Increased Gastric Acid Secretion in Cholecystokinin-1 Receptor-Deficient Otsuka Long-Evans Tokushima Fatty Rats

Abstract

Background: It is hypothesized that cholecystokinin stimulates acid secretion directly and indirectly by binding to CCK-2 (CCK-B/gastrin) receptors on both parietal and enterochromaffin-like cells. At the same time, however, it inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells and thereby exerts a tonic inhibition on the parietal cells. To test the validity of this hypothesis, we determined gastric acid secretion in the CCK-1 (CCK-A) receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods: Gastric acid secretion was determined in the acute fistula OLETF and the control Long-Evans Tokushima Otsuka (LETO) rats. Plasma concentrations of gastrin, CCK, somatostatin and histamine were determined by radioimmunoassay. The levels of CCK-2 receptor mRNA in the mucosa of the glandular stomach were determined by Northern blot analysis. Results: Pentagastrin- and CCK-8-stimulated as well as basal acid outputs in OLETF rats were significantly higher than those in LETO rats. CCK-2 receptor antagonist reduced basal acid outputs and completely suppressed CCK-8-stimulated acid secretion in both strains. CCK-8 enhanced the pentagastrin-stimulated gastric acid output in OLETF rats, but not in LETO rats. In LETO rats, CCK-1 receptor antagonist increased CCK-8-stimulated gastric acid secretions to those in OLETF rats. The level of CCK-2 receptor mRNA in the stomach in OLETF rats was 2-fold higher than that in LETO rats. In OLETF rats, plasma concentrations of CCK and histamine were higher, whereas somatostatin concentrations were lower than those in LETO rats, with no change in basal plasma gastrin concentrations. Conclusions: These results in the CCK-1 receptor-deficient OLETF rats confirmed that CCK stimulates acid secretion by binding to CCK-2 receptors, but at the same time inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells in the gastric mucosa.