title: Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists.
abstract: Transient lower esophageal sphincter (LES) relaxation is the major mechanism of gastroesophageal reflux. This study uses an established ferret model to evaluate GABA(B) 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 GABA(B) receptor agonists baclofen (7 micromol/kg ip), CGP-44532, and SKF-97541 (both ED(50) <0.3 micromol/kg) reduced reflux episodes and transient LES relaxations. The putative peripherally selective GABA(B) receptor agonist 3-aminopropylphosphinic acid (80-240 micromol/kg) was ineffective, as was the GABA(A) receptor agonist muscimol (5 micromol/kg). Baclofen's inhibition of transient LES relaxations and reflux was unaffected by low-affinity GABA(B) receptor antagonists CGP-35348 and CGP-36742 at 100 micromol/kg but was reversed by higher-affinity CGP-54626 and CGP-62349 (0.7 micromol/kg) or by CGP-36742 at 200 micromol/kg. Therefore, GABA(B) receptor inhibition of reflux shows complex pharmacology. Our and other data indicate the therapeutic potential for these drugs.
authors.affiliation: Nerve-Gut Research Laboratory, Department of Gastrointestinal Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
authors.forename: L A
authors.initials: LA
authors.lastname: Blackshaw
authors.forename: E
authors.initials: E
authors.lastname: Staunton
authors.forename: A
authors.initials: A
authors.lastname: Lehmann
authors.forename: J
authors.initials: J
authors.lastname: Dent
mesh_terms: D000818:Animals; D001418:Baclofen / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003679:Deglutition / Q000502:physiology; D004943:Esophagogastric Junction / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D005289:Ferrets; D018755:GABA Agonists / Q000627:therapeutic use*; D005764:Gastroesophageal Reflux / Q000517:prevention & control*; D006863:Hydrogen-Ion Concentration; D008365:Manometry; D009126:Muscle Relaxation / Q000187:drug effects*; D063065:Organophosphonates / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D010721:Phosphinic Acids; D011312:Pressure; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: C112036:3-amino-2-(S)-hydroxypropyl-methyl-phosphinic acid; D018755:GABA Agonists; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; C068457:3-aminopropyl(methyl)phosphinic acid; D005680:gamma-Aminobutyric Acid; D001418:Baclofen