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.     

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.     

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.     

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 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.     

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.A portion of this work has appeared in abstract form (Gastroenterology 82:1161, 1982) and was presented at the Annual Meeting of the American Gastroenterological Association, Chicago (Illinois), on May 18, 1982.     

A small dose of somatostatin inhibits the secretin stimulated secretion of bicarbonate, amylase, and chymotrypsin in man

The effects of a small dose of somatostatin (0.025 mg/h) on the pancreatic secretion of bicarbonate, amylase, and chymotrypsin during stepwise increasing doses of secretin was examined in six healthy volunteers. The secretion of bicarbonate, amylase, and chymotrypsin in response to secretin was significantly reduced by somatostatin. Both output and concentration of pancreatic enzymes were reduced, whereas the concentration of bicarbonate remained unchanged. The pattern of inhibition suggests that somatostatin is a competitive inhibitor of secretin in the stimulation of pancreatic secretion of bicarbonate, which supports the hypothesis of a direct effect of somatostatin on the exocrine secretory cells of the pancreas. The pattern of inhibition of amylase and chymotrypsin secretion is different and difficult to interpret from the present study, but somatostatin may inhibit also the secretin stimulated pancreatic secretion of enzymes completely, as the inhibitory effect seemed to decline when larger doses of secretin were applied.     

Exocrine pancreatic secretion and immunoreactive secretin release after repeated intraduodenal infusions of bile in man

The exocrine pancreatic secretion of water, bicarbonate, amylase, trypsin, chymotrypsin, and lipase and the plasma concentration of immunoreactive secretin (IRS) were studied before and after repeated intraduodenal infusions of cattle bile in man. After endoscopic cannulation of the main pancreatic duct, juice was collected in 5-min samples for 20 min. A solution of 6 g dried cattle bile in 60 ml water was then infused into the duodenum through a separate catheter attached to the outside of the duodenoscope. Juice was collected for another 20 min. After this period a solution of 6 g dried cattle bile in 40 ml water was infused into the duodenum, and juice again collected for 20 min. Blood was frequently drawn from an arm vein for estimation of plasma concentration of secretin by radioimmunoassay. Both bile infusions caused significant rises in flow rate, bicarbonate concentration and output, and IRS (p less than 0.05). Enzyme concentrations decreased significantly after intraduodenal bile infusions (p less than 0.05). Outputs of enzymes rose significantly after the first bile infusion; however, a rise after the second bile infusion was found only for amylase. Further, a significant decrease in amylase and lipase concentration was found after the second bile infusion. The findings indicate that the increase in proteolytic enzyme and lipase secretion was due to a washout phenomenon. The increase in the plasma concentration of secretin after repeated bile infusions, with a corresponding effect on flow rate and bicarbonate secretion, indicates that secretin may be the main factor responsible for the exocrine pancreatic secretion caused by intraduodenal bile infusions.     

Pancreatic secretion obtained by endoscopic cannulation of the main pancreatic duct and secretin release after duodenal acidification in man.

The main pancreatic duct was cannulated in 12 individuals with a teflon catheter by means of a side-viewing duodenscope. Six individuals received a duodenal infusion of 40 ml 100 mmol/l HCl over 5 min, while the other six served as controls for basal pancreatic secretion. Pancreatic juice was collected in 5-min samples, and blood was frequently drawn for radioimmunoassay of immunoreactive secretin (IRS). In the control group, during 20-min cannulation of the main pancreatic duct, no effect was seen on basal secretion of water, bicarbonate, or alpha-amylase--nor did the IRS levels change. After duodenal acidification there was a significant increase in IRS (p less than 0.02), reaching the highest level at 7 min. The mean flow rate, bicarbonate concentration, and bicarbonate output showed a significant increase as compared to the control group (p less than 0.02), the highest levels being reached in the third 5-min period after the start of the duodenal acidification. The alpha-amylase output was also significantly higher after acidification (p less than 0.02) than in the control group, but the mean alpha-amylase concentration decreased after acidification, reaching its nadir in the third 5-min sample (p less than 0.02). The present results demonstrate a basal and HCl-stimulated pancreatic secretion collected by endoscopic cannulation of the main pancreatic duct in man together with plasma IRS levels.     

Physiological significance of secretin in the pancreatic bicarbonate secretion. II. Pancreatic bicarbonate response to a physiological increase in plasma secretin concentration.

The pancreatic response to physiological concentrations of secretin obtained after minute boluses of exogenous secretin was studied in 16 normal volunteers. Output of bicarbonate into the duodenum was measured by duodenal aspiration in 5 subjects and by endoscopic cannulation of the pancreatic duct in 11 subjects. Pure natural porcine secretin was injected intravenously in doses of 125, 250, and 500 fmol x kg-1 body weight (0.0013, 0.0027, and 0.0054 clinical units x kg-1). All three doses of secretin increased plasma secretin concentration, duodenal bicarbonate concentration, and duodenal bicarbonate output significantly. The bicarbonate output measured by the two techniques did not differ significantly. The increments in median plasma secretin concentration were 1.6, 3.0, and 6.4 pmol x 1(-1) after secretin, 125, 250 and 500 fmol x kg-1, and the corresponding 15-min bicarbonate output 283, 442, and 1435 micromol, respectively. The concentrations of secretin in plasma found after these doses of secretin are of the same order of magnitude as the secretin concentrations found during physiological conditions in man. It is concluded that the physiological concentrations or secretin influence pancreatic bicarbonate secretion.     

Exocrine pancreatic secretion and immunoreactive secretin (IRS) release after intraduodenal instillation of bile in man.

Six subjects with a normal endoscopic pancreatogram were investigated after an overnight fast by means of a side-viewing duodenoscope. After cannulation of the main pancreatic duct, juice was collected in five-minute samples for 20 minutes. An iso-osmolar solution of 6 g cattle bile was then infused into the duodenum through a separate catheter attached to the outside of the duodenoscope, and pancreatic juice collected in five-minute samples for another 20 minutes. Blood was frequently drawn from an arm vein through an indwelling catheter for estimation of immunoreactive secretin (IRS) by radioimmunassay. The flow rate of pancreatic juice and outputs of bicarbonate, amylase, and protein increased significantly after intraduodenal infusion of bile. A significant rise in plasma IRS was also found after instillation of bile in the duodenum.     

Effect of dopamine infusion on gastric and pancreatic secretion and on gastrin release in man.

The effect of dopamine infusion on basal and pentagastrin-stimulated gastric secretion, on basal and secretin-CCK-PZ-stimulated pancreatic secretion, and on basal and meal-induced gastrin release has been evaluated in healthy volunteers. Both basal and stimulated gastric acid secretion were significantly inhibited during dopamine infusion with a significant rebound to pre-infusion values after discontinuing dopamine. These effects were prevented by pretreatment with the antidopaminergic drug, metoclopramide. A slight but now significant decrease in amylase and bicarbonate outputs was also observed during dopamine infusion, while gastrin release did not change. These data suggest the existence of dopaminergic mechanisms in the regulation of gastric acid secretion in man.     

External pancreatic secretion after bombesin infusion in man.

The effect of bombesin on external pancreatic secretion was studied in seven healthy volunteers and intwo patients with a two-thirds gastrectomy and a pancreatic fistula. After bombesin infusion (15 ng/kg/min), gastrin levels were significantly raised in all volunteers, but remained at basal levels in the gastrectomized patients. Bombesin was effective in stimulating pancreatic secretion in all patients. The volume of secretion increased tow-fold when compared with basal volume. Amylase and trypsin concentrations and outputs in the duodenal juice were greatly agumented (amylase concentration: basal, 70 dye U/ml; post-bombesin, 620 dye U/ml. Amylase output: basal, 1000 dye U/15 min; post-bombesin, 15,800 dye U/15 min). Secretin, when administered in conjunction with bombesin, partially inhibited its secretory effect. Bicarbonate secretion was slightly stimulated by bombesin, but at a very low level. A similar pattern of results was obtained in the two gastrectomized patients. In man, bombesin exerts an effect on pancreatic secretion that mimics the effect of CCK-PZ, thus confirming the results obtained in the experimental animal. Gastrin does not play a fundamental role in this phenomenon.     

Inhibition of pancreatic secretion in man by cigarette smoking

Cigarette smoking has been linked to an elevated incidence of duodenal ulcer disease in smokers, although the mechanism is unclear. In 23 young normal subjects single or double secretin tests were performed during non-smoking and smoking periods. Cigarette smoking inhibited the secretion of pancreatic juice and bicarbonate in light smokers (< one pack/day for < three years). Heavy smokers (> one pack/day for > three years) exhibited depressed pancreatic secretory rates during non-smoking periods. Inhibition of pancreatic alkaline secretion by cigarette smoking could be the link between the habit and duodenal ulcer disease.     

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.     

Action of secretin on pancreatic enzyme secretion in man. Studies on pure pancreatic juice

The action of pure, natural secretin on the pancreatic secretion of enzymes was investigated in six patients with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery. Secretin infused for five successive 50 minute periods at increasing doses of 0.03, 0.1, 0.3, 0.9 and 2.7 clinical units (CU)/kg/h, produce a dose dependent increase in protein and lipase output. A weak but significant (p less than 0.02) increase of enzyme output above the fasting level was already observed with the lowest dose. The maximal output of protein and lipase, observed with the highest dose of secretin infused, corresponded to about 50% of that induced by maximal doses of cerulein (100 ng/kg/h) plus secretin (1 CU/kg/h). As far as bicarbonate is concerned, the lowest dose of secretin (0.03 CU/kg/h) significantly (p less than 0.001) stimulated bicarbonate output. The dose of 0.9 CU/kg/h of secretin evoked a bicarbonate output of 526 +/- 49 micromol/min; trebling the dose of secretin did not significantly increase the output of bicarbonate above this value. Increasing doses of secretin induced a dose related increase in calcium output. There was a close parallel between calcium and protein outputs, suggesting that the increase in calcium output reflected primarily an increase in the enzyme-associated fraction of pancreatic juice calcium. It is concluded that secretin stimulates pancreatic enzyme secretion in man probably by a direct action on the acinar cells.     

Effects of somatostatin on gastric secretion and gastrin release in man.

Somatostatin, a recently synthesized hypothalamic growth hormone release-inhibiting factor (GIF), was used in the cyclic and linear form. In all subjects studied, the cyclic GIF inhibited gastrin secretion during basal conditions as well as during a standard food stimulus, with immediate rebound after the infusion was stopped. Similar responses were observed in a hypophysectomized patient, indicating that this effect of GIF was independent of suppression of growth hormone secretion. Cyclic and linear GIF, when administered in normal subjects during an infusion of synthetic human gastrin I, almost totally suppressed gastric secretion. The results indicate that GIF is a potent inhibitor of gastric secretion and gastrin release.     

Plaunotol stimulates endogenous secretin release and exocrine pancreatic secretion in rats

The effect of the new antiulcer agent plaunotol on the release of endogenous secretin and the pancreatic exocrine secretion was investigated in anesthetized rats. In 48 rats with pancreatic and biliary diversion, continuous intraduodenal infusion of plaunotol in 3 graded doses (5, 20 and 80 mg/h/rat) resulted in significant increases in both circulating plasma secretin concentration and pancreatic exocrine secretion, including volume and bicarbonate output, in a dose-dependent manner (r = 0.655, p less than 0.001; r = 0.598, p less than 0.001; r = 0.436, p less than 0.01, respectively). The pancreatic bicarbonate output was closely correlated to plasma secretin concentrations (r = 0.631, p less than 0.001). Amylase output also increased after plaunotol administration, but not in a dose-dependent manner (r = 0.092, n.s.). These findings suggest strongly that the increase in pancreatic secretion of fluid and bicarbonate output was mainly due to increased endogenous secretin release resulting from plaunotol administration.     

Effect of low-dose exogenous secretin and somatostatin on pentagastrin-stimulated gastric acid secretion in man

The inhibitory effect of intravenous infusion of secretin (0.05 CU kg-1h-1) and somatostatin (60 pmol kg-1h-1), given alone or in combination, on pentagastrin-stimulated (100 ng kg-1 h-1) acid secretion was studied in 10 healthy subjects. Secretin inhibited acid secretion by 54% (p less than 0.05), and somatostatin inhibited by 70% (p less than 0.05). The combined infusion of secretin and somatostatin decreased acid output by 64% (p less than 0.05). The differences between the three groups were not significant (p greater than 0.05). Median plasma concentrations of secretin and somatostatin were of the same magnitude as seen after duodenal acidification. The present study did not demonstrate any interaction between secretin and somatostatin in the inhibition of gastric acid secretion.