Pancreatic polypeptide and vagal stimulation of gastric and pancreatic secretion in dogs

In four dogs provided with pancreatic, gastric, and esophageal fistulae, the effects of bovine pancreatic polypeptide (BPP) infused at a physiological dose level (240 pmol per kg/hr) on gastric and pancreatic responses to sham-feeding were studied. The maximal gastric and pancreatic secretion was produced by pentagastrin and secretin, and OP-CCK infusion, respectively, with or without additions of BBP. Exogenous BPP did not change gastric acid and pepsin outputs stimulated by pentagastrin or sham-feeding, but significantly inhibited basal and maximally stimulated pancreatic protein secretion. The peak pancreatic protein, but not bicarbonate response to sham-feeding was reduced by about 31% by BPP. This reduction by BPP amounted to about 57% when the pancreas was stimulated maximally by OP-CCK. It is concluded the PP released by cephalic-vagal excitation does not affect gastric secretion, but inhibits pancreatic protein secretion, and thus might contribute to the lower pancreatic response to sham-feeding as compared with that produced by exogenous stimulants such as secretin and OP-CCK.     

The effect of pancreatic polypeptide and peptide YY on pancreatic blood flow and pancreatic exocrine secretion in the anesthetized dog

Pancreatic polypeptide (PP) and peptide YY (PYY) are inhibitors of pancreatic exocrine secretion in vivo but not in vitro, which suggests intermediate mechanisms of action. To examine the role of pancreatic blood flow in these inhibitory effects, xenon-133 gas clearance was used to measure pancreatic blood flow while simultaneously measuring pancreatic exocrine secretion. PP or PYY (400 pmol/kg/h) was administered during the intermediate hour of a 3-h secretin (125 ng/kg/h)/cholecystokinin octapeptide (CCK-8) (50 ng/kg/h) infusion. Exocrine secretion and pancreatic blood flow during the PP or PYY hours were compared with that observed in the first and third hours of the secretin/CCK-8 infusion. PP and PYY significantly inhibited secretin/CCK-8-induced pancreatic exocrine secretion. In addition, PYY (but not PP) significantly reduced pancreatic blood flow during secretin/CCK-8 stimulation. Nevertheless, there was no correlation between pancreatic blood flow and bicarbonate or protein outputs. It is concluded that changes in pancreatic blood flow do not mediate the inhibitory effects of PP or PYY on the exocrine pancreas.     

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.     

Pancreatic polypeptide release stimulated by food, secretin and cholecystokinin in chronic pancreatitis

The pancreatic polypeptide (PP) release after a standard meal and the PP release and the pancreatic secretion of bicarbonate and amylase after stimulation by secretin GIH, 1 CU kg-1 intravenously, and by cholecystokinin (CCK), 1 Ivy dog unit kg-1 intravenously, have been investigated in 10 patients with chronic pancreatitis. Significant correlations were found between the integrated PP responses after food and hormonal stimulation (p less than 0.05), between the integrated PP response and the peak serum PP concentration after food (p less than 0.01) and after secretin/CCK (p less than 0.01), and between the peak serum PP concentrations obtained after food, secretin, and CCK (p less than 0.01). The pancreatic outputs of bicarbonate and amylase and the peak amylase concentration after hormonal stimulation were significantly correlated (p less than 0.01), but no significant correlation was found between any one of these variables of exocrine pancreatic function and the PP release. It is concluded that, in chronic pancreatitis, food, secretin, and CCK stimulate PP release similarly and that no correlation can be established between the PP release and the exocrine pancreatic secretion.     

Neurotensin and the exocrine pancreas

It has been postulated that neurotensin (NT) has a physiological role in the regulation of the exocrine pancreas, but this is controversial. Using the Thomas cannula canine model, the effect of intravenous NT, in physiological and pharmacological doses on exocrine pancreatic secretion, and on plasma pancreatic polypeptide, secretin and cholecystokinin (CCK) levels is reported. The infusion of physiological doses of NT alone (0.2 pmol/kg per min) did not stimulate pancreatic secretion; however, in conjunction with secretin, NT stimulated protein and bicarbonate output, the latter synergistically. Higher doses of NT (20 and 100 pmol/kg per min) resulted in a dose-dependent stimulation of pancreatic volume, bicarbonate and protein secretion. Cholinergic blockade with atropine reduced pancreatic secretion stimulated by low doses of NT (2–20 pmol/kg per min), but at higher doses (100 pmol/kg per min) protein secretion was reduced whilst bicarbonate secretion was enhanced. The infusion of graded doses of NT had no effect on plasma secretin or CCK levels. In contrast, NT did release pancreatic polypeptide in a dose-dependent manner, but only at pharmacological infusion levels. NT, acting synergistically with other hormones, may thus play a role in exocrine pancreatic stimulation.     

Potentiation of cholecystokinin and secretin-induced pancreatic exocrine secretion by endogenous insulin in humans

To investigate the effects of endogenous insulin on pancreatic exocrine secretion in humans, we evaluated the pure pancreatic juice obtained by endoscopic cannulation of the main pancreatic duct in 21 healthy subjects (14 men and seven women). Samples of pancreatic juices were collected after intravenous injection of either glucose (50%, 40 ml), secretin (0.25 CU/kg), and cholecystokinin-8 (CCK) (40 ng/kg), or a combination of glucose, secretin, and CCK in six 5-min periods. The responses of plasma glucose, insulin, and C-peptide to intravenous administration of glucose were measured. After infusion of glucose, the plasma insulin and C-peptide levels were significantly increased and remained at high levels during 30-min experiments, intravenous administration of secretin and CCK resulted in significant increases of pancreatic secretion including volume, bicarbonate, and protein output. When glucose was simultaneously administered with secretin and CCK, pancreatic secretion was significantly increased, more than the effects achieved by the secretin and CCK. However, glucose alone did not increase basal pancreatic secretion. These observations suggest that endogenous insulin intensifies pancreatic secretion stimulated by secretin and CCK in humans.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats.

We investigated the possible role of endogenous secretin and cholecystokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r = 0.665, 0.736 and 0.517, respectively) (P less than 0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r = 0.721 and 0.546, respectively) (P less than 0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P less than 0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats.     

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.     

Potentiating effect of CCK and secretin on rat exocrine pancreas and its cholinergic dependence.

We investigated whether physiological doses of cholecystokinin (CCK) potentiate the stimulating effect of a physiological dose of secretin on exocrine pancreatic secretion, and the effect of atropine on this potentiating action in rats. Pure pancreatic juice was collected from anesthetized rats prepared by pancreatic duct and bile duct cannulation. Intravenous infusion of CCK-8 in three different doses, 0.03, 0.06, and 0.12 micrograms/kg/h, significantly increased pancreatic juice volume and amylase output, dose-dependently. Simultaneous infusion of CCK-8 in graded doses with secretin in a dose of 0.03 CU/kg/h, produced a dose-related increase in pancreatic secretory response significantly greater than the response to CCK-8 alone (p less than 0.05) and greater than the sum of the response to secretin alone and CCK-8 alone. The incremental pancreatic secretion, including juice volume and amylase output, in response to intravenous infusion of CCK-8 with secretin, was significantly suppressed by intravenous administration of atropine in a dose of 100 micrograms/kg/h (p less than 0.01). Thus, it is concluded that CCK-8 and secretin in physiological doses potentiate each other's stimulatory action on exocrine pancreatic secretion and this potentiating action appears to be cholinergic-dependent.     

Cholecystokinin (CCK) in the amino acid uptake and enzyme protein secretion by the pancreas in humans

Summary Activation of type A receptors by CCK or cerulein is known to stimulate pancreatic enzyme secretion, but its role in the amino acid (AA) consumption and enzyme synthesis remains unclear. In our study, we used loxiglumide, a potent CCK-A-receptor antagonist, to investigate the role of CCK-A receptors in pancreatic consumption of circulating AAs and enzyme secretion. Five healthy male volunteers were intubated with double-lumen duodenal tube, and duodenal aspirates were collected during 60-min basal periods and then during pancreatic stimulation with iv infusion of secretin (80 pmol/kg/h) plus cerulein (50 pmol/kg/h) during three consecutive 30-min periods. The same procedure was repeated, but secretin-cerulein infusion was combined with a constant dose of loxiglumide (20 μmol/kg/h). The volume and outputs of HCO₃ ⁻, protein and enzymes (amylase and trypsin) in duodenal aspirates and gallbladder volume (by sonography) were determined at 30-min intervals. Plasma samples were drawn for total plasma AA assay by ninhydrin method to assess the pancreatic uptake of free AAs. Infusion of secretin plus cerulein caused a several-fold increase in the volume of duodenal aspirate and the outputs of HCO₃ ⁻, protein, and enzymes. During those periods, plasma AA level decreased from initially 2.20±0.3 mmol/L to 1.09±0.3 mmol/L (p<0.01) and the gallbladder volume from initially 28±8 mL to 2±0.4 mL. This increase in pancreatic secretory outputs was accompanied by significant increments in plasma insulin, glucagon, PP, and somatostain. After addition of loxiglumide to the secretin-cerulein infusion, the pancreatic volume and HCO₃ ⁻ outputs were unchanged, but the increments in protein and enzyme outputs and in plasma hormone levels decreased to preinfusion values. The total plasma AA level remained, however, unchanged after loxiglumide. Addition of loxiglumide almost completely prevented the contraction of the gallbladder. These results indicate that CCK-A receptors are involved in the secretin-cerulein-stimulated exocrine pancreatic protein enzyme secretion and islet hormone release, but do not appear to be involved in the pancreatic AA consumption.     

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.     

Mechanisms of terbutaline-induced inhibition of exocrine pancreatic secretion in humans

Terbutaline, a selective beta 2-adrenoreceptor agonist, has recently been advocated as a potential agent for treating patients with pancreatic fistulae. In the present study, we attempted to quantify the presumed effects of terbutaline on exocrine pancreatic secretion in humans and to characterize possible mechanisms of action. In six healthy volunteers, the pancreas was stimulated by infusion of graded doses of secretin (15.5-250 ng/kg/h) or by infusion of secretin (15.5 ng/kg/h) plus graded doses of caerulein (3.3-30 ng/kg/h). The experiments were repeated in each subject without and with administration of terbutaline. Pancreatic secretion was assessed by a marker perfusion technique and plasma somatostatin and pancreatic polypeptide (PP) levels by radioimmunoassay. Terbutaline had no significant effect on secretin-stimulated pancreatic secretion, but significantly inhibited caerulein-stimulated pancreatic fluid secretion and trypsin output. Plasma somatostatin and PP levels were not affected by terbutaline. The inhibitory effect required the administration of pharmacologically large doses of terbutaline. We conclude that the weak inhibitory effect of terbutaline on exocrine pancreatic secretion is not mediated via somatostatin nor PP and that our data do not support a major role for beta-adrenergic mechanism as regulator of pancreatic secretion.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats

We investigated the possible role of endogenous secretin and cholecytokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r=0.665, 0.736 and 0.517, respectively) (P<0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r=0.721 and 0.546, respectively) (P<0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P<0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats. The results of this study were presented at The 7th International Symposium of Gastrointestinal Hormones in Shizuoka, Japan, Nov. 1–4, 1988, and appeared in abstract form in Biomedical Research 1988;9(Suppl. 1):114. This work was supported in part by grants from the Japanese Ministry of Education and the Ministry of Welfare. The authors are grateful to Y. Hirasawa, B.S. and M. Takeda, B.S. for their technical assitance.     

Stimulation of exocrine pancreatic secretion by met-enkephalin.

The effect of met-enkephalin on pure exocrine pancreatic secretion was studied in five subjects with external transduodenal drainage of the main pancreatic duct carried out after biliary tract surgery. Intravenous infusion of a low dose of met-enkephalin (0.15 micrograms/kg/h) during submaximal pancreatic stimulation with secretin (25 ng/kg/h) and cerulein (10 ng/kg/h) significantly increased pancreatic outputs. Bicarbonate secretion increased 50% above control values, a more marked effect than the increase in enzyme secretion (maximal rise averaged 22%). The effect of the peptide was rapid, persisted for the duration of met-enkephalin infusion and then tended gradually to diminish.     

In vivo action of bombesin on exocrine pancreatic secretion in the rat: independent of cholecystokinin and cholinergic mediation

This study evaluates the effect of bombesin on pancreatic enzyme secretion in the rat and determines whether the stimulatory action of bombesin is mediated through the release of cholecystokinin (CCK) or via a cholinergic pathway. We performed in vivo experiments on conscious rats prepared with cannulae inserted in the pancreatic duct, in the external jugular vein, and in the duodenum. Intravenous infusion of bombesin stimulated pancreatic protein output in a dose-dependent fashion. Bombesin infused at 5 micrograms/kg/h stimulated pancreatic protein secretion from a basal of 12 +/- 5 to 42 +/- 10 mg/h. Infusion of proglumide (400 mg/kg/h) did not affect the stimulatory effect of bombesin on pancreatic protein secretion (38 +/- 5 mg/h). In contrast, infusion of proglumide abolished the pancreatic protein output elicited by intravenous infusion of CCK8 (500 ng/kg/h). This suggests that bombesin does not act through CCK to mediate exocrine pancreatic secretion. In separate studies we intravenously infused rats with atropine (100 micrograms/kg/h) prior to infusion with bombesin. Administration of atropine slightly decreased secretory volume but did not affect the action of bombesin. Combined administration of atropine and proglumide also did not affect pancreatic protein output stimulated by bombesin. Since infusion of neither proglumide nor atropine inhibited the stimulatory action of bombesin, the action of bombesin in the rat is probably direct and not through the release of CCK or via a cholinergic pathway.     

Insulin inhibits secretin-induced pancreatic bicarbonate output via cholinergic mechanisms

INTRODUCTION: Exogenous insulin inhibits secretin-stimulated pancreatic bicarbonate output via a dose-dependent mechanism; this effect is prevented by pancreatic denervation. AIMS: To investigate possible cholinergic mediation, we examined the effect of bethanechol on secretin-stimulated pancreatic secretion during euglycemic, hyperinsulinemic clamp. METHODOLOGY: In four dogs with chronic pancreatic fistulas, euglycemic, hyperinsulinemic clamp (1.25 mU/kg/min) was begun after a 30-minute basal period; computer-assisted glucose administration maintained euglycemia. Control studies were performed with volume-matched and rate-matched vehicle infusion. After 1 hour, secretin infusion was begun at a dosage of 16 ng/kg/h; the dose was doubled every 30 minutes. The studies were then repeated during background bethanechol infusion (90 microg/kg/h) begun 30 minutes after clamp initiation. Pancreatic juice was analyzed for bicarbonate and protein; serum samples were analyzed for glucose and insulin. RESULTS: Exocrine outputs and serum glucose and insulin levels did not differ in the basal period. Insulin levels were significantly elevated during the euglycemic, hyperinsulinemic clamp (62 microU/mL versus 12 microU/mL; p < 0.01); glucose levels did not differ. As before, secretin-induced bicarbonate output was inhibited by euglycemic, hyperinsulinemic clamp. The inhibitory effect of insulin was reversed by bethanechol. Despite the euglycemic, hyperinsulinemic clamp, secretin-induced bicarbonate output was potentiated by bethanechol at higher secretin doses (p < 0.05). CONCLUSION: These data confirm that cholinergic mechanisms mediate insulin's inhibition of secretin-induced pancreatic bicarbonate output.     

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.     

Effect of rabbit anti-pancreatic polypeptide serum on postprandial pancreatic exocrine secretion in dogs

To determine whether pancreatic polypeptide (PP) is a physiologic inhibitor of pancreatic secretion, we have studied the effects of normal rabbit serum and anti-PP serum on pancreatic secretion during infusion of a physiologic dose of PP or intragastric food instillation in dogs. Infusion of 180 pmol/kg X h of PP, previously incubated with normal rabbit serum, induced increases in plasma PP (220 +/- 21 pmol/L) similar to those after the meal (213 +/- 51 pmol/L) and was accompanied by significant inhibition of pancreatic flow rate, bicarbonate output, and protein output (p less than 0.05) stimulated by secretin and cholecystokinin (n = 6). However, when the effect of exogenous PP was studied after in vivo administration of anti-PP serum or after previous in vitro incubation with anti-PP serum, no inhibition of pancreatic secretion was found, indicating that immunoneutralization of PP blocks the biologic activity of the hormone. Intragastric instillation of 400 ml of liver extract resulted in significant increases in pancreatic flow rate and outputs of protein and bicarbonate (p less than 0.01; n = 8), both during administration of normal rabbit serum and anti-PP serum. The postprandial increase in pancreatic secretion during administration of anti-PP serum was not significantly different from that during administration of normal rabbit serum. We, therefore, conclude that PP is not a physiologic inhibitor of postprandial pancreatic secretion.     

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.