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

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, approximately 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.