Role of secretin and CCK in the stimulation of pancreatic secretion in conscious dogs. Effects of atropine and somatostatin

The role of gut hormones, such as secretin and CCK, in the stimulation of pancreatic secretion by duodenal HCl or oleate and by meat feeding has been studied in conscious dogs before and after pretreatment with atropine and somatostatin. Plasma hormones were measured by specific and sensitive radioimmunoassays. Duodenal perfusion with HCl and oleate stimulated dose-dependently pancreatic HCO3 and protein secretion and raised plasma levels of secretin and CCK, respectively. Atropine reduced significantly both HCO3 and protein secretion but did not affect plasma secretin and CCK levels in these studies. Both exocrine pancreatic secretion and plasma secretin and CCK levels were suppressed by somatostatin. Meat feeding caused a marked pancreatic HCO3 and protein secretion accompanied by a significant increase in plasma secretin and CCK which seem to play an important role in the postprandial pancreatic stimulation. Both atropine and somatostatin reduced the pancreatic secretion induced by exogenous hormones but only somatostatin, but not atropine, significantly decreased plasma secretin and CCK responses to intestinal stimulants. We conclude that both atropine and somatostatin reduce the pancreatic responses to duodenal HCl or oleate or to meat feeding but only somatostatin is capable of suppressing the release of secretin and CCK.     

Effect of L-364,718 on GRP-stimulated pancreatic and gastric secretions and GI peptides in conscious dogs

The effect of L-364,718, a cholecystokinin (CCK) receptor antagonist, on exocrine pancreatic secretion, gastric secretion, and plasma levels of gastrointestinal (GI) peptides stimulated by gastrin-releasing peptide (GRP) was examined in five conscious dogs. Intravenous infusion of graded doses of synthetic porcine GRP (18, 36, and 178 pmol/kg/h) caused significant and dose-dependent increases in pancreatic and gastric juice secretion and in plasma levels of pancreatic polypeptide (PP), CCK, and gastrin. Intravenous injection of L-364,718 (20 nmol/kg) significantly inhibited GRP-stimulated pancreatic outputs of juice volume, protein, and amylase and plasma PP release. L-364,718, however, did not affect gastric juice volume and plasma levels of CCK and gastrin. The results suggest that endogenously released CCK is, at least in part, responsible for GRP-stimulated pancreatic protein and enzyme secretions and PP release in dogs. The results further suggest that GRP-stimulated pancreatic secretion might be, in part, a direct response of GRP to exocrine pancreas.     

Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats

Nitric oxide (NO) is one of the important biologic mediators in regulation of gastrointestinal (GI) functions, but the influence of NO on the release of secretin and cholecystokinin (CCK) and exocrine pancreatic secretion has not been adequately investigated in the rat. The aim of this study was to determine the role of NO on endogenous and exogenous secretin- or CCK-stimulated pancreatic exocrine secretion both in anesthetized and conscious rats. Experiments were carried out in four different groups of rats with duodenal pancreatobiliary cannulas and jugular vein catheters. Group 1: During duodenal infusion of 0.05N HCl or 15% casein (pH 7.0), N-nitro-L-arginine (NNA), an inhibitor of NO-synthase in graded doses (2.5, 5, 10 mg/kg/h), was infused intravenously. Group 2: One hour after starting intravenous secretin at 5 pmol/kg/h or intravenous CCK-8 at 0.06 microg/kg/h, NNA in graded doses was administered intravenously. Group 3: In conscious rats, NNA (5 mg/kg/h) was given intravenously for 1 hour after a meal. Group 4: L-Arginine at 100 mg/kg/h was infused intravenously during the period of NNA (5 mg/kg/h) infusion in groups 1, 2, and 3. Pancreatic juice was collected at 30-minute intervals to measure volume, as well as output of bicarbonate and protein. At the end of the experiment, plasma secretin, vasoactive intestinal polypeptide (VIP) and CCK levels were determined by radioimmunoassay (RIA). NNA dose dependently inhibited the pancreatic secretion of fluid and bicarbonate stimulated by duodenal acidification, exogenous secretin, and a meal. NNA dose dependently inhibited the pancreatic secretion of protein stimulated by duodenal infusion of casein, exogenous CCK, and a meal. L-Arginine significantly reversed the NNA-induced inhibition of pancreatic secretion in all experiments. NNA did not alter significantly the plasma levels of secretin, VIP, and CCK. Our results indicated that endogenous NO plays a significant role in the regulation of pancreatic exocrine secretion stimulated by secretin and CCK. However, NO does not influence the release of secretin, VIP, or CCK in the rat.     

Effect of total extrinsic denervation and atropine on HCl-stimulated pancreatic exocrine secretion and CCK release in conscious dogs.

In 10 dogs with pancreatic fistulas, we studied the effect of extrinsic pancreatic innervation and atropine on protein and bicarbonate secretion and cholecystokinin (CCK) release after intraduodenal perfusion with HCl. Before and after extrinsic denervation of the pancreas, the dogs were given 0.05 M HCl in increasing doses (1.5-48 mmol/h). Tests were repeated with atropine. Increasing doses of HCl resulted in a dose-dependent release of protein and bicarbonate output in both the intact and the denervated pancreas. However, pancreatic denervation significantly decreased pancreatic secretion in response to low loads but not to high loads of HCl. HCl-stimulated CCK release was not altered by pancreatic denervation. In the intact pancreas, atropine significantly reduced bicarbonate and protein response to low loads but not to high doses of HCl. In the denervated gland, atropine had no further inhibitory effect on exocrine pancreatic secretion. Furthermore, atropine showed no influence on HCl-stimulated CCK release under either condition.     

Cholinergic component in the human pancreatic secretory response to intraintestinal oleate.

To determine the role of cholinergic reflexes on pancreatic secretory response to food, we studied the effect of atropine on amylase secretion in response to the octapeptide of cholecystokinin (CCK8) and to intraintestinal oleate. Four studies were done in six healthy volunteers. The duodenal content was aspirated by a double lumen tube while synthetic secretin (41 pmol/kg/h) was infused as a background in all the studies. Graded doses of CCK8 IV or 0.42 M oleate pH 9.4 at 25 ml/h into the intestine with and without atropine 1.8 mg were given on different days. CCK-like immunoreactivity (LI) in the plasma was measured by RIA during the intraintestinal oleate studies. CCK8 stimulated pancreatic enzyme secretion in a dose related fashion, an effect that was not modified by atropine. Intraintestinal oleate also stimulated pancreatic secretion and increased the CCK-LI in the plasma. Atropine significantly (p less than 0.05) decreased the pancreatic enzyme secretion before and during intraintestinal oleate, without effect on the CCK-LI levels. We conclude: (1) that the effect of exogenous CCK on pancreatic secretion of enzymes is not affected by atropine; (2) intraintestinal oleate stimulates pancreatic enzyme secretion significantly by an atropine-sensitive mechanism; (3) probably the atropine effect is a blockade of a cholinergic enteropancreatic reflex.     

Potentiating effect of secretin on cholecystokinin-stimulated exocrine pancreatic secretion in rats

The potentiating effect of secretin on cholecystokinin (CCK)-stimulated exocrine pancreatic secretion was studied in anesthetized rats. Intravenous infusion of CCK-8 in three different doses of 0.03, 0.06 and 0.12 micrograms/kg-hr increased pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs dose-dependently. Simultaneous infusion of CCK-8 with secretin in a dose of 0.03 CU/kg-hr produced statistically greater pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs than that by CCK-8 alone, and than the sum by secretin alone and CCK-8 alone in each dose. Proglumide (600 mg/kg-hr) significantly suppressed exocrine pancreatic secretion produced by CCK-8 (0.06 micrograms/kg-hr) plus secretin (0.03 CU/kg-hr), to the level induced by secretin alone. These results indicate that CCK-8 increased pancreatic secretion dose-dependently, and secretin in a physiological dose potentiates the stimulating effect of CCK-8 on exocrine pancreatic secretion in rats.     

Subtypes of muscarinic receptors in canine pancreatic secretion in vivo and in vitro

In conscious dogs with esophageal, gastric and pancreatic fistulae, sham-feeding and meat feeding increased the pancreatic protein secretion to a peak, reaching about 39% and 69% of CCK8 maximum, and raised plasma pancreatic polypeptide (PP) levels. Pirenzepine given intravenously (i.v.) (30 nmol.kg-1 or 3 mumol.kg-1) reduced dose-dependently the pancreatic protein and plasma PP responses to sham-feeding and meat feeding, being about 100 times less potent as an inhibitor than atropine. Neither pirenzepine nor atropine affected near-maximal pancreatic bicarbonate and protein responses to secretin (164 pmol.kg-1.h-1) and CCK8 (170 pmol.kg-1.h-1), but both antimuscarinic agents significantly inhibited pancreatic responses to lower doses of these secretagogues. When added to the incubation medium of dispersed canine pancreatic acini, pirenzepine reduced dose-dependently the amylase responses only to urecholine, and not to CCK or gastrin, being about 1000 times less potent as an inhibitor than atropine. This report provides an evidence that pirenzepine inhibits pancreatic secretion in a similar manner to atropine, but that pirenzepine, in both in vivo and in vitro studies, is 2-3 orders of magnitude less potent as an inhibitor than atropine, indicating that the muscarinic pathway of the exocrine pancreas has a low affinity for pirenzepine and may thus involve M2-receptors.     

L-364,718, a new CCK antagonist,inhibits postprandial pancreatic secretion and PP release in dogs

The effects of L-364,718, a new CCK receptor antagonist, on food-stimulated exocrine pancreatic secretion and plasma levels of PP, insulin, CCK, and gastrin were examined in four conscious dogs with pancreatic fistulas. Intravenous injections of L-364,718 (20 nmol/kg) significantly inhibited pancreatic protein and enzyme responses by food (33% inhibition) but not juice volume output. Both rapid and secondary prolonged postprandial rises of plasma PP were also significantly suppressed by L-364,718 (50% inhibition); however, plasma levels of insulin were not altered. Postprandial levels of gastrin were not affected by L-364,718 administration, whereas 3-hr integrated CCK response was significantly enhanced by L-364,718. This study indicates that L-364,718 inhibits pancreatic protein and enzyme secretion and the release of pancreatic polypeptide stimulated by food in conscious dogs. This inhibition might be due to the selective blockage of receptor binding of circulating CCK molecules. The results suggest that L-364,718 may be useful for the physiological and pathophysiological studies associated with CCK.     

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.     

Effect of pancreatic proteases on plasma cholecystokinin, secretin, and pancreatic exocrine secretion in response to sodium oleate

The effect of pancreatic proteases or juice on the sodium oleate-stimulated pancreatic secretion and plasma concentrations of secretin and cholecystokinin in anesthetized rats was investigated. Each rat received sodium oleate in a dose of 0.12 mmol.h-1 via a duodenal tube. Sodium oleate infusion significantly increased pancreatic secretion (volume and protein output) compared with the saline given the control group. The increase in pancreatic secretion paralleled significant elevations of plasma concentrations of secretin and cholecystokinin. To determine a possible role of pancreatic proteases on the responses induced by sodium oleate, saline, chymotrypsin, and trypsin, a combination of chymotrypsin and trypsin or pancreatic juice was infused into the duodenum. The pancreatic secretion was significantly reduced by pancreatic proteases or pancreatic juice, and the reduction paralleled the decreases in plasma concentrations of the two hormones. These agents suppressed both pancreatic secretion and plasma hormone levels in the following order of magnitude: (pancreatic juice or chymotrypsin + trypsin) greater than (trypsin) greater than (chymotrypsin). The reduction of pancreatic secretion by pancreatic proteases was reversed by intravenous administration of secretin and cholecystokinin in physiological doses. It is concluded that negative-feedback regulation of pancreatic secretion is operative in the intestinal phase in rats and that both secretin and cholecystokinin are involved in the regulation.     

The trophic effect on the pancreas of long-term continuous intravenous infusion of secretin and a cholecystokinin-like peptide in rats

Rats were treated for 5 days with continuous intravenous infusion of different doses of secretin and Thr28Nle31CCK25-33 (CCK-LP) alone and combined. The trophic effect on the pancreas was evaluated by means of pancreatic weight and contents of DNA, RNA, and protein. The acute effects on pancreatic protein secretion were studied in anesthetized rats. The findings generally confirmed the trophic effects of secretin and CCK-like peptides on the pancreas. No convincing evidence of potentiation was found between small doses of secretin and CCK-LP for either pancreatic growth or protein secretion. The maximal dose of CCK-LP was the same for pancreatic growth and for protein secretion (2.5 micrograms/kg-h). Potentiation was demonstrated between secretin and the maximal dose of CCK-LP for protein secretion. The maximal effect of CCK-LP on pancreatic growth, however, was not enhanced by secretin.     

Effect of synthetic human cholecystokinin-33 on pancreatic blood flow in dogs

We have examined the effect of synthetic human cholecystokinin (CCK-33 and CCK-8) on pancreatic blood flow and protein output in anesthetized dogs. Human CCK-33 and CCK-8 increased pancreatic blood flow and protein output in a dose-related manner. There were no significant differences in increasing pancreatic blood flow between human CCK-33 and CCK-8, and increases in blood flow were closely related to the increase of the pancreatic enzyme secretion. L-364,718 (20 nmol/kg) caused a potent inhibition of CCK-stimulated pancreatic blood flow as well as protein output. The degree of inhibition by L-364,718 was dependent on the amount of CCK infused. This study demonstrates that increasing effect on pancreatic blood flow may be one of the biological actions of CCK mediated via CCK receptor. The CCK-33, one of longer molecular forms of CCK, is an important biological stimulator of pancreatic blood flow as well as of exocrine pancreatic secretion.     

Effect of ninety-five percent pure cholecystokinin on gastrin-stimulated acid secretion in man and dog.

In 5 human subjects, 95% pure cholecystokinin (CCK) given as a background infusion in doses of 42, 84, or 168 pmol kg-1 h-1 did not significantly alter acid secretion in response to graded doses (11-300 pmol kg-1 h-1) of synthetic human gastrin-17-I. The 168 pmol kg-1 h-1 dose of CCK produced maximal pancreatic amylase output. In 3 subjects, 337 pmol kg-1 h-1 of CCK slightly stimulated acid secretion when given alone and tended to reduce acid secretion in response to gastrin, but each of the subjects experienced cramping abdominal pain. The increment in acid secretion produced by CCK alone was similar to that produced by maximally effective doses of carboxyl-terminal octapeptide of CCK. In dogs with gastric and pancreatic fistulas, 168 pmol kg-1 h-1 of CCK produced maximal pancreatic protein output and slightly stimulated gastric acid secretion. In dogs with gastric fistulas and Heidenhain pouches, the lowest dose of CCK that inhibited gastrin-stimulated acid secretion was 674 pmol kg-1 h-1. We conclude that in man and dog 95% pure CCK weakly stimulates gastric acid secretion and inhibits gastrin-stimulated acid secretion but these actions occur only with doses of CCK that are maximal or supramaximal for pancreatic enzyme secretion. Because of the high dose requirement, these effects are unlikely to be physiologically significant.     

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 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. 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 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. 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.     

Development and regulation of porcine pancreatic function

Summary A surgical and experimental procedure was developed to enable the collection of pure and inactivated pancreatic juice during the growth of the pig. Studies have shown that, during the suckling period, both the basal and the secretory responses to suckling are low, if present at all. After weaning, basal levels of the total exocrine secretion, total protein, amylase, and trypsin, respectively, increase slightly, while the postprandial levels of total protein, amylase, trypsin, lipase, colipase, and carboxylester lipase, respectively, increase markedly. The pancreatic juice enzyme composition changes qualitatively and the antibacterial activity of the pancreatic juice also significantly increases. Piglet age appeared to be of minor importance, since weaning at either 4 or 6 wk of age gave the same results. Secretin and CCK administered together in supraphysiological doses only significantly affect exocrine function from 3–4 wk of age. However, CCK may also affect the exocrine pancreas indirectly via reflexes initiated intraduodenally. Milk consumption in the suckling pig leads to a postprandial increase in glucose levels but not insulin. Milk, appears to be able to regulate the exocrine pancreas to produce only the amount and type of enzymes required for digestion. Thus, milk components or digestive products may affect pancreas function regulation. Studies show that enterostatin, the procolipase activation peptide, may inhibit pancreatic secretion mediated indirectly through the GI tract. Pancreastatin, an endocrine peptide, inhibits both insulin secretion and protein and trypsin secretion to pancreatic juice. In hypoinsulinemic (alloxan + streptozotocin diabetes) pigs (15–20 kg), no postprandial pancreatic juice response is seen, although CCK 33 + secretin can stimulate pancreatic secretion. Hypoinsulinemic pigs have a reduced capacity for glucose tissue utilization, suggesting that tissue metabolism and exocrine pancreas secretion are related.     

Stimulatory effect of hypercalcemia on pancreatic secretion is prevented by pretreatment with cholecystokinin and cholinergic agonists

Recently, we demonstrated that hypercalcemia causes marked stimulation of feline exocrine pancreatic secretion, and that this effect is absent when a large dose of cholecystokinin (CCK) is infused prior to induction of hypercalcemia. To investigate this effect in more detail, anesthetized cats were given calcium i.v. after preadministration of CCK or urecholine (a cholinergic agonist) at specific doses, or of saline as a control. We found that the hypercalcemia-induced stimulation of pancreatic protein secretion was abolished after preadministration of CCK at large doses. After the prestimulus dose was decreased or the calcium dose was increased, however, the pancreatic secretory response to hypercalcemia was preserved. In contrast, the response to a submaximal dose of CCK was unchanged after prestimulation with a large dose of CCK. Similar results were obtained when urecholine instead of CCK was used as prestimulus. These findings indicate that loss of pancreatic responsiveness to hypercalcemia following prestimulation with CCK is dependent on doses of both prestimulus and calcium used, and that it is not specific for prestimulation with CCK but also inducible by cholinergic agonists. They further suggest that this phenomenon is not due to exhaustion of pancreatic secretory capacity, but may reflect decreased sensitivity to the hypercalcemic stimulus instead.     

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?μmol kg ^?1 , which would block the CCK‐B receptors, or a 1000 times higher dose (300?μmol 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.     

Effects of C-terminal fragments of cholecystokinin on exocrine and endocrine secretion from isolated perfused rat pancreas

The ability of various C-terminal fragments of cholecystokinin (CCK) to increase pancreatic exocrine and endocrine secretion was examined in the isolated perfused rat pancreas. CCK octapeptide (CCK-8) induced biphasic dose-response curves for stimulation of pancreatic juice and amylase secretion. Maximal pancreatic juice and amylase output were obtained with 100 pM CCK-8. Concentrations of CCK-8 that caused pancreatic exocrine secretion also increased insulin release in the presence of 8.3 mM glucose. The tetrapeptide of CCK also simultaneously stimulated both exocrine and endocrine secretion, but was about 100,000 times less potent than CCK-8. By contrast both deca- and tetradecapeptide of CCK at a concentration of 100 pM stimulated secretion of pancreatic juice and amylase, and elicited insulin release comparably to CCK-8. The complete CCK-8 sequence was required as deamidated CCK-8 was without effects on exocrine and endocrine pancreatic secretion at a concentration of 100 pM. The present observations suggest that the structural requirements for CCK-induced insulin secretion are the same as those for CCK-induced exocrine secretions, and that the amino acids in position 5-8 and the amidated residue on the C-terminus are required for physiological activity of CCK on both the exocrine and endocrine pancreas. It is concluded that C-terminal fragments of CCK with eight or more amino acid residues are potent potentiators of insulin release as well as pancreatic exocrine stimulants.     

Comparison of loxiglumide, a cholecystokinin receptor antagonist, and atropine on hormonal and meal-stimulated pancreatic secretion in man

The effects of loxiglumide, a potent cholecystokinin (CCK)-receptor antagonist, and atropine, a muscarinic receptor blocker, on exocrine pancreatic secretion stimulated by hormones (secretin plus CCK) and a Lundh test meal were studied in healthy young volunteers. Loxiglumide infused intravenously in gradually increasing doses (2-16 mumol/kg-h) caused a dose-dependent inhibition of pancreatic enzyme secretion induced by intravenous infusion of a constant dose of secretin (82 pmol/kg-h) plus CCK-8 (85 pmol/kg-h) but had relatively smaller influence on duodenal volume flow and bicarbonate output. Atropine (20 nmol/kg) also caused a significant reduction in pancreatic enzyme secretion but failed to affect the volume flow or bicarbonate secretion induced by secretin plus CCK, possibly owing to the high doses of secretin and CCK used in these tests. Both loxiglumide and atropine inhibited the pancreatic enzyme response to a Lundh meal, but atropine was more effective in the early phase and loxiglumide in the late phase of the postprandial secretion. Neither loxiglumide nor atropine affected the plasma gastrin and CCK levels, but both antagonists reduced plasma pancreatic polypeptide responses to the Lundh meal. We conclude that 1) loxiglumide results in a relatively stronger suppression of the pancreatic enzyme than aqueous-alkaline secretion induced by secretin plus CCK, whereas atropine inhibits only enzyme secretion; and 2) both loxiglumide and atropine suppress the pancreatic enzyme responses to the meal stimulation without affecting the postprandial plasma gastrin and CCK responses.     

Thr28, Nle31 CCK-9--an useful CCK analogue in stimulation tests of pancreatic exocrine function

In the present study we examined the effect of Thr28 Nle31-CCK 25-33 (CCK-9) on pancreatic exocrine function in man. In subjects without pancreatic disease CCK-9 together with i.v. secretin (0.5 CU/kg/h) elicited a maximal stimulation of amylase output at a dose of 10 pmol/kg/h while trypsin and chymotrypsin were stimulated maximally at a dose of 30 pmol/kg/h. Higher doses of 60 and 100 pmol/kg/h had no additional effects. Lipase secretion was stimulated by secretin alone with no additional effect of CCK-9. During all doses of CCK-9 no side effects were observed. In patients with chronic pancreatitis a dose of 30 pmol/kg/h was also sufficient to obtain maximal enzyme output. In conclusion this derivative of CCK can be considered as a potent and useful alternative to amphibian caerulein in direct pancreatic function tests.