutual antagonism, depressing their concentration-response curves.

Conclusions: Both cisapride and R 76186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76 186 is a selective and potent 5-HT4 receptor agonist.

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Authors and Affiliations

  1. Department of Human and Animal Physiology, Wageningen Agricultural University, Wageningen, The Netherlands

    Michel R. Briejer & Louis M. A. Akkermans

  2. Department of Gastrointestinal Pharmacology, Janssen Research Foundation, B-2340, Beerse, Belgium

    Ann L. Meulemans & Jan A. J. Schuurkes

  3. Heymans Institute of Pharmacology, University of Gent Medical School, Gent, Belgium

    Romain A. Lefebvre

Authors
  1. Michel R. Briejer
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  2. Louis M. A. Akkermans
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  3. Ann L. Meulemans
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  4. Romain A. Lefebvre
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  5. Jan A. J. Schuurkes
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Correspondence to M. R. Briejer at the above address in Belgium

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Briejer, M.R., Akkermans, L.M.A., Meulemans, A.L. et al. Cisapride and a structural analogue, R 76186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens. Naunyn-Schmiedeberg's Arch Pharmacol 347, 464–470 (1993). https://doi.org/10.1007/BF00166736

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  • DOI: https://doi.org/10.1007/BF00166736

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