Pancreatic exocrine secretion and immunoreactive secretin release after intraduodenal instillation of 1-phenyl-1-hydroxy-n-pentane and HCl in rats

Portal plasma immunoreactive secretin (IRS) concentrations, pancreatic juice flow, and amylase output were simultaneously measured in response to intraduodenal infusion of 1-phenyl-1-hydroxy-n-pentane (PHP), as well as infusion of hydrochloric acid (HCl). These data were compared with those obtained from intravenous bolus injections of synthetic porcine secretin in anesthetized rats. The intraduodenal infusion of PHP or HCl at a rate of 2 ml/min for 2 min produced a dose-related increase in portal plasma secretin concentrations, pancreatic juice flow, and amylase output. However, the mechanism of secretin release by PHP seems to differ from that of HCl. The secretin response to 0.1 N HCl infused at a rate of 0.1 ml/min for 30 min was complete after 10 min, despite continued infusion, while PHP stimulated a secetin release which persisted for 10 min after cessation of infusion. The pH in the second portion of the duodenum, following PHP infusion, remained consisitently greater than 6.3. PHP-stimulated pancreatic exocrine secretions were only partially suppressed by somatostation, while secretin release was almost completely inhibited. However, intraduodenal PHP may stimulate the release of secretin along with other gastrointestinal hormones, and the endogenous release of these hormones may not be inhibited by somatostatin.     

Influence of topical anesthetic, anticholinergic and ganglionic blocking agents on endogenous secretin release and pancreatic secretion in dogs

The role of parasympathetic including local nerve control on the release of endogenous secretin and pancreatic secretion was studied in four conscious dogs prepared with both Thomas duodenal and gastric fistulae. Plasma secretin levels and pancreatic response during intraduodenal infusion of hydrochloric acid (HCl, graded doses doubling every 30 minutes from 0.3 to 2.4 mEq/10 min) rose significantly in dose-related fashion. Either atropine or hexamethonium, when given intramuscularly, did not inhibit HCl-stimulated endogenous release of secretin, but significantly suppressed pancreatic water, bicarbonate and protein secretions. Oxethazaine, when infused with HCl, suppressed a rise in both plasma secretin concentration and pancreatic secretion. The results obtained led to the conclusion that endogenous release of secretin is not under parasympathetic nervous control, but stimulated directly by intestinal contents.     

Effect of Atropine on Pancreatic Bicarbonate Output and Plasma Concentrations of Immunoreactive Secretin in Response to Intraduodenal Stimulants

In conscious dogs with gastric and pancreatic Thomas fistulas we studied the effect of atropine (50 μg kg^-1 intravenously) on pancreatic bicarbonate output and plasma concentrations of immunoreactive secretin in response to intraduodenal bolus injections of HCl (0.75 mmol), L-tryptophan (1 mmol), and sodium oleate (1 mmol). The 10-min integrated bicarbonate response to HCl was 1.7 times greater than the response to oleate and 2.8 times greater than that to tryptophan. Atropine significantly (p < 0.05) depressed the 10-min integrated bicarbonate response to HCl, oleate, and tryptophan by 67%, 79%, and 61%, respectively. HCl and oleate, but not tryptophan, significantly increased plasma secretin concentrations over basal levels. Atropine did not significantly alter basal plasma concentrations of secretin or the 10-min integrated plasma secretin response to HCl and oleate. We conclude that 1) intraduodenal tryptophan stimulates pancreatic bicarbonate secretion by an atropine-sensitive mechanism, release of secretin not being involved, and 2) in the presence of atropine the depressed pancreatic bicarbonate response to HCl and oleate is not due to decreased release of endogenous secretin.     

Effects of endogenous and exogenous secretin on plasma pancreatic polypeptide concentrations in dogs

Summary The effects of exogenous and endogenous secretin with or without intravenous glucose infusion upon islet hormone secretion were studied in four conscious mongrel dogs fitted with a duodenal fistula. Intravenous infusion of secretin for 1 h at doses of 0.5 and 4 U/kg raised plasma secretin concentrations to physiological and pharmacological levels respectively, without affecting plasma insulin and pancreatic polypeptide concentrations. In contrast, bolus injections of secretin at high concentrations produced significant increases of plasma insulin at 0.5 U/kg and 4 U/kg and of pancreatic polypeptide at 4 U/kg. Plasma glucagon did not change during intravenous infusion of low dose secretin (0.5 U · kg^–1 · h^–1), but decreased during infusion of 4 U · kg^–1 · h^–1 or bolus injection of secretin (0.5 U/kg). Intravenous infusion of glucose together with secretin (0.5 U/kg and 4 U/kg) did not affecf plasma insulin, glucagon, or pancreatic polypeptide levels significantly compared with the changes caused by glucose infusion alone. Intraduodenal instillation of HCl, which produced plasma secretin concentrations similar to those evoked by intravenous infusion of secretin (4 U · kg ^–1 · h^–1), led to a rise in plasma pancreatic polypeptide. It is concluded that the stimulatory effects of secretin on insulin and pancreatic polypeptide and the inhibitory effect on glucagon are pharmacological, and that increase of plasma pancreatic polypeptide after intraduodenal infusion of HCl is not mediated by endogenous secretin.     

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.     

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 duodeno-scope. 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 < 0.05). A significant reduction in plasma concentration of IRS (p < 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.     

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.     

Role of cholecystokinin in pancreatic bicarbonate secretion in dogs

We investigated the effects of endogenous and exogenous cholecystokinin (CCK) on pancreatic exocrine secretion, in particular that of bicarbonate. In six dogs prepared with gastric cannulas and Thomas duodenal cannulas, intraduodenal administration of corn oil (Lipomul) incubated with hog pancreatic enzymes significantly increased pancreatic secretion of both bicarbonate and protein. Increase in pancreatic secretion of both bicarbonate and protein was accompanied by the increase in plasma CCK concentration. However, the increase in bicarbonate as well as protein secretion was blocked by proglumide, a CCK antagonist, given intravenously. In contrast, intraduodenal infusion of undigested Lipomul failed to stimulate the pancreatic exocrine secretion or release of endogenous CCK. These observations indicate that endogenous CCK plays an important role in secretion of both bicarbonate and protein stimulated by digested corn oil. In a group of four dogs with pancreatic fistulas, intravenous infusion of CCK potentiated the stimulatory effect of secretin on pancreatic bicarbonate secretion. The stimulatory effect as well as potentiating effect of CCK on pancreatic bicarbonate secretion was blocked by infusion of proglumide. We conclude that endogenous CCK plays a significant role in fat-stimulated pancreatic secretion, and it is apparent that both endogenous CCK and secretin are equally important for stimulation of pancreatic bicarbonate secretion, which results from potentiation of the action of the two hormones.     

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.     

Secretin release in coeliac disease. Plasma secretin concentration and bicarbonate output to the duodenum after intraduodenal acid infusion in coeliac patients before and after treatment

Infusion of 40 ml 0.1 mol/l HCl into the duodenum in eight untreated coeliac patients was followed by an increase of the plasma immunoreactive secretin (IRS) concentration from 1.6 +/- 0.2 pmol/l to a peak level of 2.4 +/- 0.3 pmol/l (p less than 0.05). After treatment with a gluten-free diet, the same patients showed an increase from 1.4 +/- 0.3 pmol/l to a peak level of 5.5 +/- 0.9 pmol/l after intraduodenal acid infusion, which was significantly higher than before treatment (p less than 0.01). In control subjects, intraduodenal acid infusion was followed by an increase from 1.4 +/- 0.2 pmol/l to 6.7 +/- 1.1 pmol/l, which was significantly higher than in untreated coeliac disease (p less than 0.01) but did not differ from what was found in treated coeliac patients. Significant differences in pH, volume, or bicarbonate content of the duodenal aspirates or the basal IRS levels were not found.     

Characterization of secretin release in response to food and intraduodenal administration of fat and hydrochloric acid

The development and validation of a radioimmunoassay that detects release of secretin in plasma in response to low doses of secretagogues [intraduodenal HCl (0.033 meq/min); intraduodenal sodium oleate (0.04 mmol/min)] or an oral mixed meal in conscious dogs is described. Plasma secretin levels increased significantly (P<0.05) in response to an oral mixed meal in conscious dogs from a basal level of 4.0 to a peak level of 12.3 pg/ml at 15 min. Infusion of graded doses of HCl (2, 4, 8, 16, meq/hr for 30 min) intraduodenally in six dogs resulted in significant elevation of plasma secretin levels in a dose-dependent manner. The pancreatic bicarbonate and volume outputs correlated with the dosage of HCl administered and with the elevations in plasma secretin concentrations. Intraduodenal infusion of increasing doses of sodium oleate (2.4, 4.8, 9.6, and 19.2 mmol in 15-min periods) resulted in a significant (P<0.05) elevation of plasma levels of secretin.Supported by grants from the National Institutes of Health (5R37 DK 15241, PO1 DK 35608).     

Effect of atropine on pancreatic bicarbonate output and plasma concentrations of immunoreactive secretin in response to intraduodenal stimulants

In conscious dogs with gastric and pancreatic Thomas fistulas we studied the effect of atropine (50 micrograms kg-1 intravenously) on pancreatic bicarbonate output and plasma concentrations of immunoreactive secretin in response to intraduodenal bolus injections of HCl (0.75 mmol), L-tryptophan (1 mmol), and sodium oleate (1 mmol). The 10-min integrated bicarbonate response to HCl was 1.7 times greater than the response to oleate and 2.8 times greater than that to tryptophan. Atropine significantly (p less than 0.05) depressed the 10-min integrated bicarbonate response to HCl, oleate, and tryptophan by 67%, 79%, and 61%, respectively. HCl and oleate, but not tryptophan, significantly increased plasma secretin concentrations over basal levels. Atropine did not significantly alter basal plasma concentrations of secretin or the 10-min integrated plasma secretin response to HCl and oleate. We conclude that 1) intraduodenal tryptophan stimulates pancreatic bicarbonate secretion by an atropine-sensitive mechanism, release of secretin not being involved, and 2) in the presence of atropine the depressed pancreatic bicarbonate response to HCl and oleate is not due to decreased release of endogenous secretin.     

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.     

Effect of atropine on pancreatic responses to endogenous and exogenous secretin

The role of cholinergic innervation in endogenous release of secretin from the intestinal mucosa, and in exocrine pancreatic secretion was examined by means of atropine administration in 4 chronic gastric-fistula and pancreatic-fistula dogs during pancreatic response to various doses of synthetic secretin and to various rates of intraduodenal acid load. Atropine infused in a dose of 100µg/kg/hr caused a deep and prolonged decrease of pancreatic flow rate and bicarbonate output reaching a maximum of about 70% of the pre-atropine level of pancreatic secretion. The inhibition occurred regardless of the level of pancreatic response examined, and no significant difference between the effects of atropine on pancreatic responses to exogenous and endogenous secretin was found. Intraduodenal infusion of atropine caused significantly greater inhibition of the pancreatic response to intestinal acidification than that to exogenous secretin. This suggests that release of secretin from the intestinal mucosa might be under the cholinergic control of local nerves.     

Effects of a protein meal, intraduodenal HCl, and oleic acid on portal and peripheral venous secretin and on pancreatic bicarbonate secretion.

We have studied the effect of a protein meal on secretin (IRS) concentration in dogs and humans using a radioimmunoassay of improved sensitivity (8 pg/ml). After a meal, pancreatic bicarbonate secretion (PBS) increased markedly and proximal duodenal pH decreased from 6.2 to 4.3. Portal and peripheral IRS concentrations, however, remained unchanged in eight dogs and five patients with cirrhosis of the liver. Similarly, an alkaline solution of sodium oleate (pH 9.2) stimulated PBS but not IRS. Intraduodenal administration of various amounts of HCl in dogs demonstrated that acid-stimulated PBS was invariably accompanied by rises in peripheral venous IRS concentration. We conclude that the postprandial stimulation of PBS involves mechanisms more complex than acid-stimulated secretin release.     

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.     

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.     

Role of CCK-A receptor in the regulation of pancreatic bicarbonate secretion in conscious rats: a study in naturally occurring CCK-A receptor gene knockout rats.

Whether cholecystokinin (CCK) has a direct action on duct cells and the role of CCK-A receptor in bicarbonate secretion were examined by comparing the results obtained from OLETF (CCK-A receptor-deficient rats) and control (LETO) rats. Rats were prepared with cannulae for draining bile and pancreatic juice separately, with two duodenal cannulae and an external jugular vein cannula. The experiments were conducted without anesthesia. The responses of bicarbonate secretion to intravenous infusion of CCK, acetyl-beta-methylcholine (Ach), and 2-deoxy-D-glucose (2DG), and to intraduodenal infusion of HCl and a liquid meal were examined. To examine the synergistic effect between CCK and secretin, the effect of CCK during a background secretin infusion was examined in LETO rats. CCK did not stimulate bicarbonate secretion in either strain, nor in LETO rats with secretin infusion. When gastric acid secretion was prevented by administration of omeprazole, Ach did not increase bicarbonate secretion, but 2DG did in both strains. Intraduodenal infusion of HCI and a liquid meal significantly increased bicarbonate secretion in both strains; however, the responses were much less in OLETF than LETO rats. In conclusion, intravenous injection of CCK did not stimulate bicarbonate secretion, and the lack of CCK-A receptor decreased bicarbonate secretion in response to luminal stimulants.     

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 pancreastatin on pancreatic exocrine secretion in vivo and in vitro

The effects of pancreastatin on pancreatic exocrine secretion were examined both in vivo and in vitro in rats. Pancreastatin inhibited pancreatic fluid and protein outputs stimulated by the exclusion of pancreatic juice from the intestine with the intraduodenal infusion of Trasylol but did not inhibit bicarbonate output stimulated by HCl in vivo in conscious rats. However, pancreastatin did not affect amylase release from dispersed acini or Ca concentration in acinar cells. Therefore, it is concluded that pancreastatin inhibits pancreatic exocrine secretion but the effect is indirect.