Effect of low dose secretin and caerulein on pure pancreatic bicarbonate secretion and plasma secretin in man

In six healthy volunteers pure pancreatic juice was obtained by endoscopic cannulation of the main pancreatic duct. Following a 20-min basal period, secretin (0.03 CU/kg, h) was intravenously infused alone for 20 min and then with caerulein 15 ng/kg, h for further 20 min. From a basal level of 28 +/- 13 mu mol/5 min, secretin by itself significantly increased pancreatic bicarbonate to 182 +/- 24 mu mol/5 min. A further significant two-fold increase to 396 +/- 50 mu mol/5 min was observed during caerulein. The increment in plasma secretin of 2.1 +/- 0.3 pmol/l is comparable to the rise that may be observed post-prandially. It is concluded that secretin in combination with cholecystokinin may indeed play a physiological role in the regulation of duodenal pH.     

Inhibition by somatostatin of secretin-stimulated pancreatic secretion in man: a study with pure pancreatic juice.

The action of somatostatin on compostition and flow rate of pure pancreatic juice obtained by endoscopic cannulation of the main pancreatic duct was evaluated in 5 healthy volunteers. Synthetic secretin (0.06 CU/kg-h) was intravenously infused throughout the 80-min study. Bicarbonate concentrations in pancreatic juice achieved constant levels (117 +/- 3 muEq/ml) after 10 min, whereas a steady state of juice flow (7.3 +/- 1.4 ml/5 min) was attained after 15 min of secretin infusion. In the third 20-min period, cyclic somatostatic (5 mug/kg-h i.v.) was given, leading to a decrease in pancreatic flow rate by 47% after 10 min, and by 67% after 15 min of somatostatin administration. Alrady 5 min after the infusion of somatostatin had been discontinued, pancreatic flow rate gradually recovered; presomatostatin levels, however, were not reached within 20 min. Cyclic AMP varied roughly in accordance with bicarbonate concentrations, whereas the chloride concentrations were reciprocally related. Bicarbonate, sodium, potassium, protein, and cyclic GMP concentrations did not change substantially due to somatostatin.     

The influence of intraduodenal administration of pancreatic juice on the bile-induced pancreatic secretion and immunoreactive secretin release in man

The exocrine pancreatic secretion of water, bicarbonate, amylase, and protein and the plasma levels of immunoreactive secretin (IRS) were studied after intraduodenal infusions of bile and pancreatic juice. Pancreatic secretion was obtained by endoscopic cannulation of the main pancreatic duct. Bile and pancreatic juice were infused into the duodenum through separate catheters attached to the outside of the duodenoscope. The unstimulated secretion was collected for 20 min. After intraduodenal stimulation of the pancreatic secretion with a nearly neutral solution of dried cattle bile, juice was collected for another 20-min period. Then, pure pancreatic juice was infused into the duodenum. It was shown that pancreatic juice reduced the flow rate and output of bicarbonate, amylase, and protein significantly (p less than 0.05). A significant reduction in plasma concentration of IRS (p less than 0.05) was also found. In the controls, i.e., when no pancreatic juice was instilled into the duodenum, a further increase in flow rate, bicarbonate secretion, and IRS was found. It is concluded that the exocrine pancreatic secretion and IRS release induced by intraduodenal administration of bile may be depressed by reinfusions of pancreatic juice. The corresponding effect on bicarbonate secretion and IRS release found in this study supports the view that secretin may play an important role in the exocrine pancreatic secretion induced by intraduodenal infusion of bile.     

Studies of pure human pancreatic juice

The test-combination from Fa. Boehringer Mannheim GmbH for measuring citric acid present in foodstuffs is also suitable for use in human pancreatic juice. Accuracy, within-run and between-day imprecision are satisfactory. The detection limit of the method is at least 10 mumol citrate/l pancreatic juice. The limit can be reduced when exact additions of citrate are given to the pancreatic juice and then evaluated using regression analysis. The presence of Ca-ions and possibly also trypsin in the material to be tested does not interfere with the reaction. It is, however, necessary to remove proteins from the sample. Deproteinization can be performed either by ultrafiltration or with perchloric acid.     

Effects of morphine on human pancreatic secretion: studies on pure pancreatic juice.

Data concerning the effects of morphine on human pancreatic secretion are fragmentary and inconclusive. In the present study, we evaluated the effects of morphine on pure pancreatic secretion in nine subjects with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery. Intravenous infusion of a small dose of morphine, 40 microgram/kg/h, during pancreatic stimulation with secretin and cholecystokinin, caused a significant increase in volume, bicarbonate, and calcium secretion, and a significant decrease in protein secretion. The stimulatory effect on water and electrolyte secretion was rapid and much more pronounced, reaching about 45-50% of the control levels, whereas the inhibition of protein output was slightly delayed and of lesser magnitude, reaching about 20-25% of the control values. Both effects were long-lasting. The addition of naloxone, potent opiate antagonist, prevented in part the effects of morphine on pancreatic secretion, suggesting that specific opiate receptors might be involved in these effects.     

Presence of hormonal polypeptides in the pure pancreatic secretion in man under stimulation by cerulein and secretin

We have investigated in stimulated human pancreatic juice the presence of the following peptides: insulin, glucagon, gastrin, somatostatin, VIP and secretin. Collection of pancreatic juice (3 periods: 20 min each) was completed by endoscopic cannulation of the pancreatic duct during the infusion of secretin (0.5 U/kg/h) and cerulein (75 ng/kg/h) in 6 healthy volunteers. Pure pancreatic juice was recovered in the presence of kallikrein inhibitor (iniprol 8,000 U/ml) in refrigerated collection tubes (4 degrees C). The material was acidified, boiled for 5 min and centrifuged. Radioimmunoassays were performed on the supernatant solutions. The elution profiles on Sephadex G 25 gel filtration of the immunoreactivities were compared with standard samples of hormones, immuno-reactive insulin, glucagon and somatostatin were found in every sample: insulin was present at a constant level (50 microU/ml) during the three periods of collection; glucagon was encountered in large amounts in the first sample and decreased significantly during the subsequent periods; somatostatin which occurred at a low level during the first period was significantly increased in the following periods. Gastrin, VIP and secretin were undetectable or only inconstantly found in very small amounts. These results are in agreement with a two-directional secretion of the human pancreatic endocrine cells. The cellular origin and function of these exocrine secreted peptides need further studies.     

Studies on the effect of glucagon on human pancreatic secretion by analysis of endoscopically obtained pure pancreatic juice

The effect of glucagon on human exocrine pancreatic secretion was evaluated in ten patients by analysis of pure pancreatic juice. Pancreatic juice was obtained by endoscopic cannulation of the pancreatic duct at 2-min intervals during constant intravenous infusion of secretin (1 U per kg of body weight per hr) plus caerulein (0.04 micrograms per kg of body weight per hr). Since steady secretion was established 20 minutes after the start of juice collection, a further five 2-min fractions were collected as controls, then constant intravenous infusion of glucagon (15 micrograms per kg of body weight per hr) was commenced. Pancreatic juice was collected for a further 20 minutes. The control fractions and post-glucagon fractions were compared in each patient using Student's test. Glucagon depressed secretin-caerulein-stimulated pancreatic secretions. More uniform reductions were observed in the concentration and output of protein and enzymes. Individual variations were observed in the secretory volume and bicarbonate concentration and output. Amylase and lipase were depressed in a parallel fashion in seven patients and in the remaining three, amylase was more depressed than lipase. The post-glucagon reduction in pancreatic secretion was not proportional to the rise in plasma glucagon and blood glucose.     

Effect of secretin and jejunal acidification on gastric and pancreatic secretion in man

The inhibitory effect of intravenous secretin and intrajejunal acid infusion on basal and pentagastrin-induced gastric acid secretion as well as the stimulatory influence of both infusions on pancreatic flow rate and bicarbonate output were compared in two groups of healthy subjects.

Secretin strongly inhibited basal acid output and slightly decreased pentagastrin induced gastric secretion.

Intrajejunal acid infusion did not affect the gastric secretion but resulted in an increase in pancreatic volume flow and bicarbonate output reaching about 40% of the pancreatic response to secretin¹ infused intravenously in a dose of 2 units per kilogram per hour.

It is concluded that this provides evidence that secretin is a strong inhibitor of spontaneous gastric acid secretion and that acid in the jejunum causes the release of secretin in man.

     

Effect of secretin and graded doses of CCK-PZ on pancreatic secretion in man

We have studied the effects of cholecystokinin-pancreozymin (CCK-PZ) from the GIH laboratory in Stockholm, Sweden, on the electrolyte and enzyme secretion of the pancreas. CCK-PZ in variable doses has been given together with a constant secretin dose of 2 clinical units per kilogram hour (CU/kg-hr). The results obtained were compared with a second group of tests where secretin alone was administered in the same dose. CCK-PZ given with the same dose of secretin that produced maximal fluid and electrolyte flow does not potentiate the total bicarbonate response but does slightly increase bicarbonate concentration. The variations observed are due to the presence of acinar and biliary factors. On the other hand, administration of CCK-PZ produces a greater maximal enzyme response than we have obtained in prior studies after injection of Boots pancreozymin or caerulein. For this reason we prefer CCK-PZ to other products in pancreatic studies.     

Inhibition of secretin release and pancreatic bicarbonate secretion by somatostatin infusion in man.

Five healthy students were investigated on two different days with or without a constant infusion of somatostatin (500 microgram/h) into an arm vein a fluoroscopically placed Lagerl?f tube was used for the collection of gastric and duodenal juice. After 30-min basal period, 40 ml 100 mmol/l HCl was infused into the midpart of the duodenum over 5 min through a thin catheter attached to the tube. Plasma immunoreactive secretin was measured by radioimmunoassay employing 125I-labelled synthetic secretin, antibody against synthetic secretin, and standards prepared from pure natural porcine secretin. Secretin levels without somatostatin infusion were 4.6+/-0.7 pmol/l (mean+/-S.E.M.) basally and rose to a peak of 21.8+/-6.2 pmol/l after duodenal acidification (p less than 0.05) and with somatostatin infusion were 4.4+/-0.4 pmol/l basally and rose to a peak of 6.7+/-1.7 pmol/l (n.s.) after duodenal acidification. Pancreatic bicarbonate output increased from 8.0+/-2.5 mumol/min (mean+/-S.E.M.) to 283+/-44 mumol/min without somatostatin infusion (p less than 0.05) and from 6.7+/-2.1 mumol/min to 70+/-13 mumol/min somatostatin (p less than 0.05). This study shows that somatostatin (500 microgram/h can inhibit the release of secretin and the pancreatic bicarbonate secretion after duodenal acidification in man.     

Plasma secretin and pancreatic bicarbonate response to exogenous secretin in man.

The dose response of duodenal bicarbonate production during synthetic porcine secretin infusions was studied in six healthy volunteers and related to plasma secretin immunoreactivity. Secretin was infused in each individual at four different doses from 0-1 to 2-7 CU/kg/h, each infusion lasting for 60 minutes. Mean maximal bicarbonate secretion was 33 +/- 4 mEq/h. The secretin plasma level for half maximal bicarbonate response was estimated to be 22 pmol/l. As this level is reported to be achieved by intraduodenal acidification in man, it is concluded that secretin may well play a part in the control of duodenal pH.     

The effect of duodenal acidification on plasma secretin and gastrin and pancreatic bicarbonate secretion in man.

Plasma secretin, plasma gastrin and pancreatic bicarbonate output were measured in three healthy youths before and after a 10 min period of duodenal infusion of 50, 75 and 100 ml 100 mmol/1 HCl. Plasma secretin rose to a shortlived peak within 10 min, whereas plasma gastrin fell gradually to values significantly below the basal level 60 min after the start of duodenal acidification. Pancreatic bicarbonate output showed a more sustained increase following duodenal acidification. Significant positive correlations were obtained between plasma secretin and infused dose of HCl, between pancreatic bicarbonate output and infused dose of HCl and between plasma secretin and pancreatic bicarbonate output. The calculated maximal pancreatic bicarbonate output (Vmax) of 30.6 mEq/h and the calculated dose of secretin to elicit half maximal pancreatic bicarbonate output (S50) of 0.2 CU/kg-h following duodenal acidification were comparable to that seen after intravenous infusion of secretin. No significant correlation was found between plasma secretin and plasma gastrin. It is suggested that the pancreatic stimulation subsequent to duodenal acidification is mainly effected by release of secretin, and that the fall in plasma gastrin may be caused by a HCl-induced inhibition of gastrin release from the duodenum.     

Inhibition of secretin stimulated pancreatic secretion by pancreatic polypeptide.

The effect of PP on secretin-stimulated pancreatic secretion was assessed in five healthy subjects. During an intravenous infusion of BPP at a dose which produced plasma levels similar to those seen after meals in healthy young adults the volume and bicarbonate content of duodenal juice was reduced by 25% (p less than 0.05) and 24% (p less than 0.05) respectively, while protein and bilirubin concentrations were more markedly reduced by 68% (p less than 0.0005) and 67% (p less than 0.0005) respectively. PP, thus, may be an important inhibitory factor in the control of bilirubin and pancreatic enzyme secretion in man.     

Lactoferrin in pure pancreatic juice

Lactoferrin as assayed by a radial immunodiffusion technique was studied in pure pancreatic juice collected at endoscopic retrograde cholangiopancreatography from 23 patients with chronic pancreatitis, 12 with acute pancreatitis, 21 with pancreatic cancer, and 29 cases of nonpancreatic gastrointestinal disease. No clear difference between lactoferrin concentrations in the chronic pancreatitis patients and other groups was found. Moreover, most lactoferrin levels were below the limit of detection in our assay. In addition, lactoferrin total protein ratios did not appear to be of value in the differential diagnosis of chronic pancreatitis. These results seem to be in contrast to the findings of other authors, who measured lactoferrin in duodenal fluid--which is unreliable, in our opinion--or who mainly studied chronic pancreatitis patients and few other pancreatic diseases. Lactoferrin might well be a nonspecific marker for serious pancreatic inflammation.     

Interaction of secretin and glucagon on exocrine pancreatic secretion.

Inhibition of secretin-stimulated pancreatic secretion by glucagon was studied in anesthetized dogs. Two external pancreatic fistulas were prepared in dogs for both simultaneous and separate collection of pancreatic juice secreted by the right and left lobes. Two series of experiments were preformed. In the first, graded doses of glucagon (2.5 to 20 micrograms/kg/hr) were administered against a background infusion of 2 CHR U/kg/hr of secretin. In the second, a constant dose of glucagon (20 micrograms/kg/hr) was given against a background infusion of secretin doubling from 1 to 8 U/kg/hr. Infusion of glucagon was started when flow rate became nearly constant, and continued for 60 minutes in each dose. Glucagon produced the dose-related reduction in flow rate and bicarbonate secretion, but not in amylase secretion. This inhibitory effect was almost the same in size between the right and left lobes. No significant change of plasma secretin was observed during glucagon infusion. Michealis-Menten analysis of the dose in slopes (Km) and similar intercepts of Y-axis (CMR). These results suggest that glucagon inhibits competitively secretin-stimulated pancreatic secretion by acting probably on the same receptor as secretin.     

Effect of pancreatic juice diversion on secretin release in rats

We investigated a possible role of secretin in the mechanism of exocrine pancreatic secretion after exclusion of pancreatic juice from the intestine in anesthetized rats. Diversion of pancreatic juice from the duodenum resulted in a significant increase in plasma secretin concentration from 0.76 +/- 0.39 pM at 0 time to 3.09 +/- 0.30 pM at 4 h after diversion. This increase in secretin coincided with a steady but significant increase in pancreatic secretion of volume and bicarbonate. Intraduodenal administration of fresh pancreatic juice completely reversed the diversion-induced increases in both plasma secretin and pancreatic secretion. Intravenous injection of a rabbit-antisecretin serum blocked the increase of pancreatic secretion during diversion of pancreatic juice from the duodenum. Thus, we conclude that endogenous secretin is involved in a hormonal mechanism regulating increased pancreatic exocrine secretion in pancreatic juice-diverted rats.     

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.     

Bicarbonate and cyclic AMP content of pure human pancreatic juice in response to graded doses of synthetic secretin.

In seven healthy volunteers pure pancreatic juice was obtained by endoscopic cannulation of the papilla of Vater. Synthetic secretin was intravenously infused in doses doubled every 20 min. The volume of pancreatic juice was proportional to the log of the secretin dose. A significant rise (P less than 0.05) in pancreatic juice flow was elicited at a dose as low as 8.05 ng per kg per hr. Maximum flow rate approximating 250 mul per 5 min per kg of body weight was attained during infusion of 129 ng per kg per hr. At the same dose maximal bicarbonate outputs averaging 383 muEq per hr per kg of body weight were obtained, whereas bicarbonate ion concentration approached peak values (135 +/- 9 muEq per ml) at 32.2 ng per kg per hr. Bicarbonate concentrations showed a tendency to fall at supramaximal doses. The effect of increasing secretin doses on bicarbonate and cyclic AMP concentrations was remarkably similar (rs = 0.635, P less than 0.001) suggesting the participation of cyclic AMP in human pancreatic bicarbonate secretion.