Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions.
Glucagon-like peptide-1 (GLP-1) is a neuropeptide released following meal ingestion that, among other effects, decreases gastric tone and motility. The central targets and mechanism of action of GLP-1 on gastric neurocircuits have not, however, been fully investigated. A high density of GLP-1 containing neurones and receptors are present in brainstem vagal circuits, suggesting that the gastroinhibition may be vagally mediated. We aimed to investigate: (1) the response of identified gastric-projecting neurones of the dorsal motor nucleus of the vagus (DMV) to GLP-1 and its analogues; (2) the effects of brainstem application of GLP-1 on gastric tone; and (3) the vagal pathway utilized by GLP-1 to induce gastroinhibition. We conducted our experiments using whole-cell recordings from identified gastric-projecting DMV neurones and microinjection in the dorsal vagal complex (DVC) of anaesthetized rats while monitoring gastric tone. Perfusion with GLP-1 induced a concentration-dependent excitation of a subpopulation of gastric-projecting DMV neurones. The GLP-1 effects were mimicked by exendin-4 and antagonized by exendin-9-39. In an anaesthetized rat preparation, application of exendin-4 to the DVC decreased gastric tone in a concentration-dependent manner. The gastroinhibitory effects of exendin-4 were unaffected by systemic pretreatment with the pro-motility muscarinic agonist bethanechol, but were abolished by systemic administration of the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), or by bilateral vagotomy. Our data indicate that GLP-1 activates selective receptors to excite DMV neurones mainly and that the gastroinhibition observed following application of GLP-1 in the DVC is due to the activation of an inhibitory non-adrenergic, non-cholinergic input to the stomach.
Holmes
Gregory M
GM
Neuroscience, PBRC-Louisiana State University, Baton Rouge, LA 70808, USA.
Browning
Kirsteen N
KN
Tong
Melissa
M
Qualls-Creekmore
Emily
E
Travagli
R Alberto
RA
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000077270:Exenatide; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000009:adverse effects; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology; D014688:Venoms / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
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