Gastroenterology

Gastroenterology

Volume 117, Issue 5, November 1999, Pages 1147-1154
Gastroenterology

Alimentary Tract
Activation of the GABAB receptor inhibits transient lower esophageal sphincter relaxations in dogs

https://doi.org/10.1016/S0016-5085(99)70400-2Get rights and content

Abstract

Background & Aims: Transient lower esophageal sphincter relaxation (TLESR) appears to be the most frequent motor event responsible for gastroesophageal reflux. Because TLESRs are considered to be triggered by activation of gastric mechanoreceptors, and because the γ-aminobutyric acid type B (GABAB)-receptor agonist baclofen is known to inhibit transmitter release from mechanosensitive afferents, the effects of baclofen on TLESRs in the dog were assessed. Methods: A total of 183 recordings of the pharyngeal, esophageal, lower esophageal sphincter, and gastric pressures as well as measurement of esophageal pH were performed in 15 awake dogs. Racemic baclofen, its enantiomers, and the GABAB-receptor antagonist CGP36742 were administered before stimulation of TLESRs by a liquid meal and air insufflation. The pharmacodynamics of baclofen were compared with its pharmacokinetics. Results: Baclofen dose-dependently inhibited TLESRs, with a 50% effective dose (ED50) of 1.0 μmol/kg after intravenous administration. The maximal inhibition amounted to ~80%. Intragastric baclofen was almost equally effective (ED50, 1.8 μmol/kg), compatible with the complete oral availability of the drug (100%). The inhibitory effect of baclofen resided in the pharmacologically active R enantiomer, and CGP36742 reduced some of the effects of baclofen. Conclusions: Baclofen is a potent and efficacious inhibitor of TLESRs and reflux in the dog. Activation of the GABAB receptor may be a new approach to the treatment of reflux disease.

GASTROENTEROLOGY 1999;117:1147-1154

Section snippets

General

Twelve adult Labrador retrievers (6 male) and 3 beagles (2 male) were trained to stand in a Pavlov sling. Mucosa-to-skin esophagostomies were formed, and the dogs were allowed to recover completely before any experiments were performed. The dogs were used in drug-screening experiments, but a washout of at least 2 days was allowed before further experimentation. All experiments were approved by the local ethics committee for animal experiments.

Motility measurement

The experiments have been described in detail

Results

The total number of TLESRs differed markedly between dogs but was fairly constant within each dog (n = 107 control experiments, all dogs included). No age-dependent changes in the frequency of TLESRs in control studies have been found over a period of >3 years. The control values for motility parameters are given in Table 1.

Discussion

The present study shows for the first time that the selective GABAB-receptor agonist baclofen dose-dependently inhibits TLESR. The effect of baclofen is not restricted to dogs, because an identical effect has been observed in ferrets.31 Baclofen reduced the frequency of TLESRs and prolonged the latency to the first TLESR. However, TLESRs recorded in the presence of baclofen were indistinguishable in their pressure profile from those observed in control experiments. TLESRs are believed to be

Acknowledgements

The authors thank L. A. Blackshaw, J. Dent, S. J. H. Brookes, and R. H. Holloway for helpful discussions; M. Wilsson and L. Björklund for performing the surgery; and C. Ekman for assistance with the statistical analyses.

References (52)

  • AF Sved et al.

    Tonic stimulation of GABAB receptors in the nucleus tractus solitarius modulates the baroreceptor reflex

    Brain Res

    (1992)
  • M Flärdh et al.

    Sensitive method for the determination of baclofen in plasma by means of solid-phase extraction and liquid chromatography/tandem mass spectrometry

    J Chromatogr

    (1999)
  • A Lehmann

    Effects of an N-methyl-D-aspartate receptor antagonist on transient lower esophageal sphincter relaxations (TLESRs) in the dog (abstr)

    Gastroenterology

    (1998)
  • S Yuan et al.

    Neuronal pathways and transmission to the lower esophageal sphincter of the guinea pig

    Gastroenterology

    (1998)
  • G Bonanno et al.

    Multiple GABAB receptors

    Trends Pharmacol Sci

    (1993)
  • KI Rusin et al.

    μ-Opioid and GABAB receptors modulate different types of Ca2+ current in rat nodose ganglion neurons

    Neuroscience

    (1998)
  • G Bonanno et al.

    GABAB receptors as potential targets for drugs able to prevent excessive excitatory amino acid transmission in the spinal cord

    Eur J Pharmacol

    (1998)
  • PN Izzo et al.

    γ-Aminobutyric acid immunoreactive structures in the nucleus tractus solitarius: a light and electron microscopic study

    Brain Res

    (1992)
  • Y Goto et al.

    Gastric acid and vagus nerve response to GABA agonist baclofen

    Life Sci

    (1985)
  • J Dent et al.

    Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects

    J Clin Invest

    (1980)
  • J Dent et al.

    Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux

    Gut

    (1988)
  • N Freidin et al.

    Does body posture affect the incidence and mechanism of gastro-oesophageal reflux?

    Gut

    (1991)
  • R Penagini et al.

    Motor events underlying gastro-oesophageal reflux in ambulant patients with reflux oesophagitis

    Neurogastroenterol Motil

    (1996)
  • RH Holloway et al.

    Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux

    Dig Dis Sci

    (1991)
  • MR Cox et al.

    Effect of general anaesthesia on transient lower oesophageal sphincter relaxations in the dog

    Aust NZ J Surg

    (1988)
  • RH Holloway et al.

    Effect of cisapride on postprandial gastro-oesophageal reflux

    Gut

    (1989)
  • Cited by (0)

    Address requests for reprints to: Anders Lehmann, Ph.D., Gastrointestinal Pharmacology, Astra Zeneca R & D Mölndal S-431 83 Mölndal, Sweden. e-mail: [email protected]; fax: (46) 31-776-3747.

    View full text