Research Paper
Subject Category: Gastrointestinal pharmacology
British Journal of Pharmacology (2008) 153, 1195–1202; doi:10.1038/sj.bjp.0707681; published online 21 January 2008
The role of GABAA receptors in the control of transient lower oesophageal sphincter relaxations in the dog
H Beaumont1, A-C Jönsson-Rylander2, K Carlsson2, S Pierrou2, M Ahlefelt2, L Brändén2, J Jensen2, G E Boeckxstaens1 and A Lehmann2
- 1Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
- 2AstraZeneca R&D Mölndal, Mölndal, Sweden
Correspondence: Dr H Beaumont, Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. E-mail: h.beaumont@amc.uva.nl
Received 17 September 2007; Revised 16 November 2007; Accepted 4 December 2007; Published online 21 January 2008.
Abstract
Background and purpose:
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 GABAB receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABAA receptor in the regulation of TLESRs.
Experimental approach:
TLESRs were quantified using Dentsleeve manometry in dogs, and GABAA agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABAA receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs.
Key results:
The prototypical GABAA agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABAA agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABAA 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 GABAA receptor subunits (
, 
and 
components), and but not were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the subunit.
Conclusions and implications:
The present observations demonstrate that GABAA receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABAA isoform-selective agonists to define the identity of receptors involved.
Keywords:
gastroesophageal reflux disease, GABAA, muscimol, TLESR, dogs
Abbreviations:
GERD, gastroesophageal reflux disease; LES, lower oesophageal sphincter; PBS, phosphate-buffered saline; THIP, 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridine-3-ol; TLESR, transient lower oesophageal sphincter relaxation
