CCK-B receptor antagonist YF476 inhibits pancreatic enzyme secretion at a duodenal level in pigs

Background: To evaluate the mechanisms by which cholecystokinin (CCK) regulates the exocrine pancreas, the role and location of CCK receptors in the pig were investigated using the CCK-B receptor antagonist YF476 and different administration routes of CCK. Methods: In 11 anaesthetized pigs, catheters were surgically implanted in the pancreatic duct for juice collection, and in the gastric arteries and jugular vein, so that infusions of CCK-33 could be directed to the duodenal/gastric, duodenal/ pancreatic or general circulations, respectively. Experiments were performed under control conditions, and after pretreatment by gavage feeding with YF476, using either a single, low dose of 0.3 mumol kg(-1), which would block the CCK-B receptors, or a 1000 times higher dose (300 mumol kg(-1)), which would also block the CCK-A receptors. Results: The increase in the pancreatic output of protein and the enzymes trypsin and amylase observed after the infusion of CCK-33 at 13 pmol kg(-1) to the duodenum/stomach or duodenum/pancreas was inhibited by pretreatment with YF476 at both dosages. In contrast, the increase in protein and enzyme output after the infusion of a supraphysiological dose of CCK-33 (130 pmol kg(-1)) to the general circulation was not affected by pretreatment with low dosage YF476, whereas high dosage YF476 completely inhibited the stimulated secretion. Conclusions: These data indicate that CCK-33 given locally to the duodenum in doses raising CCK to physiological plasma levels stimulates the pancreatic enzyme secretion via duodenal CCK-B receptors. Supra-physiological doses of CCK-33 to the general circulation appeared to affect the pancreatic enzyme secretion via CCK-A receptors located elsewhere than in the pancreatic and duodenal tissue.