J R Grider1, A E Foxx-Orenstein, J G Jin. 1. Departments of Physiology and Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA.
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, 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.
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.
Authors: N H Prins; J F Van Haselen; R A Lefebvre; M R Briejer; L M Akkermans; J A Schuurkes Journal: Br J Pharmacol Date: 1999-07 Impact factor: 8.739
Authors: N H Prins; N P Shankley; N J Welsh; M R Briejer; R A Lefebvre; L M Akkermans; J A Schuurkes Journal: Br J Pharmacol Date: 2000-04 Impact factor: 8.739