Activation of the GABA(B) receptor inhibits transient lower esophageal sphincter relaxations in dogs.
OBJECTIVE
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 gamma-aminobutyric acid type B (GABA(B))-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 GABA(B)-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 (ED(50)) of 1.0 micromol/kg after intravenous administration. The maximal inhibition amounted to approximately 80%. Intragastric baclofen was almost equally effective (ED(50), 1.8 micromol/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 GABA(B) receptor may be a new approach to the treatment of reflux disease.
Lehmann
A
A
Gastrointestinal Pharmacology, Astra Zeneca R&D Mölndal, Mölndal, Sweden. Anders.Lehmann@astrazeneca.com
Antonsson
M
M
Bremner-Danielsen
M
M
Flärdh
M
M
Hansson-Brändén
L
L
Kärrberg
L
L
D000818:Animals; D001418:Baclofen / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004943:Esophagogastric Junction / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018755:GABA Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010528:Peristalsis / Q000502:physiology; D011312:Pressure; D018080:Receptors, GABA-B / Q000502:physiology*; D013237:Stereoisomerism; D013270:Stomach / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C079148:(3-aminopropyl)(n-butyl)phosphinic acid; D001418:Baclofen