Glucagon-Like Peptide-1 Modulates Neurally-Evoked Mucosal Chloride Secretion in Guinea Pig Small Intestine In Vitro.

Glucagon-like peptide-1 (GLP-1)acts at the G protein-coupled receptor, GLP-1R, to stimulate secretionof insulin and to inhibit secretion of glucagon and gastric acid.Involvement in mucosal secretory physiology has received negligibleattention. We aimed to study involvement of GLP-1 in mucosalchloride secretion in the small intestine. Ussing chamber methods, inconcert with transmural electrical field stimulation (EFS), were usedto study actions on neurogenic chloride secretion. ELISA was used tostudy GLP-1R effects on neural release of acetylcholine (ACh).Intramural localization of GLP-1R was assessed with immunohistochemistry.Application of GLP-1 to serosal or mucosal sides offlat-sheet preparations in Ussing chambers did not change baselineshort-circuit current (Isc), which served as a marker for chloridesecretion. Transmural EFS evoked neurally mediated biphasic increasesin Isc that had an initial spike-like rising phase followed by asustained plateau-like phase. Blockade of the EFS-evoked responsesby tetrodotoxin indicated that the responses were neurally mediated.Application of GLP-1 reduced the EFS-evoked biphasic responses ina concentration-dependent manner. The GLP-1 receptor antagonistexendin-(9 –39) suppressed this action of GLP-1. The GLP-1 inhibitoryaction on EFS-evoked responses persisted in the presence ofnicotinic or vasoactive intestinal peptide receptor antagonists but notin the presence of a muscarinic receptor antagonist. GLP-1 significantlyreduced EFS-evoked ACh release. In the submucosal plexus,GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons,and vasoactive intestinal peptide-IR neurons. Our results suggestthat GLP-1R is expressed in guinea pig submucosal neurons and thatits activation leads to a decrease in neurally evoked chloride secretionby suppressing release of ACh at neuroepithelial junctions in theenteric neural networks that control secretomotor functions.