Vagally mediated effects of glucagon-like peptide 1: in vitro and in vivo gastric actions

J Physiol. 2009 Oct 1;587(Pt 19):4749-59. doi: 10.1113/jphysiol.2009.175067. Epub 2009 Aug 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology
  • Exenatide
  • Female
  • Gastrointestinal Motility / drug effects
  • Gastrointestinal Motility / physiology
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide 1 / physiology
  • In Vitro Techniques
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Nitric Oxide Synthase / adverse effects
  • Patch-Clamp Techniques
  • Peptides / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stomach / drug effects*
  • Stomach / innervation*
  • Stomach / physiology
  • Vagus Nerve / drug effects*
  • Vagus Nerve / physiology
  • Venoms / pharmacology

Substances

  • Enzyme Inhibitors
  • Peptides
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester