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 gastrointestinal motility through vagal afferents and central nervous mechanisms; however, no data is available about a direct influence on the gastrointestinal wall. Our aim was to investigate the effects of GLP‐1 on the spontaneous and evoked mechanical activity of mouse duodenum and colon and to identify the presence and distribution of GLP‐1 receptors (GLP‐1R) in the muscle coat. Methods Organ bath recording technique and immunohistochemistry were used. Key Results Glucagon‐like peptide‐1 (up to the concentration of 1 μmol L^?1) failed to affect spontaneous mechanical activity. It caused concentration‐dependent reduction of the electrically evoked cholinergic contractions in circular smooth muscle of both intestinal segments, without affecting the longitudinal muscle responses. Glucagon‐like peptide‐1 inhibitory effect was significantly antagonized by exendin (9–39), an antagonist of GLP‐1R. In both intestinal preparations, GLP‐1 effect was not affected by guanethidine, a blocker of adrenergic neurotransmission, but it was significantly reduced by N_ω‐nitro‐l‐arginine methyl ester, inhibitor of nitric oxide (NO) synthase. Glucagon‐like peptide‐1 failed to affect the contractions evoked by exogenous carbachol. Immunohistochemistry demonstrated GLP‐1R expression in the enteric neurons. 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 suggest that GLP‐1 is able to act in the enteric nervous system by decreasing the excitatory cholinergic neurotransmission through presynaptic GLP‐1Rs, which modulate NO release.