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.     

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.     

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.     

The unstimulated pancreatic secretion obtained by endoscopic cannulation, and the plasma secretin levels in man.

The technique of collecting juice from the main pancreatic duct by siphonage is described. The juice was collected in 5-min fractions under basal conditions for 20 min (32 subjects) and extended to 60 min (6 subjects). Flow rate and bicarbonate concentration were significantly higher during the first collected samples, whereas concentrations of amylase and protein rose during the first 20 min of the study. All variables remained nearly constant after this period. Immunoreactive secretin (IRS) in peripheral plasma was significantly higher immediately after cannulation of the main pancreatic duct, as compared to the pre-endoscopic level. When the catheter was left in the duct and pancreatic juice drained, the IRS stabilized at a level not significantly different from the pre-endoscopic level. Positive correlations were found between flow rate and plasma level of IRS and between flow rate and bicarbonate concentrations. A negative correlation was found between the flow rate and concentrations of amylase and protein. The higher flow rate, plasma level of IRS, and bicarbonate concentration at the beginning of the examination may be due to the presence of acid and/or bile in the duodenal contents shortly after the endoscope enters the duodenum. Later in the procedure the levels have stabilized, which indicates that little or no acid or bile is passing into the duodenum. It is also concluded that secretin may be one factor responsible for the basal pancreatic secretion in man.     

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.     

Effect of intraduodenal oligopeptide on rat pancreatic exocrine secretion and release of secretin and CCK]

We investigated whether intraduodenal (id) oligopeptide with three or four amino acids residues (pH 7.0) stimulates pancreatic exocrine secretion and release of endogenous plasma secretin and CCK in anesthetized rats. Id administration of oligopeptides in three doses (25, 100, 400 mg/hr) at a speed of 4 ml/hr resulted in dose-related increases in pancreatic secretion of pancreatic juice volume, bicarbonate, and amylase outputs (r = 0.598, 0.673, and 0.426, P less than 0.05 -- 0.001), and plasma concentrations of secretin and CCK (r = 0.743, 0.425, P less than 0.001 and 0.05). Intravenous administration of CCK-antagonist, CR1505 (5 mg/kg.hr) markedly inhibited oligopeptide-stimulated amylase output, but did not affect pancreatic juice volume and bicarbonate output. These results suggest that id oligopeptide increases pancreatic exocrine secretion and releases endogenous secretin and CCK.     

Luminal bile regulates cholecystokinin release in conscious rats

The effects of intraluminal bile on cholecystokinin release and pancreatic exocrine secretion were studied in conscious rats. Since it has been suggested that bile acid may influence pancreatic secretion indirectly by interacting with luminal protease activities, intraduodenal protease activities were eliminated by pancreatic juice diversion accompanied with simultaneous intraduodenal infusion of aprotinin. This treatment resulted in gradual increases in pancreatic juice flow, bicarbonate and protein outputs, and an increase in plasma cholecystokinin levels, reaching plateau levels 2 hr after the start of the treatment. When endogenous bile was excluded from the intestine, the pancreatic secretion and plasma cholecystokinin concentrations further increased. The intraduodenal infusion of sodium taurocholate during bile pancreatic juice diversion inhibited cholecystokinin release, while pancreatic protein output was only transiently decreased. The results indicate that bile in the duodenum directly regulates cholecystokinin release, probably through its major components, bile salts.     

Stimulatory and inhibitory effects of bile salts on rat pancreatic secretion.

The effects of various species of bile salts (chenodeoxycholate, deoxycholate, ursodeoxycholate and cholate, and their taurine and glycine conjugates) on pancreatic exocrine secretion were studied in conscious rats with external bile and pancreatic fistulae. For examination of the stimulatory effects of bile salts, bile and pancreatic juice were collected for a basal period of 90 minutes and returned to the intestine, and then solutions of bile salts (60 mmol/L) were infused intraduodenally at a rate of 1 mL/h for 2 hours. For examination of their inhibitory effects, pancreatic secretion was stimulated by exclusion of the bile and pancreatic juice; and then solutions of the bile salts were again infused intraduodenally. Chenodeoxycholate, glycochenodeoxycholate, ursodeoxycholate, deoxycholate, and its conjugates (glycodeoxycholate and taurodeoxycholate) significantly increased the fluid, bicarbonate and protein outputs, and bicarbonate concentration, with decrease in protein concentration. These increases were partially inhibited by infusion of either a cholecystokinin antagonist or secretin antibody. In contrast, cholate, taurocholate, tauroursodeoxycholate, glycoursodeoxycholate, and taurochenodeoxycholate inhibited pancreatic secretion and increase in the plasma cholecystokinin concentration produced by exclusion of bile and pancreatic juice. Thus, some bile salts, including taurocholate and taurochenodeoxycholate (major bile salts in rat bile) inhibited pancreatic secretion and cholecystokinin release, whereas some other bile salts increased pancreatic secretion via cholecystokinin release and secretin release.     

Effect of fatty acid on secretin release and cholinergic dependence of pancreatic secretion in rats

We investigated the effects of oleic acid in the duodenum on pancreatic exocrine secretion and plasma secretin, and determined the role of cholinergic dependence on pancreatic secretion and secretin release in response to oleic acid in anesthetized rats. Oleic acid emulsion (pH 6.5) in three different doses of 0.06, 0.25, and 1 mmol/h was infused intraduodenally for 1 h with or without intravenous administration of atropine in a dose of 100 micrograms/kg/h. Intraduodenal administration of oleic acid resulted in significant increases in pancreatic juice volume and bicarbonate output, in a dose-related manner (p less than 0.001). Plasma secretin concentration caused dose-dependent elevation (p less than 0.001) by oleic acid, which correlated very well with bicarbonate output in response to oleic acid (p less than 0.001). Atropine inhibited pancreatic secretion including juice volume and bicarbonate output stimulated by oleic acid in each dose, statistically significantly (p less than 0.05-0.01), but did not affect plasma secretin concentration. Thus, we conclude that oleic acid in the duodenum stimulates pancreatic secretion and endogenous secretin release in rats, and that secretin release is not influenced by the cholinergic tone, although pancreatic secretory response is inhibited significantly.     

Fat and pancreatic secretion

In 10 healthy volunteers we investigated the effects of intraduodenal oleic acid at various concentrations (0-40 mM) and at various degrees of emulsification on pancreaticobiliary secretion and the release of secretin and cholecystokinin (CCK) into plasma. We found that the release of the two hormones was directly related to the dose of fat and to the degree of emulsification. The threshold of CCK release (and amylase output) was low in comparison with the threshold for secretin release (and bicarbonate or volume output). When the degree of emulsification of the fat was increased, no simple relation was observed between hormone levels and pancreatic exocrine secretion. The output of bile salts was identical at various fat concentrations. We conclude that both secretin and CCK are dose-dependently released by emulsions of oleic acid in normal man and that the thresholds for release are probably different.     

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.     

Effect of intraluminal bile on the feedback regulatory mechanism of pancreatic enzyme secretion in conscious rats

The effect of intraluminal bile on the well-known feedback regulatory mechanism of exocrine pancreatic secretion exerted by intraluminal trypsin was investigated in conscious rats with pancreatic, biliary and duodenal fistulae. The stimulated pancreatic enzyme secretion caused by diversion of bile-pancreatic juice from the intestine was apparently suppressed by intraduodenal reintroduction of pancreatic juice or bile-pancreatic juice, while it was slightly suppressed by intraduodenal reintroduction of bile. Although additional reintroduction of bile did not alter the already suppressed pancreatic enzyme secretion by the presence of pancreatic juice in the intestine, diversion of bile stimulated the suppressed pancreatic enzyme secretion by intraluminal bile-pancreatic juice. Infusion of sodium taurocholate into the duodenum with diversion of bile-pancreatic juice effectively inhibited pancreatic enzyme secretion. The inhibitory effect seemed to be dependent on the concentration of taurocholate infused into the duodenum. The results suggest that bile and bile acid have an important role in the feedback regulatory mechanism of pancreatic enzyme secretion, at least partly directly inhibiting the secretion.     

Regulatory effects on the pancreas of intraduodenal pancreatic juice and trypsin in the Syrian golden hamster

The effect of intraduodenal trypsin activity on pancreatic exocrine secretion was studied in conscious Syrian golden hamsters provided with bile-pancreatic fistulae. The secretion (secretory volume, amylase and protein output) was stable during a collection period of 14 h without any duodenal infusions. Infusion into the duodenum of bicarbonate or bile did not affect the secretion. When, however, bile-pancreatic juice or trypsin was administered intraduodenally, a marked depression of amylase and protein output was found. After addition of trypsin inhibitor--in a dose sufficient to eliminate all trypsin activity--to either of the two infusates the secretion was restored to the initial values. In a long-term experiment (10 days) repeated subcutaneous injections of cholecystokinin caused a significant increase of pancreatic protein and amylase content in the hamster. Oral trypsin inhibitor administration for 10 days had similar, although not so pronounced effects. Subcutaneous secretin administration was without effect in this respect. The results show that pancreatic enzyme secretion in the Syrian golden hamster is controlled by a negative feedback regulation exerted by intraluminal trypsin. The findings also suggest that both cholecystokinin and orally administered trypsin inhibitor exert trophic effects on the pancreas.     

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 bile salts on pancreatic secretion in rabbits: ursodeoxycholate infused into the duodenum stimulates pancreas

The effects of six species of bile salts, deoxycholate, ursodeoxycholate, glycodeoxycholate, tauroursodeoxycholate, chenodeoxycholate, and cholate (DCA, UDCA, GDC, TUDC, CDCA, CA), on pancreatic secretion were examined in anesthetized rabbits. When bile salts were infused intraduodenally, only UDCA significantly increased the pancreatic juice flow and bicarbonate output, whereas the increase in protein output was only transient. In contrast, UDCA infused intravenously did not affect the pancreatic secretion. Furthermore, none of the other bile salts, either intraduodenally or intravenously administered, had any significant effect on pancreatic exocrine function. Pancreatic responses to the intraduodenally administered UDCA in terms of fluid, bicarbonate, and protein secretion were similar to those of secretin infused intravenously. Thus, it was suggested that UDCA infused intraduodenally stimulates pancreatic secretion, possibly via the release of a secretin-like substance(s) from the duodenal wall.     

Mediation of trypsin inhibitor-induced pancreatic hypersecretion by secretin and cholecystokinin in rats.

We investigated a hormonal mechanism in a trypsin inhibitor-induced pancreatic hypersecretion in rats. Intraduodenal administration of a synthetic trypsin inhibitor, camostat, resulted in significant increases in plasma concentration of both secretin and cholecystokinin in a dose-related manner that paralleled a significant increase in exocrine pancreatic secretion. To eliminate the effect of circulating secretin in rats, a rabbit antisecretin serum was given IV that resulted in a 77% reduction in bicarbonate secretion stimulated by intraduodenal camostat. A cholecystokinin receptor antagonist, MK-329, also inhibited significantly the camostat-induced increase in pancreatic secretion; volume and bicarbonate output were reduced by 35% each and amylase output by 73%. The combined administration of antisecretin serum and MK-329 completely abolished the pancreatic exocrine secretion stimulated by camostat. These observations indicate that the camostat-stimulated pancreatic exocrine secretion is mediated by the increased release of both secretin and cholecystokinin in rats.     

Effect of intraduodenai infusion of tocamphyl on pancreatic exocrine secretion and gastrointestinal hormone release in rats

Tocamphyl is a synthetic choleretic that is derived from a root extract ofCurcuma longa, L. We investigated the effect of tocamphyl on pancreatic exocrine secretion and bile flow, and on the release of some gastrointestinal hormones, by administering it intraduodenally using anesthetized rats. Tocamphyl stimulated pancreatic exocrine secretion in terms of volume and amylase output in a dose-related manner. Neither a CCK-receptor antagonist, CR1505 (loxiglumide), nor atropine sulfate infused intravenously suppressed the stimulatory effects of tocamphyl on pancreatic exocrine secretion and bile flow. The stimulatory effect on bile flow was stronger than that on pancreatic exocrine secretion. Plasma secretin levels were augmented with the increasing doses of tocamphyl, but CCK levels were not. These results indicate that intraduodenally administered tocamphyl stimulates pancreatic exocrine secretion and bile flow, and suggest that the stimulatory action is, at least in part, mediated by secretin, but not by either CCK or the cholinergic pathway.     

Mechanism of pancreatic hypersecretion in dogs with obstructive jaundice

Pancreatic exocrine function in experimental obstructive jaundice was examined using dogs. Outputs of pancreatic juice, bicarbonate and amylase were greater in dogs with obstructive jaundice than in control dogs. To further examine the hypersecretory mechanism in obstructive jaundice, we examined pancreatic exocrine secretion stimulated by secretin and pancreozymin in both the isolated perfused pancreas and pancreatic dispersed cell culture. The perfused pancreas stimulated with secretin and pancreozymin in dogs with obstructive jaundice showed higher secretion of volume, bicarbonate and amylase than in control dogs. Dispersed pancreatic cells of jaundiced dogs stimulated by secretin and pancreozymin released more bicarbonate and amylase into the media than dispersed cells of control dogs. These data suggest pancreatic hypersecretion in obstructive jaundice is not due to excessive serum levels of secretin and pancreozymin or impaired metabolism of these hormones.     

Mechanism of pancreatic hypersecretion in dogs with obstructive jaundice

Summary Pancreatic exocrine function in experimental obstructive jaundice was examined using dogs. Outputs of pancreatic juice, bicarbonate and amylase were greater in dogs with obstructive jaundice than in control dogs. To further examine the hypersecretory mechanism in obstructive jaundice, we examined pancreatic exocrine secretion stimulated by secretin and pancreozymin in both the isolated perfused pancreas and pancreatic dispersed cell culture. The perfused pancreas stimulated with secretin and pancreozymin in dogs with obstructive jaundice showed higher secretion of volume, bicarbonate and amylase than in control dogs. Dispersed pancreatic cells of jaundiced dogs stimulated by secretin and pancreozymin released more bicarbonate and amylase into the media than dispersed cells of control dogs. These data suggest pancreatic hypersecretion in obstructive jaundice is not due to excessive serum levels of secretin and pancreozymin or impaired metabolism of these hormones.     

Effect of ursodeoxycholate on pancreatic exocrine secretion in vitro and in vivo study]

In the present study, we examined the effect of ursodeoxycholate (UDCA) and it's taurine conjugate (TUDC) on rat pancreatic exocrine secretion using dispersed pancreatic acini (in vitro) and conscious rats (in vivo). In in vitro study 300 microM UDCA significantly increased 10(-12)-10(-9) M CCK-8 stimulated amylase release and change of intracellular Ca2+ concentration, but TUDC did not have these effects. In in vivo study intraduodenal infusion of UDCA but not TUDC stimulated pancreatic exocrine secretion. Intravenous infusion of secretin antibody decreased bicarbonate output, however, this increase was not prevented by CCK antagonist. Thus, it was suggested that UDCA has direct action on pancreatic acini and UDCA infused intraduodenally stimulates pancreatic secretion, possibly via the release of a secretin-like substance. The taurine conjugate has weak bioactivity on pancreatic exocrine secretion in both in vitro and in vivo.