Effect of plaunotol on release of plasma secretin and pancreatic exocrine secretion in humans

Plaunotol, an acyclic diterpene alcohol is a new antiulcer agent derived from the leaves of the plau-noi plant. We investigated the effect of plaunotol on the release of endogenous secretin with radioimmunoassay and exocrine pancreatic secretion, using a dye dilution technique with polyethylene glycol 4,000 as a nonabsorbable marker in eight human volunteers. Intrajejunal administration of plaunotol (pH 6.5) in three different doses (80, 160, and 320 mg/30 min) resulted in significant increases in both plasma secretin concentration and pancreatic bicarbonate secretion in a dose-related manner (r = 0.819 and 0.701, p less than 0.001, respectively). Bicarbonate outputs produced by plaunotol correlated well with plasma secretin concentrations (r = 0.727, p less than 0.001). Amylase output was also increased significantly by plaunotol. However, the response was not dose-dependent from that of bicarbonate output. These results indicate that endogenous secretin is released by plaunotol in humans and suggest that the increased pancreatic bicarbonate secretion can be attributed to the increased plasma secretin concentration.     

Effect of licorice extract (Fm100) on release of secretin and exocrine pancreatic secretion in humans

We investigated the effect of a fraction of licorice extract (Fm100) on release of endogenous secretin in seven human volunteers using radioimmunoassay and exocrine pancreatic secretion using a dye dilution technique with polyethylene glycol 4000 as a non-absorbable marker. Intrajejunal administration of Fm100 (pH 6.5) in three different doses (200, 400, and 800 mg/30 min) resulted in significant increases in both plasma secretin concentration and pancreatic bicarbonate output in a dose-dependent manner (r = 0.737, p less than 0.001, and r = 0.483, p less than 0.01, respectively). However, it did not influence pancreatic secretion of protein or amylase. The correlation between plasma secretin concentrations and bicarbonate outputs was also significant (r = 0.483; p less than 0.01). These results indicate that endogenous secretin is released by Fm100 in humans and suggest strongly that the increased pancreatic bicarbonate secretion is attributable to the increased plasma concentration of secretin.     

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.     

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.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats.

We investigated the possible role of endogenous secretin and cholecystokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r = 0.665, 0.736 and 0.517, respectively) (P less than 0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r = 0.721 and 0.546, respectively) (P less than 0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P less than 0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats.     

Release of secretin by licorice extract in dogs

To determine the effect of a fraction of licorice extract, FM100, on the endogenous release of secretin and exocrine pancreatic secretion, five dogs were prepared with chronic pancreatic fistulas and gastric cannulas. Intraduodenal administration of licorice extract (pH 7.4) in three different doses (0.5, 1.0, and 2.0 g) resulted in significant increases of both plasma secretin concentrations and pancreatic bicarbonate secretion in a dose-related manner. The plasma secretin concentration and pancreatic bicarbonate output produced by licorice extract correlated well. Intragastric administration of licorice extract (2 g) in 5% liver extract meal (in which pH was maintained at 5.5 by the intragastric titration method) resulted in significant increases of both plasma secretin concentration and pancreatic bicarbonate output. The increase in pancreatic bicarbonate secretion was completely abolished by intravenous infusion of a rabbit antisecretin serum in the two dogs so studied. Thus, the present study indicates that the endogenous release of secretion is involved in a mechanism of an increase in exocrine pancreatic secretin induced by FM100.     

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.     

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.     

Plasma osmolality and exocrine pancreatic secretion

To confirm the influence of plasma osmolality on exocrine pancreatic secretion, hypertonic saline (4% saline) was given intravenously to dogs with gastric and pancreatic fistulae. Intravenous administration of hypertonic saline caused a reduction of pancreatic juice flow and bicarbonate output, but did not alter protein output stimulated by secretin and cerulein. The changes of pancreatic juice flow(X) exhibited negative correlations with the changes in plasma osmolality(Y) (Y = -2.2X + 6.4, r = -0.74, p less than 0.01). Plasma osmolality and plasma vasopressin level were measured simultaneously. Plasma osmolality was elevated from 292 to 315 mOsm/kg with concurrent increase of plasma vasopressin level from 2.4 to 19.6 pg/mL. On the other hand, exogenous administration of vasopressin inhibited pancreatic juice flow and bicarbonate output dose-dependently. In conclusion, elevation of plasma osmolality decreased exocrine pancreatic secretion stimulated by secretin and cerulein, and vasopressin may play an important role in its mechanism.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats

We investigated the possible role of endogenous secretin and cholecytokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r=0.665, 0.736 and 0.517, respectively) (P<0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r=0.721 and 0.546, respectively) (P<0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P<0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats. The results of this study were presented at The 7th International Symposium of Gastrointestinal Hormones in Shizuoka, Japan, Nov. 1–4, 1988, and appeared in abstract form in Biomedical Research 1988;9(Suppl. 1):114. This work was supported in part by grants from the Japanese Ministry of Education and the Ministry of Welfare. The authors are grateful to Y. Hirasawa, B.S. and M. Takeda, B.S. for their technical assitance.     

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.     

Release of cholecystokinin and exocrine pancreatic secretion in response to an elemental diet in human subjects

We investigated in human volunteers the effects of an elemental diet (ED) containing amino acids on release of endogenous cholecystokinin (CCK) using a highly sensitive and specific radioimmunoassay of CCK and exocrine pancreatic secretion using a dye dilution technique with polyethylene glycol 4000 as a nonabsorbable marker. Intrajejunal administration of ED at three different infusion rates (12.5, 25, and 50 ml/30 min) resulted in a significant increase in plasma CCK concentration in a dose-related manner. Plasma concentrations of gastrin or secretin, however, did not change. Pancreatic secretion of protein, amylase, and bicarbonate also increased significantly. The change in pancreatic secretion of protein, amylase, and bicarbonate output paralleled that of the circulating CCK level but not that of plasma secretin. Thus, the dose of amino acid contained in ED recommended for clinical use can significantly stimulate the release of CCK from the upper small intestine, raising the plasma concentration of CCK. This level can evoke a significant increase in exocrine pancreatic secretion.This work was supported by United States Public Health Grant NIH AMDDK 25962.     

Neurotensin and the exocrine pancreas

It has been postulated that neurotensin (NT) has a physiological role in the regulation of the exocrine pancreas, but this is controversial. Using the Thomas cannula canine model, the effect of intravenous NT, in physiological and pharmacological doses on exocrine pancreatic secretion, and on plasma pancreatic polypeptide, secretin and cholecystokinin (CCK) levels is reported. The infusion of physiological doses of NT alone (0.2 pmol/kg per min) did not stimulate pancreatic secretion; however, in conjunction with secretin, NT stimulated protein and bicarbonate output, the latter synergistically. Higher doses of NT (20 and 100 pmol/kg per min) resulted in a dose-dependent stimulation of pancreatic volume, bicarbonate and protein secretion. Cholinergic blockade with atropine reduced pancreatic secretion stimulated by low doses of NT (2–20 pmol/kg per min), but at higher doses (100 pmol/kg per min) protein secretion was reduced whilst bicarbonate secretion was enhanced. The infusion of graded doses of NT had no effect on plasma secretin or CCK levels. In contrast, NT did release pancreatic polypeptide in a dose-dependent manner, but only at pharmacological infusion levels. NT, acting synergistically with other hormones, may thus play a role in exocrine pancreatic stimulation.     

Peptide YY inhibits pancreatic secretion by inhibiting cholecystokinin release in the dog

Peptide YY inhibits the pancreatic exocrine secretion (bicarbonate, water, and protein) that is stimulated by cholecystokinin, secretin, or neurotensin in the dog, but whether peptide YY inhibits the release of gut peptides that stimulate pancreatic exocrine secretion is not known. Six dogs were prepared with gastric, pancreatic, and cecal cannulas. On separate days, a single dose of sodium oleate (3, 6, 7.5, 9, 12, 15, or 18 mmol/h) was given intraduodenally for 90 min, either alone (control) or in combination with peptide YY (25, 50, 100, 200, or 400 pmol/kg.h, i.v.). We measured plasma levels of cholecystokinin-33/39, secretin, neurotensin, and peptide YY by radioimmunoassay. During infusion of peptide YY, the integrated release of cholecystokinin (3.3 +/- 0.5 ng-[0-90] min/ml) was decreased significantly (p less than 0.05) when compared with control values (5.6 +/- 0.6). Release of secretin and neurotensin was not affected. A positive correlation (p less than 0.05) was found between the release of cholecystokinin and pancreatic protein output in both control (r = 0.68) and peptide YY-treated (r = 0.67) groups. Release of peptide YY was significant after intraduodenal or intracolonic administration of sodium oleate. These studies demonstrate that inhibition of pancreatic protein secretion by peptide YY in dogs is mediated, at least in part, by an inhibition of the release of cholecystokinin.     

Plasma osmolality and exocrine pancreatic secretion

To confirm the influence of plasma osmolality on exocrine pancreatic secretion, hypertonic saline (4% saline) was given intravenously to dogs with gastric and pancreatic fistulae. Intravenous administration of hypertonic saline caused a reduction of pancreatic juice flow and bicarbonate output, but did not alter protein output stimulated by secretin and cerulein. The changes of pancreatic juice flow(X) exhibited negative correlations with the changes in plasma osmolality(Y)(Y = -2.2X + 6A, r = -0.74,p < 0.01). Plasma osmolality and plasma vasopressin level were measured simultaneously. Plasma osmolality was elevated from 292 to 315 mOsm/kg with concurrent increase of plasma vasopressin level from 2.4 to 19.6 pg/ mL. On the other hand, exogenous administration of vasopressin inhibited pancreatic juice flow and bicarbonate output dose-dependently. In conclusion, elevation of plasma osmolality decreased exocrine pancreatic secretion stimulated by secretin and cerulein, and vasopressin may play an important role in its mechanism.     

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.     

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.     

Potentiation of cholecystokinin and secretin-induced pancreatic exocrine secretion by endogenous insulin in humans

To investigate the effects of endogenous insulin on pancreatic exocrine secretion in humans, we evaluated the pure pancreatic juice obtained by endoscopic cannulation of the main pancreatic duct in 21 healthy subjects (14 men and seven women). Samples of pancreatic juices were collected after intravenous injection of either glucose (50%, 40 ml), secretin (0.25 CU/kg), and cholecystokinin-8 (CCK) (40 ng/kg), or a combination of glucose, secretin, and CCK in six 5-min periods. The responses of plasma glucose, insulin, and C-peptide to intravenous administration of glucose were measured. After infusion of glucose, the plasma insulin and C-peptide levels were significantly increased and remained at high levels during 30-min experiments, intravenous administration of secretin and CCK resulted in significant increases of pancreatic secretion including volume, bicarbonate, and protein output. When glucose was simultaneously administered with secretin and CCK, pancreatic secretion was significantly increased, more than the effects achieved by the secretin and CCK. However, glucose alone did not increase basal pancreatic secretion. These observations suggest that endogenous insulin intensifies pancreatic secretion stimulated by secretin and CCK in humans.     

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.     

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.