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

Background and 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 hC-GRPS-37 inhibited both mechanical responses by 750%-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.