Peripheral GABAB agonists stimulate gastric acid secretion in mice.
1 We characterized the effects of intravenous GABA and preferential GABAA (muscimol), GABAB (R-baclofen and SKF-97541) and GABAC agonists (imidazole-4-acetic acid) on gastric acid secretion in urethane-anesthetized mice implanted with a gastric cannula, and determined the role of vagal cholinergic mechanisms, and gastrin and somatostatin by using peptide immunoneutralization, the SSTR2 antagonist, PRL-2903, and SSTR2 knockout mice. 2 The selective GABA(B) agonists R-baclofen (0.1-3 mg kg(-1), i.v.) and SKF-97541 (0.01-0.3 mg kg(-1), i.v.) induced a dose-related stimulation of gastric acid secretion. SKF-97541 was about 10 times more potent than R-baclofen stimulating gastric acid secretion. Neither GABA (0.1-100 mg kg(-1), i.v.) nor muscimol (0.1-3 mg kg(-1)) nor imidazole-4-acetic acid (0.1-10 mg kg(-1)) affected basal gastric acid secretion. 3 Stimulatory effects of SKF-97541 (0.1 mg kg(-1), i.v.) were blocked by the selective GABAB antagonist, 2-hydroxysaclofen, cholinergic blockade with atropine, subdiaphragmatic vagotomy or gastrin immunoneutralization. 4 Somatostatin immunoneutralization or SSTR2 blockade with PRL-2903 enhanced the secretory response to SKF-97541 (0.1 mg kg(-1), i.v.) by 78 and 105%, respectively. 5 In SSTR2 knockout mice, SKF-97541 (0.1 mg kg(-1), i.v.) increased basal gastric acid secretion by 48%. Neither GABA nor muscimol nor imidazole-4-acetic acid modified basal gastric acid secretion in SSTR2 knockout mice. 6 These results indicate that, in mice, stimulation of GABAB receptors increases gastric acid secretion through vagal- and gastrin-dependent mechanisms. Somatostatin implication might be secondary to the release of gastrin and the increase in gastric luminal acidity.
Piqueras
Laura
L
Department of Physiology, Pharmacology and Toxicology, Cardenal Herrera CEU University, Valencia, Spain.
Martinez
Vicente
V
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001418:Baclofen / Q000031:analogs & derivatives* / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009118:Muscimol / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D018079:Receptors, GABA / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D013004:Somatostatin / Q000276:immunology; D013997:Time Factors; D014628:Vagotomy; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; C087200:GABA-C receptor; D005755:Gastrins; D007093:Imidazoles; D009943:Organophosphorus Compounds; C121568:PRL 2903; D010456:Peptides, Cyclic; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; C068457:3-aminopropyl(methyl)phosphinic acid; D009118:Muscimol; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D001285:Atropine; D003847:Deoxyglucose; D010418:Pentagastrin; D001418:Baclofen; C005954:imidazoleacetic acid; C057491:2-hydroxysaclofen