Glucagon-like peptide-2 modulates neurally evoked mucosal chloridesecretion in guinea pig small intestine in vitro

Glucagon-like peptide-2 (GLP-2) isan important neuroendocrine peptide in intestinal physiology. It influencesdigestion, absorption, epithelial growth, motility, and bloodflow. We studied involvement of GLP-2 in intestinal mucosal secretorybehavior. Submucosal-mucosal preparations from guinea pigileum were mounted in Ussing chambers for measurement of shortcircuitcurrent (Isc) as a surrogate for chloride secretion. GLP-2 actionon neuronal release of acetylcholine was determined with ELISA.Enteric neuronal expression of the GLP-2 receptor (GLP-2R) wasstudied with immunohistochemical methods. Application of GLP-2(0.1–100 nM) to the serosal or mucosal side of the preparationsevoked no change in baseline Isc and did not alter transepithelial ionicconductance. Transmural electrical field stimulation (EFS) evokedcharacteristic biphasic increases in Isc, with an initially rapid risingphase followed by a sustained phase. Application of GLP-2 reducedthe EFS-evoked biphasic responses in a concentration-dependentmanner. The GLP-2R antagonist GLP-2-(3-33) significantly reversedsuppression of the EFS-evoked responses by GLP-2. Tetrodotoxin,scopolamine, and hexamethonium, but not vasoactive intestinal peptidetype 1 receptor (VPAC1) antagonist abolished or reduced to nearzero the EFS-evoked responses. GLP-2 suppressed EFS-evoked acetylcholinerelease as measured by ELISA. Pretreatment with GLP-2-(3-33) offset this action of GLP-2. In the submucosal plexus, GLP-2Rimmunoreactivity (-IR) was expressed in choline acetyltransferase-IRneurons, somatostatin-IR neurons, neuropeptide Y-IR neurons, andvasoactive intestinal peptide-IR neurons. We conclude that submucosalneurons in the guinea pig ileum express GLP-2R. Activation ofGLP-2R decreases neuronally evoked epithelial chloride secretion bysuppressing acetylcholine release from secretomotor neurons.