The role of GABA(A) receptors in the control of transient lower oesophageal sphincter relaxations in the dog.

British Journal of Pharmacology
H BeaumontA Lehmann

Abstract

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. 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. 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...Continue Reading

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Citations

Dec 19, 2009·Journal of Neurophysiology·Hong Gao, Bret N Smith
Jan 20, 2012·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·W O RohofG E Boeckxstaens
Apr 28, 2012·Acta Paediatrica·Robert CottonJeff Reese
Apr 12, 2012·Journal of Veterinary Internal Medicine·A C ZacutoP C Belafsky

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