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|Title:||Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists|
|Citation:||American Journal of Physiology. Gastrointestinal and Liver Physiology, 1999; 277(4):G867-G874|
|Publisher:||American Physiological Society|
|L. Ashley Blackshaw, Esther Staunton, Anders Lehmann, and John Dent|
|Abstract:||Transient lower esophageal sphincter (LES) relaxation is the major mechanism of gastroesophageal reflux. This study uses an established ferret model to evaluate GABAB receptor agonists’ ability to reduce triggering of transient LES relaxations. One hundred sixty manometric/pH studies were performed on 18 conscious ferrets. In untreated animals, intragastric infusion of 25 ml glucose (pH 3.5) led to 2.0 ± 0.6 reflux episodes over the first 30 min. Twenty-nine of forty-seven reflux episodes occurred during transient LES relaxation, and 18 occurred after downward drifts (<1 mmHg/s) in basal LES pressure. The GABABreceptor agonists baclofen (7 μmol/kg ip), CGP-44532, and SKF-97541 (both ED50 <0.3 μmol/kg) reduced reflux episodes and transient LES relaxations. The putative peripherally selective GABAB receptor agonist 3-aminopropylphosphinic acid (80–240 μmol/kg) was ineffective, as was the GABAA receptor agonist muscimol (5 μmol/kg). Baclofen’s inhibition of transient LES relaxations and reflux was unaffected by low-affinity GABAB receptor antagonists CGP-35348 and CGP-36742 at 100 μmol/kg but was reversed by higher-affinity CGP-54626 and CGP-62349 (0.7 μmol/kg) or by CGP-36742 at 200 μmol/kg. Therefore, GABABreceptor inhibition of reflux shows complex pharmacology. Our and other data indicate the therapeutic potential for these drugs.|
|Keywords:||Esophagogastric Junction; Animals; Ferrets; Gastroesophageal Reflux; Phosphinic Acids; gamma-Aminobutyric Acid; Baclofen; Organophosphorus Compounds; GABA Agonists; Manometry; Behavior, Animal; Deglutition; Muscle Relaxation; Hydrogen-Ion Concentration; Pressure; Time Factors; Female; Organophosphonates|
|Rights:||Copyright © 1999 the American Physiological Society|
|Appears in Collections:||Medicine publications|
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