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

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.

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 micromol kg, which would block the CCK-B receptors, or a 1000 times higher dose (300 micromol kg), which would also block the CCK-A receptors.

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 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) to the general circulation was not affected by pretreatment with low dosage YF476, whereas high dosage YF476 completely inhibited the stimulated secretion.

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.