AGI October 40/4

Blackshaw, L. Ashley, Esther Staunton, Anders Lehmann, and John Dent. Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G867– G874, 1999.—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 6 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 GABAB receptor 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, GABAB receptor inhibition of reflux shows complex pharmacology. Our and other data indicate the therapeutic potential for these drugs.