The influence of exogenous cyclic nucleotides and theophylline on the hydrokinetic and ecbolic function of the isolated perfused canine pancreas (author's transl)

The influence of exogenous cyclic nucleotides or theophylline either on basal or stimulated volume and protein secretion is studied on the isolated perfused canine pancreas in dependence on varied extracellular calcium concentrations. Bt2cAMP or theophylline do not influence basal secretory rates of pancreatic juice but potentiate secretin-stimulated volume output. They additionally increase basal protein secretion under exclusive secretin stimulation and potentiate dose-dependently CCK- or acetylcholine-induced protein output. The hydrokinetic and ecbolic effects of Bt2cAMP and theophylline persist in a calcium-free medium but fail in normalizing inhibited protein secretion during calcium deprivation. Bt2cGMP neither increases basal nor stimulated volume and protein secretion. The demonstrated influence of Bt2cAMP and theophylline on ductal volume and acinar protein secretion accomplishes two criteria, as suggested by Sutherland, for cAMP as second messenger for secretin and CCK or acetylcholine as well.     

Behavior of cellular cyclic nucleotides after hydrokinetic or ecbolic stimulation of the canine pancreas

The studies deal with the influence of secretin and various ecbolic secretagogues on tissue levels of cAMP and cGMP in vivo and in the isolated perfused canine pancreas. The mutual behaviour of cellular cAMP and cGMP is observed and compared with the time course of the respective secretory events. Synthetic secretin as well as CCK, acetylcholine or Caerulein likewise elevate tissue cAMP and cGMP simultaneously. There exists no difference in the magnitude of increase and in the time course of changes in tissue cyclic nucleotide levels between hydrokinetic and ecbolic stimulation. The rise in cAMP and cGMP coincides with the onset of the respective secretory events and reaches peak values contemporarily to the excretory maxima. The following decrease in tissue cyclic nucleotides approximatively parallels juice or enzyme secretion in the isolated perfused pancreas but differs widely in vivo. Under this condition cAMP and cGMP rapidly fall to basal levels during undiminished excretory function and show a second rise after cessation of the latter. Secretin and various ecbolic secretagogues do not increase tissue content of cyclic nucleotides in the same dose-dependent manner as can be observed with pancreatic secretion. The behaviour of cAMP and cGMP after addition of secretin and CCK or acetylcholine remains widely unchanged during calcium-free perfusion in spite of an extensive excretory inhibition. The corresponding rise in cellular cAMP and cGMP in the sequence of hydrokinetic as well as of ecbolic stimulation points to an analogous intracellular mediation of various secretagogues in different target cells of the exocrine canine pancreas.     

Hepatic bile and pancreatic exocrine secretions evoked by gastrointestinal peptides in sheep

The secretory response of hepatic bile and exocrine pancreas to gastrointestinal peptides has been studied in chronically cannulated sheep. Pancreatic juice flow and protein output were evoked dose dependently by intraportal injection of secretin, CCK-8, caerulein, VIP and neurotensin. However, biliary secretion was evoked by only secretin. Biliary and pancreatic exocrine secretions were enhanced by delivered gastric juice into the duodenum as followed by the increased plasma concentration of immunoreactive secretin (IRS). Results suggest that secretin is the major peptide that regulates pancreatic exocrine secretion and hepatic bile production in the sheep.     

Caerulein-induced acute pancreatitis in the rat. Pancreatic secretory response to cholecystokinin.

The response of pancreatic exocrine secretion to cholecystokinin (CCK), has been studied in experimental acute pancreatitis induced in rats by supramaximal doses of caerulein. Several doses of caerulein were used (4, 20 and 40 micrograms/Kg) and each one was administered by four subcutaneous injections over 3 h at hourly intervals. Pancreatic juice was collected 9 h after the first injection. The caerulein-treated animals showed a statistically significant increase in serum amylase levels. Secretory activity of ductular cells remained unchanged in all the caerulein-treated animals, but total protein and amylase secretion decreased significantly at all the caerulein doses used, both in resting conditions and under stimulation with CCK (1.25 micrograms/Kg/h). Despite this the acinar cells of rats treated with the lowest dose of caerulein retained a certain degree of secretory function since amylase activity in pancreatic juice was greater than in other groups of rats treated with higher doses of caerulein. Moreover, the percentage of increase observed in total protein and amylase in response to CCK respect to basal secretion is similar to that of the untreated animals. At higher doses (20 and 40 micrograms/Kg) the secretory capacity in response to CCK was inhibited. Therefore CCK administration in slight acute pancreatitis could be used as a therapy since it favours the secretion of pancreatic enzymes at percentual levels similar to those of the controls.     

Secretin differentially sensitizes rat pancreatic acini to the effects of supramaximal stimulation with caerulein

Supramaximal stimulation of the rat pancreas with CCK, or its analog caerulein, triggers acute pancreatitis and a number of pancreatitis-associated acinar cell changes including intracellular activation of digestive enzyme zymogens and acinar cell injury. It is generally believed that some of these various acinar cell responses to supramaximal secretagogue stimulation are interrelated and interdependent. In a recent report, Lu et al. showed that secretin, by causing generation of cAMP and activation of PKA, sensitizes acinar cells to secretagogue-induced zymogen activation, and, as a result, submaximally stimulating concentrations of caerulein can, in the presence of secretin, trigger intracellular zymogen activation. We found that secretin also sensitizes acinar cells to secretagogue-induced cell injury and to subapical F-actin redistribution but that it did not alter the caerulein concentration dependence of other pancreatitis-associated changes such as the induction of a peak plateau intracellular [Ca(2+)] rise, inhibition of secretion, activation of ERK1/2, and activation of NF-kappaB. The finding that secretin sensitizes acinar cells to both intracellular zymogen activation and cell injury is consistent with the concept that these two early events in pancreatitis are closely interrelated and, possibly, interdependent. On the other hand, the finding that, in the presence of secretin, caerulein can trigger subapical F-actin redistribution without inhibiting secretion challenges the concept that disruption of the subapical F-actin web is causally related to high-dose secretagogue-induced inhibition of secretion in pancreatic acinar cells.     

Three-day continuous drainage of pancreatic juice in the cortisone-treated conscious rat: Analysis of enzyme activities and ultrastructural changes

Summary We have investigated the short-term effects of hydrocortisone (60 mg/kg per day) and placebo on basal and stimulated pancreatic secretion in the conscious rat. Volume and enzyme secretion were determined; fine structural changes were examined simultaneously.The pancreatic and bile ducts were cannulated separately; pancreatic juice was drained via an isolated fistula, and bile was recirculated into the duodenum. The application of hydrocortisone led to an almost complete inhibition of the secretory response of the exocrine pancreas when stimulated with 0.25 U secretin in combination with 5 × 10^-8 g caerulein per h. It strongly affected the secretion rates of volume, protein, lipase, chymotrypsin, trypsin and carboxypeptidase, whereas the secretion rate of alpha-amylase continued to show a slight increase after stimulation.After stimulation with secretin and caerulein, the hydrocortisone-treated animals showed a higher density of zymogen granules in the acinar cell and an increase in the number of autophagic vacuoles in comparison to the equally stimulated placebo-treated rats.It is concluded that the short-term inhibition of pancreatic secretion by hydrocortisone occurs largely as a result of an inhibition of cellular enzyme discharge.Supported by the Deutsche Forschungsgemeinschaft, Ga 279     

Neurotensin interacts with carbachol, secretin, and caerulein in the stimulation of the exocrine pancreas of the rat in vitro

In the present investigation the effect of neurotensin on pancreatic secretion of isolated pancreatic lobules from the rat was examined. We found a dose- and time-dependent stimulation of amylase release beginning with a concentration of 10(-9) M neurotensin. This response was potentiated by the cholinergic agonist carbachol, the gastrointestinal peptide secretin, and the CCK analogue caerulein. As we found neurotensin-immunoreactive nerves within the pancreas and as neurotensin-like immunoreactivity is present in the circulation (found previously), neurotensin may well be a further peptide taking part in the regulation of exocrine pancreatic secretion either as a hormone or a neurotransmitter. Neurotensin would then cooperate with cholinergic mechanisms, secretin, and CCK.     

Effects of pancreatic polypeptide on the pancreatic exocrine secretion stimulated by secretin and cholecystokinin in the conscious pig

Fourteen castrated male Large White pigs, weighing 42.5 +/- 1.0 kg, were fitted with pancreatic and duodenal fistulae for pancreatic secretion studies. Moreover, catheters were placed in a carotid artery for blood sampling and in a jugular vein for peptide infusion. Pancreatic juice was automatically restituted to the animals and continuously sampled for analysis on experimental days. Following an 8-day recovery period, perfusion studies were performed after an overnight fast. After a 30-min basal period, sustained pancreatic flow and protein output were obtained and maintained throughout the assay with secretin (36 pmol/kg/h) and CCK-8 (600 pmol/kg/h) infusion. Then, 200, 400, 600, 800 or 1200 pmol/kg/h of porcine pancreatic polypeptide (PP) were infused for 60 min. Secretin + CCK infusion was continued for 1 h after PP infusion was stopped. Each dose of PP was given on a separate day. Neither pancreatic flow nor bicarbonate output were affected whatever the dose of infused PP. On the contrary, protein concentration and output decreased with the lowest dose of PP (200 pmol/kg/h) and the diminution was more pronounced with the other doses. With 600 pmol/kg/h as well as with 800 and 1200 pmol/kg/h of PP, pancreatic protein output fell to about 20% of values obtained with secretin + CCK. Plasma levels of PP were below or similar to postprandial values for 200, 400 and 600 pmol/kg/h and they were significantly larger with 800 and 1200 pmol/kg/h. Protein concentration and output returned to values obtained with secretin + CCK infusion after cessation of PP infusion. In conclusion, porcine PP given in physiological doses to the pig decreases pancreatic protein output whereas pancreatic flow remains unaffected.     

Effects of some gastrointestinal peptides on pancreatic growth in rats (preliminary results)

The purpose of this study was to estimate the effects of cholecystokinin (CCK), somatostatin (SS) pancreatic polypeptide (PP) and their interaction with each other, given them in single doses, on pancreatic secretion and pancreatic growth after long-term treatment in rats. The acute secretory effects of the above mentioned peptides were studied on conscious rats supplied with pancreatic, gastric and jugular vein cannulae. The pancreatic growth was characterized by measurements of pancreatic weight, desoxyribonucleic acid (DNA), protein, trypsin and amylase content after 5 days treatment. Amylase output was increased by caerulein alone, and given it in combination with somatostatin (SS), while its value decreased by SS alone. After 5 days treatment, the pancreatic weight, trypsin and amylase activity (hypertrophy) was increased by caerulein, and these values were not altered by S alone. In combinative administration of caerulein with somatostatin, the stimulatory effect by caerulein was decreased. PP given alone or in combination with caerulein decreased both the basal and stimulated amylase output. PP given for 5 days decreased pancreatic trypsin and amylase contents and counteracted the stimulatory effect by caerulein to these enzymes' contents. It has been concluded that: 1. caerulein stimulates both pancreatic enzyme secretion and pancreatic growth; 2. somatostatin inhibits the pancreatic secretion and caerulein induced pancreatic growth, but it does not affect the spontaneous growth of pancreas; 3. pancreatic polypeptide inhibits the pancreatic secretion and decreases pancreatic trypsin and amylase contents.     

Effect of ligands that increase cAMP on caerulein-induced zymogen activation in pancreatic acini

The pathological activation of proteases within the pancreatic acinar cell is critical to initiating pancreatitis. Stimulation of acinar cells with supraphysiological concentrations of the CCK analog caerulein (CER) leads to protease activation and pancreatitis. Agents that sensitize the acinar cell to the effects of CCK might contribute to disease. The effects of physiological ligands that increase acinar cell cAMP [secretin, VIP, and pituitary adenylate cyclase activating peptide (PACAP)] on CER-induced responses were examined in isolated rat pancreatic acini. Each ligand sensitized the acinar cell to zymogen activation by physiological concentrations of CER (0.1 nM). VIP and PACAP but not secretin also enhanced activation by supraphysiological concentrations of CER (0.1 muM). A cell-permeable cAMP analog also sensitized the acinar cell to CER-induced activation. The cAMP antagonist Rp-8-Br-cAMP inhibited these sensitizing effects. These findings suggest that ligands that increase acinar cell cAMP levels can sensitize the acinar cell to the effects of CCK-induced zymogen activation.     

Cyclic nucleotides, calcium, bicarbonate, and protein secretion in canine pancreatic juice in response to cholecystokinin-pancreozymin.

The secretion of cyclic AMP, cyclic GMP, protein, calcium, and bicarbonate in the pancreatic juice of three nonanesthetized dogs with chronic gastric and duodenal Thomas cannulae has been studied. Intravenous infusions of increasing doses of cholecystokinin-pancreozymin (CCK) (1.5, 3, 6, 12, 24 Crick Harper-Raper (CHR) U kg-1 h-1) were administered together with a continuous submaximal dose of secretin (1 clinical unit (CU) kg-1 h-1). Doubling CCK doses every 45 min induced a parallel increase in the output of both cyclic nucleotides. Cyclic AMP output peaked at between 15 and 30 min for 3 and 6 U kg-1 h-1 of CCK and later for 12 and 24 U kg-1 h-1 of CCK whereas cyclic GMP output increased more constantly. Calcium output followed a pattern similar to that of cyclic GMP secretion. Flow rate and protein output attained their peaks at between 30 and 45 min. A strong linear correlation was found between the quantities of cyclic AMP, cyclic GMP, and the quantities of protein secreted in response to each CCK dose. This study demonstrates the presence of cyclic GMP in the canine pancreatic juice and the dose-dependent stimulation of the secretion of cyclic GMP and cyclic AMP by CCK in the presence of secretin.     

Lack of CCK-like pancreatic stimulation by intraduodenal amino acids in the anesthetized cat

We have attempted to demonstrate a pancreatic secretory response to intraduodenal amino acids in the anesthetized cat. In four cats stimulated with supramaximal doses of secretin, protein concentrations in pancreatic juice were measured after intraduodenal bolus injection of various amino acids, IV CCK, or electrical stimulation of the vagus nerve. In addition, the duodenum was perfused with phenylalanine (50 mM) for 30 min in two cats, and the vagus nerve stimulated electrically for 15 min in one. In no case did amino acids produce pancreatic protein secretion, whereas CCK and vagal stimulation always did so. We conclude that this insensitivity to amino acids in the cat is a species difference from the dog and man.     

Atrial natriuretic factor stimulates exocrine pancreatic secretion in the rat through NPR-C receptors

Increasing evidence supports the role of atrial natriuretic factor (ANF) in the modulation of gastrointestinal physiology. The effect of ANF on exocrine pancreatic secretion and the possible receptors and pathways involved were studied in vivo. Anesthetized rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into the duodenum. ANF dose-dependently increased pancreatic secretion of fluid and proteins and enhanced secretin and CCK-evoked response. ANF decreased chloride secretion and increased the pH of the pancreatic juice. Neither cholinergic nor adrenergic blockade affected ANF-stimulated pancreatic secretion. Furthermore, ANF response was not mediated by the release of nitric oxide. ANF-evoked protein secretion was not inhibited by truncal vagotomy, atropine, or Nomega-nitro-l-arginine methyl ester administration. The selective natriuretic peptide receptor-C (NPR-C) receptor agonist cANP-(4-23) mimicked ANF response in a dose-dependent fashion. When the intracellular signaling coupled to NPR-C receptors was investigated in isolated pancreatic acini, results showed that ANF did not modify basal or forskolin-evoked cAMP formation, but it dose-dependently enhanced phosphoinositide hydrolysis, which was blocked by the selective PLC inhibitor U-73122. ANF stimulated exocrine pancreatic secretion in the rat, and its effect was not mediated by nitric oxide or parasympathetic or sympathetic activity. Furthermore, CCK and secretin appear not to be involved in ANF response. Present findings support that ANF exerts a stimulatory effect on pancreatic exocrine secretion mediated by NPR-C receptors coupled to the phosphoinositide pathway.     

A secretin releasing peptide exists in dog pancreatic juice

Canine pancreatic juice has been shown to stimulate exocrine pancreatic secretion in the dog. In the present study we investigated whether there is a secretin-releasing peptide in canine pancreatic juice. Pancreatic juice was collected from the dogs with Thomas gastric and duodenal cannulas while pancreatic secretion was stimulated by intravenous administration of secretin at 0.5 microg/kg/h and CCK-8 at 0.2 microg/kg/h, respectively. The pancreatic juice was separated into three different molecular weight (MW) fractions (Fr) by ultrafiltration (Fr 1; MW > 10,000, Fr 2; MW=10,000-4,000 and Fr 3; MW < 4,000), respectively. All the fractions were bioassayed in anesthetized rats. Fraction 3 dose-dependently and significantly stimulated pancreatic juice flow volume from 78.0% to 99.4% (p<0.05) and bicarbonate output from 128.9% to 202.1% (p<0.01), respectively. Plasma secretin concentration also increased from 1.2 +/- 0.5 pM to 5.0 +/- 0.8 pM and 6.0 +/- 1.0 pM (p<0.05). None of these fractions increased pancreatic protein secretion or plasma CCK level. The stimulatory effect of Fraction 3 on pancreatic secretion and the release of secretin was completely abolished by treatment with trypsin (1 mg/ml for 60 min at 37 degrees C) but not by heating (100 degrees C, 10 min). Intravenous injection of a rabbit anti-secretin serum, which rendered plasma secretin almost undetectable in rat plasma, also abolished Fr 3-stimulated pancreatic secretion of fluid and bicarbonate secretion. These observations suggest that a secretin-releasing peptide exists in the canine pancreatic juice. It is trypsin-sensitive and heat-resistant. This peptide may play a significant physiological role on the release of secretin and regulation of exocrine pancreatic secretion.     

Role of cholecystokinin in the control of gastric somatostatin in the rat: in vivo and in vitro studies.

Cholecystokinin (CCK) has been shown to be a powerful stimulus for somatostatin release from isolated canine fundic D-cells in short-term culture. The influence of the CCK analogue caerulein on the secretory activity of the D-cell in the intact stomach in vitro and the effect of elevated plasma levels of endogenous CCK on gastric somatostatin stores in vivo were investigated in the rat. Basal somatostatin secretion from the isolated, vascularly perfused rat stomach preparation was not affected by various doses of caerulein. Slight stimulation of somatostatin-like immunoreactivity (SLI) release by epinephrine was significantly inhibited by caerulein, whereas caerulein did not alter half-maximal stimulation of SLI secretion by isoproterenol. Rats with chronically elevated plasma CCK levels induced by experimental exocrine pancreatic insufficiency did not show any change in tissue concentrations of SLI or in D-cell number, both in the antrum and corpus. These data suggest that CCK--in contrast to dogs--is not an important modulator of gastric somatostatin in the rat.     

Electrophoretic and cytological evidence for heterogeneity of pancreatic acinar cell responsiveness to carbachol,caerulein and secretin

Summary Incubation of rat pancreatic lobules for 90 min with optimal concentrations of caerulein, carbachol or secretin caused the release of about 30% of the amylase content. Combination of secretin with carbachol or caerulein increased the amylase output to about 40%. With secretin, as with carbachol or caerulein, heterogeneity of cellular responsiveness was observed, some acini being partially or completely depleted of their zymogen granules, whereas others appeared to be resting. When secretin was combined with carbachol or caerulein, granule depletion, originally confined to small groups of neighbouring acini, spread to form large areas of degranulated cells, sometimes comprising a whole section of a lobule.In dispersed acini, under the same conditions, carbachol caused the release of about 60% of the amylase content, and secretin 40%. When both secretagogues were combined, a significant increase to 78% was observed. Under these conditions, there was some important cellular damage, as indicated by the release of 20% of the amylase content and between 6 and 12% of lactate dehydrogenase into the media, in the absence of stimulus. These results were corroborated by cytological observations. On the basis of their secretory response two groups of acini can be distinguished, those that respond to carbachol, caerulein or secretin and those that respond to the combination of secretin with carbachol or caerulein. Electrophoretic patterns of secretory proteins released by lobules stimulated by these different types of secretagogues were essentially similar. The pattern was quite different, however, in the absence of a stimulus. The most striking feature was the presence of a band at 63 Kd whereas a 73.5 Kd band was found only under conditions of stimulation. The latter results support the view that under resting and stimulated conditions secretory proteins are released from distinct compartments in the acinar cell.Abbreviations used PMSF phenylmethylsulfonyl fluoride - Carbachol carbamylcholine chloride - SBTI soybean trypsin inhibitor     

The influence of cholecystokinin, vasoactive intestinal peptide and secretin on pancreatic and biliary secretion in laying hens

White Leghorn hens, 14-29 weeks old, were surgically fitted with cannulas for collecting pancreatic and biliary secretions, and a jugular cannula for continuous infusion of either cholecystokinin (CCK), vasoactive intestinal peptide (VIP), or secretin. As compared to secretory levels during saline infusion, CCK significantly stimulated biliary flow and biliverdin concentration in bile; VIP significantly depressed biliverdin concentration but enhanced bicarbonate secretion in both pancreatic and biliary secretions, and also increased total pancreatic flow. Secretin depressed biliary flow and increased pancreatic bicarbonate release. The principal hormonal regulator of biliary secretion appears to be CCK, and that of pancreatic secretion to be VIP.     

Secretin is not necessary for exocrine pancreatic development and growth in mice

Adaptive exocrine pancreatic growth is mediated primarily by dietary protein and the gastrointestinal hormone cholecystokinin (CCK). Feeding trypsin inhibitors such as camostat (FOY-305) is known to induce CCK release and stimulate pancreatic growth. However, camostat has also been reported to stimulate secretin release and, because secretin often potentiates the action of CCK, it could participate in the growth response. Our aim was to test the role of secretin in pancreatic development and adaptive growth through the use of C57BL/6 mice with genetic deletion of secretin or secretin receptor. The lack of secretin in the intestine or the secretin receptor in the pancreas was confirmed by RT-PCR. Other related components, such as vasoactive intestinal polypeptide (VIP) receptors (VPAC(1) and VPAC(2)), were not affected. Secretin increased cAMP levels in acini from wild-type (WT) mice but had no effect on acini from secretin receptor-deleted mice, whereas VIP and forskolin still induced a normal response. Secretin in vivo failed to induce fluid secretion in receptor-deficient mice. The pancreas of secretin or secretin receptor-deficient mice was of normal size and histology, indicating that secretin is not necessary for normal pancreatic differentiation or maintenance. When WT mice were fed 0.1% camostat in powdered chow, the pancreas doubled in size in 1 wk, accompanied by parallel increases in protein and DNA. Camostat-fed littermate secretin and secretin receptor-deficient mice had similar pancreatic mass to WT mice. These results indicate that secretin is not required for normal pancreatic development or adaptive growth mediated by CCK.     

Presence of somatostatin-like immunoreactivity in rat pancreatic juice: a physiological phenomenon

These studies were performed to assess the effects of various exocrine pancreatic stimuli on somatostatin-like immunoreactivity (SLI) secretion in pure rat pancreatic juice. Ingestion of a meal and subcutaneous injections of caerulein (CA), secretin (SE), and their combination (CA + SE) were compared. Basal fasting SLI output over 5 1/2 h averaged 13.7 ng/30 min; the response to feeding resulted in decreased SLI outputs from 9.7 to 1.7 ng/30 min, a reduction of 81%. SLI secretion following CA, SE, and CA + SE was similar to that obtained following feeding but the reductions of 29, 32, and 39% were less marked and of shorter duration. A return to basal SLI levels was observed only 2 1/2 h following CA administration. Increases in pancreatic volume and protein outputs following CA, SE, and CA + SE were comparable to the feeding response although less pronounced. These data indicate that SLI secretion in pure pancreatic juice can be modulated by two peptides and feeding and that its release is reduced when compared with increases in pancreatic volume and protein secretion. The observation that the peptide's response in terms of SLI output as well as protein and volume were in the same range, although less sustained than the response to a meal, indicates that all stimuli used induced a physiological response of the pancreas.     

Effect of acute hyperglycemia on basal, secretin and secretin + cholecystokinin stimulated exocrine pancreatic secretion in humans

Pancreatico-biliary secretion is reduced during acute hyperglycemia. We investigated whether alterations in pancreatico-biliary flow or volume output are responsible for the observed reduction in duodenal output of pancreatic enzymes and bilirubin during hyperglycemia. Eight healthy subjects were studied on two occasions during normoglycemia and hyperglycemia (15 mmol/l). Pancreatico-biliary output was measured by aspiration using a recovery marker under basal conditions (60 min), during secretin infusion (0.1 CU/kg.h) for 60 min and during secretin + CCK (0.5 IDU/kg.h) infusion for 60 min. Secretin was infused to stimulate pancreatico-biliary flow and volume output. Secretin significantly (P<0.005-P<0.05) increased volume and bicarbonate output and CCK significantly (P<0.01) increased the output of bilirubin, pancreatic enzymes, bicarbonate and volume, both during normoglycemia and hyperglycemia. During hyperglycemia basal, secretin stimulated and secretin + CCK stimulated total pancreatico-biliary output were significantly (P<0.005-P<0.05) reduced compared to normoglycemia. The incremental outputs, however, were not significantly different between hyper- and normoglycemia. Pancreatic volume output was significantly (P<0.05) reduced during hyperglycemia compared to normoglycemia under basal conditions (31+/-16 m/h versus 132+/-33 m/h) during secretin infusion (130+/-17 ml/h versus 200+/-34 m/h) and during secretin + CCK infusion (370+/-39 ml/h versus 573+/-82 ml/h). Plasma PP levels were significantly (P<0.05) reduced during hyperglycemia. It is concluded that 1) hyperglycemia significantly reduces basal pancreatico-biliary output 2) the incremental pancreaticobiliary output in response to secretin or secretin + CCK infusion is not significantly affected during hyperglycemia, 3) a reduction in volume output contributes to the inhibitory effect of hyperglycemia on pancreatico-biliary secretion, 4) hyperglycemia reduces PP secretion suggesting vagal-cholinergic inhibition of pancreatico-biliary secretion and volume during hyperglycemia.