Difu Guan

Endogenous cholecystokinin, the major factor responsible for dietary protein-induced pancreatic growth.

This study was undertaken to clarify the role of endogenous cholecystokinin (CCK) in induction of pancreatic growth stimulated by a high protein diet. Rats with i.v. jugular cannulae in place and kept in Bollman cages were adapted to 5% casein diet for 9 days and switched to 70% casein for 2 days. MK-329, a CCK receptor antagonist, and SMS 201–995, a somatostatin agonist, were continuously infused at 0.5 mg/kg/h and 5 pg/kg/h, respectively, starting at the onset of feeding 70% casein. The 5 and 70% casein control groups were infused with saline. Feeding 70% casein significantly stimulated pancreatic hyperplasia and tissue hypertrophy. MK-329 and SMS 201–995 totally prevented 70% casein-induced increases in pancreatic weight and total RNA and DNA contents. The results indicate that endogenous CCK is the major factor responsible for pancreatic growth induced by a high protein diet.

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.

Rat pancreatic secretory response to intraduodenal infusion of elemental vs polymeric defined-formula diet

Pancreatic protein and fluid secretion in response to intraduodenal infusion of polymeric and elemental liquid defined-formula diets were studied in conscious rats. Rats were prepared with chronic pancreatic, biliary, and duodenal cannulas and had their pancreatic secretions collected and continuously returned to the intestine during intraduodenal infusion with commercial liquid defined-formula diets. Ensure HN, a polymeric defined-formula diet containing intact protein, and two elemental diets, in which the protein component consisted of enzymatically hydrolyzed protein and free amino acids, were tested. Ensure HN strongly stimulated pancreatic protein and fluid secretion, causing a maximal 10-fold increase in protein secretion. In contrast, the elemental diets stimulated only 30% to 47% of the protein secretion caused by Ensure HN. Separate infusion of the fat, protein, and carbohydrate components of one elemental diet, RTF Elemental, showed that fat was the major stimulant, but the responses to the separate components were not significantly different from each other and none caused more than 50% of the response to the complete diet. The results demonstrate that defined-formula elemental diets are much less stimulatory for pancreatic enzyme secretion than defined-formula polymeric diets in rats. The probable explanation for this difference is the replacement of intact protein by hydrolyzed protein and amino acids in the elemental diets.

Lack of cholinergic control in feedback regulation of pancreatic secretion in the rat

The effect of atropine (100 micrograms/kg/h, i.v.) on plasma cholecystokinin and pancreatic secretion during diversion of bile and pancreatic juice from the intestine was studied in 8 conscious rats equipped with jugular vein, pancreatic, biliary, and duodenal cannulas, and with pyloric ligation and gastric drainage. Diversion of bile and pancreatic juice to the exterior for 4 h significantly increased pancreatic protein and fluid secretion. Atropine delayed the pancreatic response to diversion, but during 4 h of diversion, neither total nor incremental pancreatic protein or fluid secretion was inhibited by atropine. Plasma cholecystokinin levels were elevated after diverting bile and pancreatic juice and were not significantly reduced by atropine (23.0 +/- 6.6 pM vs. 16.0 +/- 3.9 pM at 1.5 h and 17.3 +/- 5.4 pM vs. 13.1 +/- 2.9 pM at 4 h after bile and pancreatic juice diversion; atropine-treated vs. controls, respectively). These results indicate that cholinergic nerves play no important role in feedback regulation of cholecystokinin release and that the previously reported suppressive effect of atropine on the pancreatic response to diversion of bile and pancreatic juice from the intestine was secondary to inhibition of gastric secretion.

CCK-releasing activity of rat intestinal secretion : effect of atropine and comparison with monitor peptide

A bioassay for studying the cholecystokinin (CCK)-releasing activity of intraluminal protease-sensitive bioactive peptides was developed. In conscious rats, bile and pancreatic juice were chronically diverted from the proximal intestine to the ileum to cause chronic stimulation of CCK release and pancreatic protein secretion. CCK-releasing activity of test substances was assayed during transient inhibition of CCK release by intraduodenal sodium taurocholate (78 μmol/h). Intestinal secretion as a source of the putative trypsin-sensitive intestinal CCK-releasing peptide was obtained by rapid intestinal perfusion of isolated Thiry-Vella fistulae of jejunum in conscious rats, collected with or without atropine pretreatment. Partially purified rat pancreatic secretory trypsin inhibitor (PSTI, or “monitor peptide”) was compared with ovomucoid trypsin inhibitor (OMTI) and with concentrated jejunal secretions for CCK-releasing activity and trypsin inhibitor activity. Concentrated, heat-treated jejunal secretions were the strongest stimulants of CCK release and pancreatic protein secretion in this model. OMTI had no CCK-releasing activity in this model, whereas a larger amount (∼5x, based on trypsin inhibitor activity) of PSTI weakly but significantly stimulated CCK release. CCK releasing activity manifested by pancreatic protein secretion was equivalent in intestinal washes from atropine-treated and control Thiry-Vella fistula donor rats. Concentrated jejunal secretions had no trypsin inhibitory activity, indicating that the putative intestinal CCK-releasing peptide and “monitor peptide” are different substances.

Pancreatic protein hypersecretion and elevated plasma CCK: prerequisites for increased pancreatic growth?

This study was undertaken to establish if a correlation exists between chronic elevated pancreatic secretion and growth of the pancreas. Rats provided with jugular, pancreatic, biliary, duodenal, or ileal cannulas were fed throughout the experiment with a liquid diet continuously infused into the duodenum. Four days after surgery, control rats and those infused with cerulein (CE) 0.45 pgkg/h had their pancreatic juice returned into the duodenum. Two other groups had their pancreatic juice either totally diverted outside (DO) or returned into the ileum (DI). In all groups, bile was returned into the duodenum. Pancreatic juice was collected every 4 h for 4 days with volume and protein determined. After 4 days, rats were killed and their pancreata were evaluated for weight and contents of DNA, RNA, protein, amylase, and chymotrypsinogen. The average volumes/4 h were significantly increased by 259, 241, and 270% in DO, DI, and CE rats, respectively. Protein output remained at control levels in DO rats, whereas increases of 200 and 90% above control values were observed in DI and CE rats, respectively, during the last periods of collection. Constant drainage of pancreatic juice outside (DO) had no effect on pancreatic growth; on the contrary, its reinfusion into the ileum and constant cerulein infusion were associated with impressive growth of the pancreas, with cerulein being the most potent stimulus. In conclusion these data support the hypothesis that increased protein output is associated with pancreatic growth, a phenomenon mediated by endogenous cholecystokinin.

Modulation of the relationship between amylase and chymotrypsinogen secretion in atropine- and MK329-infused rats.

We demonstrated previously in ad libitum fed and fasted rats that chymotrypsinogen and amylase secretions were weakly or not at all correlated (1). However, the mechanisms controlling these correlations remain undetermined. We investigated the influences of cholinergic and cholecystokinin-related systems on the relationship between amylase and chymotrypsinogen in rats. Animals provided with pancreatic, biliary, duodenal, and jugular vein cannulas were kept in restraint cages under controlled temperature and humidity, with a regular 12-h light cycle, and divided into five groups. The first group of fed rats was constantly infused with 200 μg kg −1 h−1 atropine, the second with 0.5 mg kg−1 h−1 MK329, and the third with both. In the group in which both drugs were simultaneously infused, 500 μg kg−1 h−1 atropine was intraperitoneally administered, whereas MK329 was infused by intravenous cannula. Two groups consisted of fasted rats, of which one was also atropinized (100 μ,g kg−1 h−I). Three-day experiments were performed separately with fed rats, and 2-day experiments with fasted rats; atropine and/or MK329 infusion was constant over 48 h, in both fed and fasted rats. Atropine alone did not alter the correlation between enzymes even though the total protein and amylase outputs decreased, whereas the chymotrypsinogen output increased; MK329, slowly but significantly, increased the correlation between enzymes, whereas it decreased the outputs for all secretory parameters. When both antagonists were simultaneously infused in fed rats, correlation coefficients between amylase and chymotrypsinogen rapidly and markedly increased. In fasted rats, atropine infusion induced a tremendous decrease in total protein and amylase mean outputs but a significant increase in chymotrypsinogen output, without any significant change in the correlation between both enzymes. These results indicate that the nonparallel secretion of amylase and chymotrypsinogen is strongly modulated by a cholecystokinin-dependent mechanism and that this modulatory process is potentiated by the parasympathetic system.