Cholecystokinin mediates feedback regulation of pancreatic enzyme secretion in rats

Abstract

Previous studies have shown that trypsin and chymotrypsin in the duodenum exert a negative-feedback regulation on pancreatic enzyme secretion in the rat. The mechanism responsible for this physiological phenomenon is unknown. By use of a specific and sensitive bioassay based on amylase release from isolated pancreatic acini, the role of cholecystokinin in the negative-feedback regulation of exocrine pancreatic secretion was examined. Rats were prepared with duodenal cannulas and pancreaticobiliary cannulas. Diversion of pancreaticobiliary juice resulted in a threefold increase in pancreatic protein output and an increase of plasma cholecystokinin from a basal level of 0.5 +/- 0.08 pM cholecystokinin octapeptide (CCK-8) to 16 +/- 4 pM CCK-8. Perfusion of trypsin (2 mg/h) or pancreaticobiliary juice returned pancreatic protein output to basal levels and plasma cholecystokinin to 2.1 +/- 1.2 and 0.33 +/- 0.1 pM, respectively. The inhibitory effect of trypsin on cholecystokinin release was enzyme and site specific, since inhibition of cholecystokinin release was not observed with perfusion of amylase into the duodenum or with trypsin into the ileum. Intravenous infusion of proglumide abolished the increase in pancreatic secretion following diversion of pancreaticobiliary juice. Intraduodenal perfusion of lidocaine, infusion of tetrodotoxin into the superior mesenteric artery, or intravenous infusion of atropine inhibited the rise in plasma cholecystokinin seen with diversion of pancreaticobiliary juice. These studies suggest that feedback regulation of pancreatic enzyme secretion in the rat is mediated by release of cholecystokinin. Furthermore, the feedback mechanism is neurally mediated, involving a cholinergic pathway.

Mechanism of acid-induced release of secretin in rats. Presence of a secretin-releasing peptide.

“…In recent years, this original observation in rats was confirmed by several groups of investigators (3)(4)(5). It has been found that the increased pancreatic secretion was due to increased release of not only CCK (3)(4)(5) but also secretin (6). However, when the increase in pancreatic secretion was reversed by either pancreatic juice or trypsin in the duodenum, the increases in plasma concentration of CCK (3)(4)(5) and secretin (6) were also abolished in rats.…”

“…They suggested that the increase in pancreatic secretion was attributed to increased release of cholecystokinin (CCK) (2). In recent years, this original observation in rats was confirmed by several groups of investigators (3)(4)(5). It has been found that the increased pancreatic secretion was due to increased release of not only CCK (3)(4)(5) but also secretin (6).…”

Inhibitory effect of CR-1409, a competitive inhibitor of cholecystokinin, on pancreatic exocrine secretion in the conscious rat.

“…Continuous infusion of 100 pmole/kg/hr of CCK produced an increase in plasma CCK level to 3.76 pM from the basal level of 0.45 pM, which is considered to be within the physiological range (Lidclle et al 1984;Louie et al 1986). Liddle et al (1984) have shown that plasma CCK level increased to 6-10 pM after the feeding of a balanced liquid meal or trypsin inhibitor.…”

“…Plasma samples thus obtained were kept at -70°C until the CCK bioassay. Plasma CCK concentrations were measured by a bioassay using dispersed acini as described by Liddle and Louie (Liddle et al 1984;Louie et al 1986). Isolated rat pancreatic acini were prepared by collagenase digestion of pancreases from fasted, ovariectomized female Sparague-Dawley rats as previously described (Liddle et al 1984).…”

“…into a polyethlene scintillation vial and dried with a flow of nitrogen at 45°C (Louie et al 1986). One ml aliquots of acini suspension were addled to the vial containing the plasma extracts or various concentrations of CCK-8 and incubated for 30 min at 37°C.…”