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.


RESULTS
Glucagon-like peptide-1 (up to the concentration of 1 mumol 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(omega)-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
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.
Dipartimento di Biologia cellulare e dello Sviluppo, Università di Palermo, 90128 Palermo, Italy.
A
A
Amato
L
L
Cinci
A
A
Rotondo
R
R
Serio
M S
MS
Faussone-Pellegrini
M G
MG
Vannucchi
F
F
Mulè
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D017615:Enteric Nervous System / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006145:Guanethidine / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D017933:Peripheral Nervous System / Q000166:cytology / Q000187:drug effects*; D018027:Receptors, Glucagon / Q000187:drug effects*; D013565:Sympatholytics / Q000494:pharmacology
D004791:Enzyme Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D013565:Sympatholytics; D019335:Nitroarginine; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D052248:Nitric Oxide Synthase Type I; D000110:Acetylcholinesterase; D006145:Guanethidine