5-HT4 receptors located on cholinergic nerves in human colon circular muscle

Authors

  • P. G. Leclere,

    1. Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
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    • The authors equally contributed to this manuscript.

  • N. H. Prins,

    1. Department of Gastrointestinal Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium
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    • The authors equally contributed to this manuscript.

  • J. A. J. Schuurkes,

    1. Department of Gastrointestinal Pharmacology, Johnson & Johnson Pharmaceutical Research & Development, A Division of Janssen Pharmaceutica N.V., Beerse, Belgium
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  • R. A. Lefebvre

    1. Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
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  • Present address: N. H. Prins, Pharsight Corporation, Mountain View, CA 94040, USA.

R. A. Lefebvre, Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.
Tel: +32 9 2403373; fax: +32 9 2404988; e-mail: romain.lefebvre@ugent.be

Abstract

Abstract  5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called ‘whole tissue’ strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in ‘isolated’ CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 μmol L−1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon.

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