CHOLECYSTOKININ (CCK) REGULATES SOMATOSTATIN SECRETION THROUGH BOTH THE CCK-A AND CCK-B GASTRIN RECEPTORS IN SHEEP/

1. Cholecystokinin (CCK) and gastrin both stimulate gastric somatostat in (SOM) secretion in vitro and thus have the potential to modulate th eir direct effects on the parietal cell. However, the relative potenci es and the mechanisms of action of CCK and gastrin on SOM secretion in vivo have not been determined. 2. The objectives of the present study were to compare the in vivo potencies of the sulphated (s) and non-su lphated (ns) forms of gastrin heptadecapeptide (G-17) and CCK octapept ide (CCK-8) on SOM secretion, and to determine the nature of the recep tors involved by repeating the studies in the presence of the CCK-A an d CCK-B/gastrin receptor antagonists L-364,718 and L-365,260, respecti vely. All experiments were performed in the chronically cannulated she ep. 3. Dose-response experiments revealed the following potencies for SOM secretion: G-17s = CCK-8s > G-17ns >> CCK-8ns. However, based on t he plasma levels achieved and a higher metabolic clearance rate (MCR) for CCK, CCK-8s was the most potent. 4. Both the CCK-A and CCK-B/gastr in receptor antagonists suppressed CCK-8s-stimulated SOM output. In co ntrast, G-17s-stimulated SOM output was inhibited by only the CCK-B/ga strin receptor antagonist. 5. Both receptor antagonists increased basa l plasma gastrin and CCK levels. 6. The predominant circulating SOM mo lecular form after both gastrin and CCK stimulation was SOM-14. 7. In conclusion, the sulphated forms of CCK and gastrin are more potent tha n the nonsulphated forms. Despite sharing a common biologically active carboxy terminus, CCK stimulates SOM secretion by both the CCK-A and CCK-B/gastrin receptors, while gastrin acts via the CCK-B/gastrin rece ptor alone. These findings explain in part why CCK is a net inhibitor of gastric acid secretion in vivo.