title: The role of GABA(A) receptors in the control of transient lower oesophageal sphincter relaxations in the dog.
abstract: OBJECTIVE
  Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA(B) receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA(A) receptor in the regulation of TLESRs.
  
  
  METHODS
  TLESRs were quantified using Dentsleeve manometry in dogs, and GABA(A) agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA(A) receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs.
  
  
  RESULTS
  The prototypical GABA(A) agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA(A) agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA(A) positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA(A) receptor subunits (alpha, beta and gamma components), alpha and beta but not gamma were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the gamma subunit.
  
  
  CONCLUSIONS
  The present observations demonstrate that GABA(A) receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA(A) isoform-selective agonists to define the identity of receptors involved.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands. h.beaumont@amc.uva.nl
authors.forename: H
authors.initials: H
authors.lastname: Beaumont
authors.forename: A-C
authors.initials: AC
authors.lastname: Jönsson-Rylander
authors.forename: K
authors.initials: K
authors.lastname: Carlsson
authors.forename: S
authors.initials: S
authors.lastname: Pierrou
authors.forename: M
authors.initials: M
authors.lastname: Ahlefelt
authors.forename: L
authors.initials: L
authors.lastname: Brändén
authors.forename: J
authors.initials: J
authors.lastname: Jensen
authors.forename: G E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.forename: A
authors.initials: A
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D049630:Esophageal Sphincter, Lower / Q000378:metabolism*; D005260:Female; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D015870:Gene Expression; D007150:Immunohistochemistry; D008297:Male; D008365:Manometry; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D009620:Nodose Ganglion / Q000378:metabolism; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D009118:Muscimol