Inhibitory effect of CR 1409 (cholecystokinin antagonist) on pancreatic exocrine secretion in rats

New cholecystokinin (CCK) receptor antagonist, CR 1409 (lorglumide), was evaluated for anti-CCK activity on pancreatic exocrine secretion in anesthetized rats in vivo, compared with proglumide. Both CR 1409 in a dose range of 0.04-25 mg/kg-hr and proglumide in a dose range of 30-600 mg/kg-hr given intravenously, showed significant inhibitory effect on pancreatic secretion in terms of juice volume and amylase output stimulated by intravenous CCK-8 (0.06 micrograms/kg-hr), in a dose-related manner. CR 1409 is about 1000 times more potent than proglumide, based on ED 50. Furthermore, intravenous administration of either CR 1409 (5 mg/kg-hr) or proglumide (600 mg/kg-hr) resulted in significant suppression on pancreatic secretion stimulated by intraduodenal casein in a dose of 400 mg/hr. Thus, very potent CCK receptor antagonist, CR 1409, inhibited pancreatic exocrine secretion stimulated by not only exogenous CCK, but also intraduodenal casein in rats.     

Somatostatin analog, SMS 201-995, inhibits pancreatic exocrine secretion and release of secretin and cholecystokinin in rats.

We studied the effect of a synthetic octapeptide somatostatin analog, SMS 201-995 (sandostatin), on pancreatic exocrine secretion and on plasma secretin and cholecystokinin (CCK) levels in vivo in anesthetized rats. The exocrine pancreas was stimulated by either intravenous infusion of both secretin (0.06 CU/kg/h) and cholecystokinin octapeptide (CCK-8) (0.03 micrograms/kg/h) or intraduodenal infusion of oleic acid (pH 6.5) in a dose of 0.25 mmol/h. Intravenous administration of SMS 201-995 in three different doses of 100, 200, and 400 ng/kg/h resulted in dose-related inhibition of pancreatic secretion in terms of volume, bicarbonate, and amylase stimulated by exogenous secretin and CCK. Intraduodenal oleic acid stimulated pancreatic secretion, including volume, bicarbonate, and amylase, and this was accompanied by a significant elevation in the plasma concentrations of secretin and CCK. Intravenous administration of SMS 201-995 in the three different doses described above caused dose-dependent suppression of the increase in pancreatic exocrine secretion as well as the plasma concentration of secretin and CCK induced by intraduodenal infusion of oleic acid. It is concluded that SMS 201-995 inhibits pancreatic exocrine secretion and the release of endogenous hormones, such as secretin and CCK, in rats.     

Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex

We have recently demonstrated that intraduodenal perfusion of trypsin inhibits phenylalanine-stimulated pancreatic enzyme secretion by suppression of release of cholecystokinin (CCK). It is not known whether trypsin in the duodenum inhibits pancreatic secretion stimulated by a cholinergic mechanism. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Volume and osmoreceptors in the duodenum, which are known to elicit pancreatic secretion through cholinergic pathways, were stimulated by infusing increasing volumes (1.0, 2.5, and 5.0 ml/min) of normal saline or increasing osmolality (300, 400, 500 mosmol) of NaCl solution. Increasing the rates of intraduodenal perfusion of normal saline or increasing the osmolality of the duodenal perfusates caused a dose-related increase in pancreatic trypsin and chymotrypsin outputs without affecting basal plasma CCK levels (0.9 +/- 0.1 pM). The volume- or osmolality-stimulated pancreatic secretions were abolished by atropine, but not by intraduodenal perfusion of trypsin. In contrast, intraduodenal perfusion of phenylalanine (10 mM) produced a significant increase in plasma CCK levels (6.7 +/- 0.8 pM) and a three- to fourfold increase in pancreatic enzyme outputs. Perfusion of the duodenum with bovine trypsin (1 g/L) reduced the plasma CCK levels to basal values and significantly attenuated the phenylalanine-stimulated enzyme secretion to 63% +/- 4% of control. Simultaneous administration of atropine and intraduodenal perfusion of trypsin completely abolished the pancreatic enzyme response to phenylalanine stimulation. These studies indicate that the intestinal phase of human pancreatic enzyme secretion is under both hormonal and neural control. Intraduodenal trypsin inhibits only pancreatic secretion mediated by CCK release, and not that mediated by cholinergic mechanisms. These observations suggest that feedback regulation of pancreatic enzyme secretion is stimulus specific.     

Effects of intraduodenal administration of a low dose of cholecystokinin (CCK) antagonist (CR-1505) on plasma CCK concentration,intestinal CCK content,and levels of CCK mRNA

The effects of the intraduodenal administration of a low dose of CR-1505 for 3–7 days on the gene expression of cholecystokinin (CCK), plasma CCK concentration, and CCK content in the intestinal mucosa were examined in rats. The simultaneous changes of protein and enzyme content in the pancreas were also determined. CR-1505 was infused continuously into the duodenum at a dose of 3 mg/kg per day, calculated to correspond to a dose of 150–200 mg/day in humans. Seven days after the administration of CR-1505, a liquid meal (4.5 kcal/3 ml) was introduced into the stomach and changes in the intestinal CCK content and plasma CCK concentration were examined. The level of CCK mRNA in the intestine was significantly higher in rats treated with CR-1505 than in control rats. The plasma CCK concentration, the CCK content of the intestinal mucosa, and the composition of pancreatic enzymes did not significantly differ in rats treated with CR-1505 and the untreated controls. In control rats, the administration of the liquid meal increased the plasma CCK concentration and significantly decreased the intestinal CCK content in water extracts, but did not affect the amount extracts in acid whereas the ingestion of the meal did not cause any significant changes in rats treated with CR-1505. These findings indicate that a low dose of CR-1505 stimulates the gene expression of CCK without enhancing CCK release or exerting an effect on the pancreas.     

Effects of trypsin inhibitor (camostate) on pancreas and CCK release in young and old female rats

Differences in pancreatic responses and CCK release to intragastric administration of a synthetic protease inhibitor (camostate) were examined in young (6-mo) and old (26-mo) female rats. When rats were sacrificed 1 hour after camostate administration (100 mg/kg), plasma CCK concentration significantly increased in both age groups and was significantly higher in young rats than in the old. Acute pancreatic responses to camostate were attenuated in old rats, compared with the young. On the other hand, 5-day administration of camostate (100 mg/kg, twice a day) increased pancreatic wet weight, chymotrypsin concentration and content in pancreas in both age groups, whereas lipase content did not increase in old rats although it significantly increased in young rats. Plasma CCK concentrations were not significantly different between young and old rats. It is concluded that the acute response of CCK release to camostate is attenuated in old rats, but the capability of chronic pancreatic adaptation of chymotrypsin content to camostate is well maintained in old rats.     

Role of cholecystokinin in pancreatic bicarbonate secretion in dogs

We investigated the effects of endogenous and exogenous cholecystokinin (CCK) on pancreatic exocrine secretion, in particular that of bicarbonate. In six dogs prepared with gastric cannulas and Thomas duodenal cannulas, intraduodenal administration of corn oil (Lipomul) incubated with hog pancreatic enzymes significantly increased pancreatic secretion of both bicarbonate and protein. Increase in pancreatic secretion of both bicarbonate and protein was accompanied by the increase in plasma CCK concentration. However, the increase in bicarbonate as well as protein secretion was blocked by proglumide, a CCK antagonist, given intravenously. In contrast, intraduodenal infusion of undigested Lipomul failed to stimulate the pancreatic exocrine secretion or release of endogenous CCK. These observations indicate that endogenous CCK plays an important role in secretion of both bicarbonate and protein stimulated by digested corn oil. In a group of four dogs with pancreatic fistulas, intravenous infusion of CCK potentiated the stimulatory effect of secretin on pancreatic bicarbonate secretion. The stimulatory effect as well as potentiating effect of CCK on pancreatic bicarbonate secretion was blocked by infusion of proglumide. We conclude that endogenous CCK plays a significant role in fat-stimulated pancreatic secretion, and it is apparent that both endogenous CCK and secretin are equally important for stimulation of pancreatic bicarbonate secretion, which results from potentiation of the action of the two hormones.     

Effects of intragastric and intrajejunal ethanol administration on canine pancreatic exocrine secretion and duodenal pH

The effect of ethanol on pancreatic exocrine secretion and intraduodenal pH was investigated in 3 dogs, after making pancreatic, gastric, and jejunal fistula. After intragastric and intrajejunal administration of ethanol the intraduodenal pH went down and pancreatic juice, pancreatic bicarbonate output was increased. The integrated value of pancreatic juice, pancreatic bicarbonate and pancreatic protein output was greater in case of intrajejunal administration rather than intragastric administration of the ethanol. After intragastric and intrajejunal administration of the ethanol the plasma concentration of CCK was unchanged. The decrease of intraduodenal pH and increase of pancreatic exocrine secretion was though be mainly due to the secondary action of gastric acid secretion stimulated by ethanol.     

Endogenous CCK release and pancreatic growth in rats after feeding a proteinase inhibitor (camostate)

The serine proteinase inhibitor camostate was fed to rats in single, daily doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg for 5, 10, or 15 days. Within 5 days, pancreatic size and protein, DNA, and enzyme content increased significantly. After prolonged administration, this trophic effect was more pronounced, and anticoordinate regulation of the synthetic rate of individual secretory proteins was observed. While enzyme content and protein synthesis of trypsinogen and chymotrypsinogen were increased, respective values for amylase were drastically reduced. Plasma levels of cholecystokinin (CCK) did not differ from controls when measured 24 h after administration of camostate. Immediately after oral feeding of camostate, CCK levels increased 10-fold above controls, reached a maximum after 90 min, and remained elevated for more than 6 h. Proglumide, a CCK-receptor antagonist, only slightly reduced the trophic action of the proteinase inhibitor. The data indicate that endogenous CCK release by a proteinase inhibitor is as potent in the modulation of pancreatic growth and individual enzyme synthesis as exogenous hormone application.     

Role of cholecystokinin in cholestyramine-induced changes of the exocrine pancreas

This study was an investigation of the role of cholecystokinin (CCK) in the stimulatory action of cholestyramine on rat exocrine pancreas. Postprandial CCK release was significantly enhanced by acute administration of cholestyramine (12.7 +/- 1.8 vs 3.7 +/- 0.5 pmol/L in controls). Over four weeks, rats were fed either regular diet or diet containing 6% cholestyramine, and were treated with the specific CCK receptor antagonist L-364,718 (2 x 0.5 mg/kg body weight/day s.c.) or DMSO (vehicle for the antagonist). Cholestyramine significantly increased pancreatic weight and trypsin and chymotrypsin contents. L-364,718 abolished these effects. Concomitant administration of antagonist and cholestyramine elevated amylase content, compared to controls. CCK levels in fasted animals did not differ between the four groups. The effect of the same dose of L-364,718 on pancreatic enzyme depletion, induced by the protease inhibitor camostate, was studied in a control experiment. A single dose of camostate (200 mg/kg) caused a 44-68% decrease in enzyme content. L-364,718 reversed this effect for all enzymes. We conclude that CCK is the mediator of cholestyramine-induced pancreatic hypertrophy and increase in content of proteases. After long-term administration, the CCK receptor antagonist, in combination with cholestyramine revealed an agonistic effect on individual, pancreatic enzyme content.     

Inhibitory effects of octreotide on luminal cholecystokinin-releasing factor, plasma cholecystokinin, and pancreatic secretion in conscious rats

INTRODUCTION: Luminal cholecystokinin-releasing factor (LCRF), purified from rat intestinal secretions, is an intraluminal regulator of cholecystokinin (CCK) secretion during bile and pancreatic juice diversion. AIM: Because the LCRF content was not influenced by intravenous administration of atropine or somatostatin, the inhibitory effect of a potent somatostatin analog octreotide on LCRF content, the plasma CCK level, and pancreatic secretion was examined. METHODOLOGY: Rats were prepared with bile and pancreatic cannulae and two duodenal cannulae and with an external jugular vein cannula. After 1.5-hour basal collection, bile and pancreatic juice was diverted for 2 hours, during which octreotide was infused intravenously or into the duodenal lumen. The changes in pancreatic secretion were recorded for 2 hours, and the plasma CCK level and LCRF content 2 hours after the treatment were measured. RESULTS: Bile and pancreatic juice diversion significantly increased pancreatic secretion and plasma CCK and LCRF levels. Intravenous infusion of octreotide (0.2 and 0.5 nmol/kg/hour) inhibited all parameters. Intraduodenal infusion of a lower dose of octreotide (33 nmol/kg/hour) inhibited pancreatic secretion, but did not inhibit CCK release or LCRF content. The higher doses (100 and 300 nmol/kg/hour) inhibited all parameters. CONCLUSION: Intravenous and intraduodenal administrations of octreotide inhibited CCK release and LCRF content and pancreatic secretion induced by bile and pancreatic juice diversion.     

Effect of intraduodenal oligopeptide on rat pancreatic exocrine secretion and release of secretin and CCK]

We investigated whether intraduodenal (id) oligopeptide with three or four amino acids residues (pH 7.0) stimulates pancreatic exocrine secretion and release of endogenous plasma secretin and CCK in anesthetized rats. Id administration of oligopeptides in three doses (25, 100, 400 mg/hr) at a speed of 4 ml/hr resulted in dose-related increases in pancreatic secretion of pancreatic juice volume, bicarbonate, and amylase outputs (r = 0.598, 0.673, and 0.426, P less than 0.05 -- 0.001), and plasma concentrations of secretin and CCK (r = 0.743, 0.425, P less than 0.001 and 0.05). Intravenous administration of CCK-antagonist, CR1505 (5 mg/kg.hr) markedly inhibited oligopeptide-stimulated amylase output, but did not affect pancreatic juice volume and bicarbonate output. These results suggest that id oligopeptide increases pancreatic exocrine secretion and releases endogenous secretin and CCK.     

Effects of secretin and caerulein on luminal feedback regulation of pancreatic enzyme secretion in rats

The stimulatory pancreatic response to exclusion of pancreatic proteases from the intestine was compared with the response to stepwise increasing doses of secretin and caerulein in conscious rats. Secretin stimulated pancreatic fluid secretion in a dose-related manner with or without intraduodenal return of pancreatic juice, while it could not significantly affect enzyme secretion. The dose response curve for enzyme secretion to caerulein was smooth during return of the juice. However, the already increased enzyme secretion by pancreatic juice diversion was only stimulated with the smallest dose of caerulein. The maximal dose of caerulein for enzyme secretion during return had been supramaximal dose during diversion. Intraduodenal trypsin inhibitor failed to stimulate enzyme secretion during diversion but induced the same stimulatory effect as the submaximal dose of caerulein during return. Different doses of intraduodenal trypsin caused an almost dose-related inhibition. It is concluded that a submaximal level of endogenous CCK might participate in the feedback regulation of pancreatic enzyme secretion in rats.     

Circulating ethanol does not stimulate pancreatic secretion in conscious rats

The purpose of this study was to test the hypothesis that circulating ethanol at concentrations of approximately 0.1 mg% stimulates pancreatic secretion. Awake rats recovered from surgery were used in these experiments. Intravenous infusion protocols were established that produced blood ethanol concentrations 0.1 mg% for over an hour. Maintenance of 0.1 mg% blood ethanol concentration or transient concentrations as high as 0.17 mg% did not cause significant increases in pancreatic protein or fluid secretion. To test whether elevated blood ethanol would augment stimulated pancreatic secretion, the trypsin inhibitor camostat was infused intraduodenally at doses of 0.05, 0.2, and 0.5 mg/hr, each dose level infused for 2 hours. Elevated blood ethanol concentrations (0.1 mg%) did not significantly affect camostat-stimulated pancreatic protein or fluid secretion. In contrast to intravenous infusion, intraduodenal infusion of ethanol significantly stimulated pancreatic protein and fluid secretion, which was associated with blood ethanol concentrations of > or =0.19 mg%. The increases in pancreatic secretion were completely blocked by intravenous infusion of the cholecystokinin (CCK) receptor antagonist CR1409. We conclude that circulating ethanol does not stimulate pancreatic secretion in awake, recovered rats and that intraduodenal ethanol-stimulated pancreatic secretion is mediated by CCK.     

Effect of atropine on responses of exocrine pancreas and plasma cholecystokinin to intraduodenal amino acids in dogs

The effect of atropine on responses of exocrine pancreas and plasma cholecystokinin (CCK) to intraduodenal mixed amino acids has been studied in conscious dogs with Thomas gastric and duodenal fistulae. Intraduodenal amino acids provoked significant increase of pancreatic protein output and of plasma CCK concentration. Atropine significantly reduced protein output only in the initial peak after amino acid administration. Atropine had no significant effect on plasma CCK. It is indicated that cholinergic nerves predominate in the early pancreatic protein response to intraduodenal amino acids and CCK prevails in the later phase, though these two factors do not seem to be the only factors responsible for the secretion.     

Pancreatic polypeptide release: role of stimulants of exocrine pancreatic secretion in dogs

There are apparent similarities in the mechanisms of the intestinal phase of exocrine and pancreatic polypeptide (PP) secretion by the pancreas. To characterize this relationship, we measured incremental responses of protein, bicarbonate, and PP to graded doses of intravenous secretin, caerulein, CCK8, CCK33, bethanechol, and intraduodenally perfused HCl, sodium oleate, and L-phenylalanine in dogs with gastric and pancreatic fistulas and compared them with average postprandial values. Secretin did not release PP at any dose studied, whereas intraduodenal HCl increased PP levels slightly at a load maximal for pancreatic secretion. Caerulein produced dose-related increases in PP secretion (maximal, 106% of meal response) but CCK8 and CCK33 had much less effect at doses equivalent for protein secretion. Bethanechol was a weak stimulant for PP only at the largest tolerable dose. L-Phenylalanine and sodium oleate markedly increased protein secretion, but only oleate clearly stimulated PP. Our results suggest a greater quantitative importance of the intestinal phase for exocrine than endocrine (PP) pancreatic secretion.     

Differential effects of atropine and a cholecystokinin receptor antagonist on pancreatic secretion

The present study evaluates the effect of atropine and of the cholecystokinin receptor antagonist loxiglumide on feedback regulation of basal pancreatic secretion in 6 healthy volunteers. The intraduodenal instillation of the protease inhibitor camostate reduced enzymatic activities of trypsin and chymotrypsin by 80%. This was accompanied by a strong increase in amylase and lipase output. The intravenous infusion of atropine (5 micrograms/kg.h) completely abolished the stimulatory effect of camostate on enzyme output. The infusion of loxiglumide (10 mg/kg.h) caused no changes in camostate-induced stimulation of enzyme output. Plasma levels of cholecystokinin were not altered after intraduodenal instillation of camostate whether atropine, loxiglumide, or saline were infused. We suggest that the protease inhibitor camostate, by inhibition of the enzymatic activity of trypsin and chymotrypsin, interferes with feedback regulation of basal pancreatic secretion in humans, and this mechanism is predominantly mediated by the cholinergic system.     

Effect of CCK antagonists CR 1409 and CR 1505 on rat pancreatic exocrine secretion in vivo

The action of cholecystokinin (CCK) antagonists CR 1409 and CR 1505 on pancreatic exocrine secretion stimulated by exogenous and endogenous CCK was studied in vivo in anesthetized rats, and compared with proglumide. Intravenous administration of CR 1409 and CR 1505 in graded doses between 0.04 and 25 mg/kg/h resulted in a dose-dependent inhibition in pancreatic juice volume and amylase output stimulated by intravenous infusion of CCK-8 in a dose of 0.06 microgram/kg/h. CR 1409 is 1,000 times and CR 1505 is 267 times more potent than proglumide, based on the ED50 (effective dose for half-maximal inhibition) for CCK-8-stimulated amylase secretion. Intraduodenal administration of casein in a dose of 400 mg/h caused significant increases in plasma CCK concentration and pancreatic secretion of juice volume and outputs of amylase and trypsin. Both CR 1409 and CR 1505 in a dose of 5 mg/kg/h suppressed the increases in pancreatic juice volume and both amylase and trypsin outputs induced by casein given intraduodenally. These results indicate that CCK antagonists including CR 1409, CR 1505, and proglumide inhibit pancreatic exocrine secretion stimulated by not only exogenous, but also endogenous CCK in rats.     

Oxyntomodulin inhibits pancreatic secretion through the nervous system in rats

Glicentin (GLIC), oxyntomodulin (OXM), and peptide YY (PYY) released in blood by ileocolonic L-cells after meals may inhibit pancreatic secretion. Whereas OXM interacts with glucagon and tGLP-1 receptors, OXM 19-37, a biologically active fragment, does not. The purpose of this study was to measure the effect of OXM, OXM 19-37, GLIC, tGLP-1, and PYY on pancreatic secretion stimulated by 2 deoxyglucose (2DG), electrical stimulation of the vagus nerves (VES), acetylcholine and cholecystokinin octapeptide (CCK8) in anesthetized rats. The effect of OXM was also studied in dispersed pancreatic acini. Plasma oxyntomodulin-like immunoreactivity (OLI) was measured by radioimmunoassay after the exogenous infusion of OXM and after an intraduodenal meal. OXM 19-37, infused at doses mimicking postprandial plasma levels of OLI, decreased pancreatic secretion stimulated by 2DG, VES, or CCK8. Similar effects were found with OXM and GLIC. OXM 19-37 did not change the pancreatic stimulation induced by acetylcholine in vivo, or CCK-induced amylase release in isolated acini. Vagotomy completely suppressed the inhibitory effect of OXM 19-37 on CCK8-stimulated pancreatic secretion. PYY inhibited the effect of 2DG, but not that of CCK8, whereas tGLP-1, even in pharmacologic doses, had no effect on stimulated pancreatic secretion. OXM, OXM 19-37, but not tGLP-1, inhibit pancreatic secretion at physiologic doses, through a vagal neural indirect mechanism, different from that used by PYY, and probably through a GLIC-related peptide-specific receptor.     

Dissociation of cholecystokinin and pancreaticobiliary response to intraduodenal bile acids and cholestyramine in humans

The role of intraduodenal bile acids in the regulation of cholecystokinin (CCK), pancreatic polypeptide (PP), and secretin as well as exocrine pancreatic and biliary secretion was investigated by means of a duodenal marker perfusion technique in volunteers. The following solutions were perfused: (1) liquid test meal, (2) test meal with 6 g cholestyramine, (3) test meal with 2 g chenodeoxycholic acid (CDC), (4) test meal with 6 g cholestyramine and 2 g CDC, (5) 6 g cholestyramine alone, and (6) 2 g CDC alone. The test meal caused an immediate increase in CCK and PP plasma levels, whereas secretin was not significantly altered. CCK release was further enhanced by addition of cholestyramine, whereas CDC inhibited release. The stimulatory effect of cholestyramine was abolished by CDC. CDC alone and in combination with the test meal stimulated secretin release. The response of PP to the test meal was not altered by addition of either compound. Cholestyramine and CDC alone caused only a very small increase in CCK levels, whereas PP was stimulated to nearly postprandial values. Meal-stimulated pancreatic and biliary secretion was significantly enhanced by cholestyramine, CDC, and the combination of both. CDC and cholestyramine alone each stimulated enzyme and bile secretion to a greater extent than the test meal. We conclude that intraduodenal bile salts are a modulator of postprandial CCK release. Changes in exocrine pancreatic and biliary and PP secretion do not necessarily parallel CCK concentrations, suggesting that different mediators are involved in the observed bile acid-induced changes in humans.     

Postprandial release of cholecystokinin after duodenum-preserving total pancreatectomy is independent of intraluminal pancreatic protease activity in dogs

The effect of meal stimulation, with and without the intraduodenal presence of pancreatic enzymes, on plasma cholecystokinin (CCK) release was studied in order to investigate the role of CCK in the putative feedback mechanism between intraduodenal pancreatic proteases and pancreatic enzyme secretion. Plasma CCK concentrations in response to a semiliquid meal, with and without the supplementation of exocrine pancreatic enzymes, were measured in 8 dogs after duodenum preserving pancreatectomy. With a well-balanced endocrine and exocrine substitution regimen all dogs were kept in good clinical condition, without steatorrhea or significant weight loss, and fasting plasma glucose levels within the normal range. Exocrine supplementation was stopped at least 3 days prior to tests. Basal plasma CCK levels after 3 days without exocrine supplementation (2.5 +/- 0.3 pM) did not significantly differ from the results with supplementation (3.0 +/- 0.5 pM) nor from the preoperative levels (2.3 +/- 0.3 pM). In addition, integrated plasma CCK responses to the meal without exocrine supplementation (330 +/- 37 pM.90 min) were not significantly different from the responses to the meal with exocrine supplementation (303 +/- 49 pM.90 min), or from the postprandial CCK response in the dogs with an intact pancreas preoperatively (390 +/- 100 pM.90 min). It is concluded that the release of CCK in dogs after total pancreatectomy is independent of intraluminal protease activity. It is therefore not likely that CCK mediates the putative feedback mechanism between intraluminal protease activity and pancreatic enzyme secretion in dogs.