Gastroenterology

Gastroenterology

Volume 115, Issue 2, August 1998, Pages 370-380
Gastroenterology

Alimentary Tract
5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine,☆☆

https://doi.org/10.1016/S0016-5085(98)70203-3Get rights and content

Abstract

Background & Aims: The peristaltic reflex induced by mucosal stimuli is mediated by intrinsic sensory calcitonin gene-related peptide (CGRP) neurons activated by 5-hydroxytryptamine (5-HT) released from enterochromaffin cells. The involvement of 5-HT4 receptors was examined with selective 5-HT4 agonists. Methods: Compartmented intestinal segments were used to measure neurotransmitter release and the mechanical components of the reflex. Results: In human jejunal and rat and guinea pig colonic segments, addition of the 5-HT4 agonist HTF 919 elicited release of CGRP only into the compartment where the 5-HT4 agonist was added; vasoactive intestinal peptide (VIP) was released only into the compartment where descending relaxation was measured, and substance P (SP) was released only into the compartment where ascending contraction was measured. The CGRP antagonist hCGRP8-37 inhibited both mechanical responses by 75%–80%. Release of CGRP, VIP, and SP as well as ascending and descending responses were inhibited by selective 5-HT4 but not by selective 5-HT3 antagonists. Similar results were obtained with a different 5-HT4 agonist, R093877. However, HTF 919 was 10–30 times more potent (median effective concentration, ~10 nmol/L for peptide release and 5 nmol/L for mechanical responses) than R093877. Conclusions: Selective 5-HT4 agonists applied to the mucosa in nanomolar concentrations trigger the peristaltic reflex in human, rat, and guinea pig intestine.

GASTROENTEROLOGY 1998;115:370-380

Section snippets

Compartmented flat-sheet preparation of guinea pig and rat colon

A three-compartment flat-sheet preparation previously described in detail1, 2 was used to measure neurotransmitter release and contraction or relaxation of circular muscle. In brief, 5-cm segments of mid-to-distal colon were opened and pinned mucosal side up to the base of a chamber and bathed in a Krebs-bicarbonate medium containing 118 mmol/L NaCl, 4.8 mmol/L KCl, 1.2 mmol/L KH2PO4, 2.5 mmol/L CaCl2, 1.2 mmol/L MgSO4, 25 mmol/L NaH2CO3, 11 mmol/L glucose, 0.1% bovine serum albumin, 10 μmol/L

Release of CGRP by the 5-HT4 agonist HTF 919

Addition of HTF 919 to the central compartment caused a concentration-dependent release of CGRP into the central compartment but not into the peripheral orad or caudad compartments in rat and guinea pig colon (Figure 1).

. Concentration-response curves for the effect of HTF 919 on (A) CGRP, (B) SP, and (C) VIP release in guinea pig and rat colonic segments. HTF 919 was added to the central compartment, and the release of all three peptides was measured in all compartments (see Materials and

Discussion

The study shows that selective 5-HT4 agonists added to the intestinal mucosa trigger the peristaltic reflex: the sequence involves activation of CGRP-containing sensory nerves resulting in release of excitatory and inhibitory neurotransmitters that regulate the orad and caudad phases of the reflex (Figure 11).

. Model depicting extrinsic and intrinsic sensory pathways mediating the peristaltic reflex. The extrinsic pathway is activated by muscle stretch and consists of CGRP neurons with cell

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    Address requests for reprints to: John R. Grider, Ph.D., Box 980551, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0551. e-mail: [email protected]; fax: (804) 828-2500.

    ☆☆

    Supported by grant DK34153 from the National Institute of Diabetes and Digestive and Kidney Diseases.

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