Peripheral motor action of glucagon-like peptide-1 through enteric neuronal receptors.

Background Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived peptide expressed in the enteroendocrine-L cells of small and large intestine and released in response to meal ingestion. Glucagon-like peptide-1 exerts inhibitory effects on gastrointestinalmotility through vagal afferents and central nervousmechanisms; however, no data is available about adirect influence on the gastrointestinal wall. Our aimwas to investigate the effects of GLP-1 on thespontaneous and evoked mechanical activity ofmouse duodenum and colon and to identify thepresence and distribution of GLP-1 receptors (GLP-1R)in the muscle coat. Methods Organ bath recordingtechnique and immunohistochemistry were used.Key Results Glucagon-like peptide-1 (up to the concentrationof 1 lmol L)1) failed to affect spontaneousmechanical activity. It caused concentration-dependentreduction of the electrically evoked cholinergiccontractions in circular smooth muscle of both intestinalsegments, without affecting the longitudinalmuscle responses. Glucagon-like peptide-1 inhibitoryeffect was significantly antagonized by exendin (9–39),an antagonist of GLP-1R. In both intestinal preparations,GLP-1 effect was not affected by guanethidine, ablocker of adrenergic neurotransmission, but it wassignificantly reduced by Nx-nitro-L-arginine methylester, inhibitor of nitric oxide (NO) synthase. Glucagon-like peptide-1 failed to affect the contractionsevoked by exogenous carbachol. Immunohistochemistrydemonstrated GLP-1R expression in the entericneurons. Furthermore, 27% of GLP-1R immunoreactive(IR) neurons in the duodenum and 79% of GLP-1R-IR neurons in the colon, co-expressed nNOS.Conclusions & Inferences The present results suggestthat GLP-1 is able to act in the enteric nervous systemby decreasing the excitatory cholinergic neurotransmissionthrough presynaptic GLP-1Rs, which modulateNO release.