Pancreatic Bicarbonate Output Research Articles

Neurotensin and xenin stimulates pancreatic exocrine secretion through the peripheral cholinergic nerves in conscious sheep

The present study aimed to clarify the effects of neurotensin and xenin on pancreatic exocrine secretion in conscious sheep and their mechanism of actions. The animals were equipped with two silastic cannulae in the common bile duct to separately collect pancreatic fluid and bile, and a silastic cannula in the proximal duodenum to continuously return the mixed fluids. NT and xenin were intravenously injected at range of 0.01–3.0 nmol/kg during the phase I of duodenal migrating motor complex. A single intravenous NT injection significantly and dose-dependently increased pancreatic fluid, protein, and bicarbonate outputs. The effect of NT at 1 nmol/kg was completely inhibited by a background intravenous infusion of atropine methyl nitrate at a dose of 10 nmol/kg/min, however, the effect was not altered by a prior injection of the neurotensin receptor subtype (NTR)-1 antagonist SR 48692 at 60 nmol/kg. Moreover, a single intravenous xenin-25 injection significantly and dose-dependently increased pancreatic fluid and protein output, whereas the effect of xenin-25 did not clearly show dose-dependence. The prior SR 48692 injection at 30 nmol/kg did not significantly alter the effects of xenin-25 at 0.3 nmol/kg, while the atropine infusion significantly inhibited the increase in fluid secretion. Under the atropine infusion, xenin-25 at 0.3 nmol/kg did not increase protein and bicarbonate outputs, whereas the inhibitory effect of the atropine was not significant compared to that of the single injection of xenin-25. A single intravenous injection of NTR-2 agonist levocabastine at 0.1–3 nmol/kg did not alter pancreatic exocrine secretion. These results suggest that both NT and xenin-25 effectively stimulates pancreatic exocrine secretion through the peripheral cholinergic system in sheep and that NTR-2 is not involved in the regulation of pancreatic exocrine secretion, however, we did not precisely determine the role of NTR-1 in the actions of both the peptides on pancreatic exocrine secretion.

Helicobacter pylori and pancreatic diseases.

A possible role for Helicobacter pylori (H. pylori) infection in pancreatic diseases remains controversial. H. pylori infection with antral predomination leading to an increase in pancreatic bicarbonate output and inducing ductal epithelial cell proliferation could contribute to the development of pancreatic cancer via complex interactions with the ABO genotype, dietary and smoking habits and N-nitrosamine exposure of the host. Although the individual study data available so far is inconsistent, several meta-analyses have reported an increased risk for pancreatic cancer among H. pylori seropositive individuals. It has been suggested that H. pylori causes autoimmune pancreatitis due to molecular mimicry between H. pylori α-carbonic anhydrase (α-CA) and human CA type II, and between H. pylori plasminogen-binding protein and human ubiquitin-protein ligase E3 component n-recognin 2, enzymes that are highly expressed in the pancreatic ductal and acinar cells, respectively. Future studies involving large numbers of cases are needed in order to examine the role of H. pylori in autoimmune pancreatitis more fully. Considering the worldwide pancreatic cancer burden, as well as the association between autoimmune pancreatitis and other autoimmune conditions, a complete elucidation of the role played by H. pylori in the genesis of such conditions could have a substantial impact on healthcare.

Duodenal application of Li+ in a submaximal therapeutic dose inhibits exocrine pancreatic secretion and modulates gastro-duodenal myoelectrical activity in a conscious pig model

This study tested whether duodenal application of lithium inhibits gastroduodenal motility, and whether it suppresses secretion from the exocrine pancreas. Five suckling pigs, 16-18 days old, were surgically fitted with 3 serosal electrodes on the wall of the gastric antrum and the duodenum for electromyography of smooth muscles, and with a pancreatic duct catheter and a duodenal T-cannula for collection and re-entrant flow of pancreatic juice. After the recovery period, on alternative days, each animal was tested once with an intraduodenal infusion of Li+ (100 mmol·L(-1) C3H5LiO3, 10 mL·kg(-1)·h(-1)) for 1 h, and once with an intraduodenal infusion of NaCl (154 mM, 10 ml·kg(-1)·h(-1)), also for 1 h, with the first treatment, i.e., Li+ or NaCl, randomly assigned. Individual pigs served as their own controls, with data recorded prior to a treatment being used as the baseline. Li+ increased the duration of quiescence (P < 0.05) and activity phase (P < 0.05) in the antrum, thus increasing (P < 0.05) the duration of antral myoelectrical cycles. Li+ shortened (P < 0.05) phase I, but it did not affect phase II or phase III or the MMC in the duodenum. Li+ inhibited pancreatic juice outflow as well as pancreatic enzyme and bicarbonate output (P < 0.05 for all pancreatic parameters).

Abstract ED02-03: Gene, environment, and risk factor interaction in pancreatic cancer

Abstract ED02-03: Gene, environment, and risk factor interaction in pancreatic cancer

Insulin inhibits secretin-induced pancreatic bicarbonate output via cholinergic mechanisms.

Exogenous insulin inhibits secretin-stimulated pancreatic bicarbonate output via a dose-dependent mechanism; this effect is prevented by pancreatic denervation. To investigate possible cholinergic mediation, we examined the effect of bethanechol on secretin-stimulated pancreatic secretion during euglycemic, hyperinsulinemic clamp. In four dogs with chronic pancreatic fistulas, euglycemic, hyperinsulinemic clamp (1.25 mU/kg/min) was begun after a 30-minute basal period; computer-assisted glucose administration maintained euglycemia. Control studies were performed with volume-matched and rate-matched vehicle infusion. After 1 hour, secretin infusion was begun at a dosage of 16 ng/kg/h; the dose was doubled every 30 minutes. The studies were then repeated during background bethanechol infusion (90 microg/kg/h) begun 30 minutes after clamp initiation. Pancreatic juice was analyzed for bicarbonate and protein; serum samples were analyzed for glucose and insulin. Exocrine outputs and serum glucose and insulin levels did not differ in the basal period. Insulin levels were significantly elevated during the euglycemic, hyperinsulinemic clamp (62 microU/mL versus 12 microU/mL; p < 0.01); glucose levels did not differ. As before, secretin-induced bicarbonate output was inhibited by euglycemic, hyperinsulinemic clamp. The inhibitory effect of insulin was reversed by bethanechol. Despite the euglycemic, hyperinsulinemic clamp, secretin-induced bicarbonate output was potentiated by bethanechol at higher secretin doses (p < 0.05). These data confirm that cholinergic mechanisms mediate insulin's inhibition of secretin-induced pancreatic bicarbonate output.

Captopril Inhibits Secretin-Induced Pancreatic Bicarbonate Output

Background. Renin–angiotensin systems function at both the organ and systemic levels. Previous studies suggest that angiotensin II (Ang II) stimulates pancreatic secretion in vitro. In contrast, in vivo studies suggest that Ang II inhibits pancreatic secretion. To further assess Ang II's influence on pancreatic secretion, we examined the effect of captopril on secretin-stimulated pancreatic output.Methods. After a 30-min basal period, four conscious dogs with chronic gastric and Herrera pancreatic fistulas received an intravenous bolus of captopril (0.1 mg/kg) followed by a continuous infusion (25 μg/kg/min). Control studies were performed with volume- and rate-matched saline infusion. After 1 h, secretin infusion was begun at 16 ng/kg/h, doubling the dose every 30 min. Pancreatic juice was analyzed for bicarbonate and protein. A paired t test was used to assess statistical significance.Results. When compared to controls, pancreatic bicarbonate outputs were lower during captopril administration; the difference between captopril and control was statistically significant at the highest secretin dose. Protein outputs also appeared lower during captopril administration, although these differences were not statistically significant.Conclusion. These data suggest that Ang II may augment secretin-induced pancreatic secretion. Further, the data seemingly refute the inhibitory role attributed to Ang II in earlier studies.

Captopril inhibits secretin-induced pancreatic bicarbonate output

Background. Renin-angiotensin systems function at both the organ and systemic levels. Previous studies suggest that angiotensin II (Ang II) stimulates pancreatic secretion in vitro. In contrast, in vivo studies suggest that Ang II inhibits pancreatic secretion. To further assess Ang II's influence on pancreatic secretion, we examined the effect of captopril on secretin-stimulated pancreatic output. Methods. After a 30-min basal period, four conscious dogs with chronic gastric and Herrera pancreatic fistulas received an intravenous bolus of captopril (0.1 mg/kg) followed by a continuous infusion (25 μg/kg/ min). Control studies were performed with volume-and rate-matched saline infusion. After 1 h, secretin infusion was begun at 16 ng/kg/h, doubling the dose every 30 min. Pancreatic juice was analyzed for bicarbonate and protein. A paired t test was used to assess statistical significance. Results. When compared to controls, pancreatic bicarbonate outputs were lower during captopril administration; the difference between captopril and control was statistically significant at the highest secretin dose. Protein outputs also appeared lower during captopril administration, although these differences were not statistically significant. Conclusion. These data suggest that Ang II may augment secretin-induced pancreatic secretion. Further, the data seemingly refute the inhibitory role attributed to Ang II in earlier studies.

Hyperglycemia alone does not inhibit secretin-induced pancreatic bicarbonate secretion.

Administration of exogenous insulin (INS) inhibits secretin-stimulated pancreatic bicarbonate (HCO3) output via a dose-dependent, neurally mediated mechanism. To determine whether this effect was due to systemic hyperinsulinemia or to reduced endogenous insulin production, we examined the effect of hyperglycemia on secretin-stimulated pancreatic secretion. Chronic pancreatic fistulae were created in six dogs. After 30 minutes of equilibration, a computer-assisted hyperglycemic clamp protocol was used to maintain glucose (GLU) levels 100 or 150 mg/dL above basal in clamp animals; control animals received volume- and rate-matched infusions of 0.9% saline. One hour after beginning the clamp period, intravenous secretin dose-response (16-125 ng/kg/h) was begun, doubling the dose every half hour. Unstimulated (0-30 minutes) HCO3, GLU, and INS levels did not differ between groups. INS and GLU levels in clamp animals were significantly elevated during clamp (30-90 minutes) and stimulated (90-210 minutes) periods. For the same periods, HCO3 secretion was not significantly changed despite profound hyperinsulinemia. We conclude that systemic hyperinsulinemia alone does not inhibit secretin-stimulated HCO3 output. Since exogenous INS exerts feedback regulation on the pancreas, we propose that suppression of endogenous INS secretion mediates the previously reported inhibitory response.

Pancreatic secretory response to intraileal amino acids: studies in dogs with an in situ neurally isolated ileum.

Intraileal carbohydrates and lipids affect the pancreatic exocrine secretion, but the effect of intraileal amino acids and the role of the extrinsic nerves of the ileum as mediators of the pancreatic bicarbonate and enzyme output are unknown. Four dogs underwent total extrinsic denervation of the entire ileum. Thomas-like cannulas were placed into the stomach, duodenum (to collect pure pancreatic juice), and at the jejuno-ileal junction. Eight neurally intact control dogs received only the three fistulas. After recovery, in both sets of dogs, dose-response studies of the pancreatic secretory response to intraileal infusion with graded loads of tryptophan (0.12-10.0 mmol/h) were performed, given against an intravenous (iv) background of secretin (20.5 pmol/kg/h) and cerulein (29.6 pmol/kg/h). On separate days, control experiments with intraileal infusion of 0.15 M NaCl were performed. In both sets of dogs, iv secretin plus cerulein significantly (p < 0.05) increased pancreatic bicarbonate and protein output above basal. Intraileal tryptophan caused a dose-dependent decrease in the pancreatic bicarbonate and protein response to secretin plus cerulein. In the dogs with denervated ileum, this inhibition was significantly stronger than in the intact animals. In both sets of dogs, the 225-min integrated bicarbonate (IBR) and protein response (IPR) to all loads of tryptophan were significantly lower than in control experiments. Both IBR and IPR were significantly lower in the denervated as compared with the intact animals. 1) Extrinsic denervation of the entire ileum is a valuable preparation to study the role of nerves in the control of pancreatic exocrine secretion; 2) both in the intact and denervated animals the amino acid tryptophan induces an "ileal brake" of the hormonally stimulated pancreatic bicarbonate and protein output; 3) the extrinsic nerves of the ileum are probably not the dominant mediators of the inhibitory action of intraileal tryptophan but rather counteract this effect.

Effect of Insulin and Glucose on Basal and Cholecystokinin-Stimulated Exocrine Pancreatic Secretion in Humans

Pancreaticobiliary secretion is reduced during acute hyperglycemia. In nondiabetics, this inhibitory effect also may result from hyperinsulinemia. Therefore we investigated the effects of acute hyperglycemia and euglycemic hyperinsulinemia on basal and cholecystokinin (CCK)-stimulated pancreaticobiliary secretion. Nine healthy volunteers (age, 22-52 years) were studied on three occasions in random order during (a) intravenous saline (control), (b) hyperglycemic hyperinsulinemic clamping (HG; plasma glucose at 15 mM), and (c) euglycemic hyperinsulinemic clamping (HI; plasma insulin at 150 mU/L, glucose at 4-5 mM). Duodenal outputs of bilirubin, amylase, trypsin, and bicarbonate were measured under basal conditions and during CCK infusion (0.25 and 0.5 IDU/kg/h). Basal pancreaticobiliary secretion was significantly (p < 0.05) reduced during both HG and HI. During low-dose CCK stimulation, HG significantly (p < 0.05) reduced bilirubin and trypsin output compared with control. In contrast, HI did not significantly reduce pancreatic enzyme and bilirubin output during low-dose CCK infusion. During high-dose CCK infusion, neither HI nor HG influenced pancreatic enzyme and bilirubin output. Pancreatic bicarbonate output was not influenced by CCK and remained significantly (p < 0.05) reduced during HI and HG compared with control. It is concluded that during both acute hyperglycemia and euglycemic hyperinsulinemia, basal pancreaticobiliary secretion is significantly reduced. CCK-stimulated pancreatic enzyme and bilirubin output is significantly reduced only during hyperglycemia. The inhibitory effect of hyperglycemia on pancreaticobiliary secretion in healthy volunteers may occur independent of insulin.

Canine pancreatic responses to intracolonic perfused nutrients.

To study the effect intracolonic perfusion of nutrients has on exocrine pancreatic secretion, six dogs were prepared with gastric, duodenal, and cecal cannulas using a modified Thomas technique. In our study protocol, we collected pancreatic juice by selective ductal cannulation after having applied several types of intracolonic stimulation: perfusion of sodium chloride, tryptophan, rice starch + glucose, or sodium oleate. All these solutions were applied together with a background dose of intravenous secretin. Our results showed a significant increase in the volume of pancreatic juice and bicarbonate output after intracolonic perfusion of sodium oleate. Other perfusions did not change these parameters. Protein output did not change in any of the cases. It seems that the ascending colon plays a regulating role in pancreatic secretion; in some conditions the colon could increase exocrine pancreatic function.

Regulation of porcine biliary secretion by secretin.

The importance of physiological plasma levels of secretin in biliary bicarbonate secretion is not known. However, in anaesthetized pigs the substantial hepatic output of bicarbonate into the duodenum in response to low doses of secretin exceeds pancreatic bicarbonate output. The aim was therefore to study the relationship between duodenal acidification, secretin and hepatic biliary bicarbonate output in the conscious pig. Göttingen minipigs (n = 22) were cholecystectomized and the common bile duct catheterized. The biliary bicarbonate secretion in response to intraduodenal HCl, secretin or pentagastrin given intravenously, and to meal was studied. Intraduodenal HCl infusion, secretin and pentagastrin given intravenously augmented hepatic bicarbonate output and plasma secretin concentrations significantly. The secretin response to acidification was sufficient to explain the subsequent increase in biliary bicarbonate secretion. Hepatic bicarbonate secretion and concentrations of CCK and secretin in plasma increased postprandially. Exclusion of bile salts from the duodenum abolished postprandial increase in bile volume and increased release of CCK in fasting and fed pigs whereas secretin release was diminished. The results demonstrate that hepatic bicarbonate secretion is stimulated by endogenous secretin and therefore may have a physiological role in duodenal neutralization.

Pancreatic bicarbonate response to intraduodenal tryptophan in dogs: role of muscarinic M1-receptors and cholecystokinin.

In dogs, 1. Activation of cholecystokinin-receptors is needed for an adequate pancreatic bicarbonate response to secretin; 2. Cholinergic nerve fibers ending on M1-receptors are probably of little or no importance for the bicarbonate response to secretin in the given dose; 3. The bicarbonate response to tryptophan, given with a secretin background, is controlled by cholinergic M1-fibers and by cholecystokinin; 4. M1-fibers mainly mediate the bicarbonate response to low loads of tryptophan, whereas cholecystokinin controls the response to low and high loads of tryptophan; and 5. Both mediators interact in a synergistic manner. In six conscious dogs with chronic gastric and duodenal fistulas, we compared the action of the M1-receptor antagonist telenzepine (20.25-81.0 nmol/kg/h), the cholecystokinin-receptor antagonist L-364,718 (0.025-0.1 mg/kg/h), and combinations of both on the pancreatic bicarbonate response to graded loads of intraduodenal tryptophan (0.37-10.0 mmol/h), given against a background of secretin (20.5 pmol/kg/h). Secretin significantly (p < 0.05) stimulated the pancreatic bicarbonate output above basal levels. All doses of L-374,718, but not telenzepine, significantly decreased the bicarbonate response to secretin by up to 64%. Additional administration of telenzepine together with L-364,718 had no further inhibitory effect on the secretin-stimulated bicarbonate output as compared to L-364,718 given alone. All loads of tryptophan significantly increased the bicarbonate output over that seen with secretin alone (= incremental bicarbonate response to tryptophan). Telenzepine significantly decreased the incremental bicarbonate response to the two lower loads (0.37-1.1 mmol/h) of tryptophan (by 82-124%); L-364,718 decreased the incremental bicarbonate response to all loads of tryptophan (by 50-118%). The incremental bicarbonate output, as well as the 180-min integrated bicarbonate response to all loads of tryptophan, were abolished by all combinations of both antagonists.

Feedback Regulation of Pancreatic Exocrine Secretion in Minipigs

Background: The mechanism behind the possible feedback regulation of pancreatic exocrine secretion is not well understood. Methods: Thirteen minipigs were prepared with fistulas to the pancreatic duct and the duodenum. Peripheral venous blood was obtained for determination of secretin and cholecystokinin (CCK) levels. Four different experiments were performed: 1) diversion and reinfusion of pancreatic juice; 2) intraduodenal infusion of NaHCO3 solution, with the same volume, bicarbonate concentration, and osmolality as the collected pancreatic secretion, and reinfusion of pancreatic juice; 3) reinfusion of pancreatic secretion for 1 h before and 2 h after a meal; and 4) diversion of pancreatic secretion and intraduodenal infusion of NaHCO3 solutions before and after a meal. Results: Reinfusing pancreatic juice significantly decreased pancreatic juice volume and bicarbonate output and slightly decreased the level of secretin in plasma. Alternating infusions of substitute NaHCO3 and pancreatic juice did not change pancreatic output of bicarbonate and protein, nor did it change the CCK and secretin levels in plasma. Replacing pancreatic juice with intraduodenal NaHCO3 infusions during a meal did not significantly modify the pancreatic secretion of bicarbonate and protein or the hormonal levels in blood. Conclusions: A negative feedback regulation of pancreatic exocrine secretion is present in starved minipigs. Duodenal acidity and plasma levels of secretin seem to be of importance, whereas duodenal enzymatic activity and the level of CCK in plasma probably are not. A postprandial negative feedback regulation through duodenal enzymatic activity and release of CCK into blood could not be shown.

Effect of pituitary adenylate cyclase-activating polypeptide on exocrine and endocrine secretion in the ovine pancreas

The role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the regulation of exocrine and endocrine pancreas was investigated in conscious sheep. Intravenous infusions of PACAP-27 and PACAP-38 (1, 3, and 10 pmol/kg/min) for 10 min during phase II of the duodenal migrating myoelectric complex accelerated pancreatic protein and amylase outputs dose-dependently. The responses in enzyme secretion to both PACAPs at the highest doses were inhibited significantly by atropine infusion (14.4 nmol/kg/min). Vasoactive intestinal polypeptide (VIP) at 3 pmol/kg/min significantly accelerated protein but not amylase outputs, although the response to the highest dose was not significantly influenced by atropine. PACAP-27 and VIP increased pancreatic juice flow and bicarbonate output dose-dependently; however, the responses to the highest dose were not altered significantly by atropine. On the other hand, intravenous injection of PACAP-38 (100 pmol/kg) did not influence basal plasma concentration of insulin, glucagon, and glucose. Moreover, PACAP-38 (1–100 pmol/kg) altered neither pancreatic endocrine response to intravenous infusion of glucose (20 μmol/kg/min) nor that to n-butyric acid (33 μmol/kg/min). These results suggest that PACAP contributes to the regulation of exocrine secretion of the ovine pancreas but not to endocrine secretion. PACAP appears to accelerate pancreatic enzyme secretion mostly via the cholinergic nerves.

Effects of MCI-727 on pancreatic exocrine secretion and acute pancreatitis in two experimental rat models.

The effects of a newly developed compound having antiulcer action, (Z)-2-(4-methylpiperazin-1-yl)-1-[4-(2-phenyl-ethyl)phenyl]-eth anone oxime hydrochloride monohydrate (MCI-727), on pancreatic exocrine secretion were studied in anesthetized rats and evaluated its preventive and therapeutic effects on acute pancreatitis in two experimental rat models. Intraduodenal administration of MCI-727 [25, 50, or 100 mg/kg body weight (wt)] stimulated a dose-dependent increase in pancreatic juice and bicarbonate output without increasing the protein output or plasma cholecystokinin concentration. MCI-727-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but not by the cholecystokinin receptor antagonist loxiglumide (50 mg/kg body wt/h) or cholinergic receptor antagonist atropine (100 mu g/kg body wt/h). In rats with acute pancreatitis induced by four subcutaneous injections of 20 mu g/kg body wt cerulein at hourly intervals over 3 h, MCI-727 administered orally at a dose of 100 mg/kg body wt 30 min before the first cerulein injection significantly reduced the increases in serum amylase and lipase activity and pancreatic wet weight and induced improvements in the results of histologic examination. Moreover, when given 30 min before and 90 min after the first cerulein injection, MCI-727 had even more dramatic protective effects on all these parameters. In addition, even when administered immediately after the last cerulein injection, MCI-727 effectively ameliorated all these alterations of acute pancreatitis. However, MCI-727 had no apparent beneficial effects on the biochemical and histologic alterations of acute pancreatitis in the severe form induced by retrograde intraductal injection of 1.0 ml/kg body wt of 4% sodium taurocholate. These findings suggest that oral administration of MCI-727 stimulates pancreatic exocrine secretion by endogenous secretin release and that it has therapeutic as well as preventive effects on mild forms of acute pancreatitis in rats.

Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats

Although secretin has been found within the brain, its central role in pancreatic exocrine function has not been previously addressed. The hypothesis that intracerebroventricular secretin enhances pancreatic volume and bicarbonate output at doses that have no effect when given intravenously was tested. Sprague-Dawley rats had a cannula stereotactically placed into the left lateral cerebral ventricle 24 hours before study. At laparotomy the bile and pancreatic ducts were separately cannulated and excluded for tared collections and bicarbonate assay. Increasing doses of intracerebroventricular secretin (0.005, 0.05, and 0.5 microgram/1.0 microliter) induced a significant dose-related increase in bicarbonate output (2.95, 3.32, and 4.02 microEq/30 min, respectively) above basal (2.62 microEq/30 min) compared with control or intracerebroventricular saline treated animals. Pancreatic volume increased to 59.7 microliters at the lowest intracerebroventricular dose and increased (p < 0.025) to 65.8 microliters at the 0.05 intracerebroventricular secretin dose when compared with basal (59.4 microliters). To show that this was not a systemic effect of secretin, intravenous infusion of secretin at 0.005 and 0.05 microgram/kg/hr failed to stimulate either volume or bicarbonate output compared with that observed with intracerebroventricular secretin over the same dose range. These observations indicate that intracerebroventricular secretin stimulates pancreatic volume and bicarbonate output and suggest that central secretin may play a role in the regulation of exocrine pancreatic secretion.

Insulin inhibits secretin-stimulated pancreatic bicarbonate output by a dose-dependent neurally mediated mechanism

Although previous reports suggest interactions between endocrine and exocrine pancreas, insulin's effect on pancreatic exocrine function remains unclear. Chronic pancreatic fistulas were created in six dogs with innervated INN and five dogs with denervated (DEN) pancreata; these animals were studied using the euglycemic, hyperinsulinemic clamp technique. After a 30-min unstimulated period, both groups received a 60-min 1.5 mU.kg-1.min-1 insulin (clamp) or vehicle (control) infusion. Intravenous secretin was then initiated at 16 ng.kg-1.h-1; the secretin dose was doubled every 30 min until 125 ng.kg-1.h-1 was achieved. These studies were then repeated in INN animals during infusion of a 10 micrograms.kg-1.h-1 atropine background. Finally, INN animals underwent a similar unstimulated period followed by a 1.25 mU.kg-1.min-1 insulin (clamp) or vehicle (control) infusion. after 60 min, a 64 ng.kg-1.h-1 secretin infusion was initiated. Insulin infusion was then increased by 0.25 mU.kg-1.min-1 at 30-min intervals until 2.0 mU.kg-1.min-1 was reached. Unstimulated (0-30 min) serum glucose and insulin levels and pancreatic bicarbonate and protein outputs did not differ between groups. Clamp (30-90 min) and stimulated (90-210 min) insulin were each significantly elevate in clamp groups (81.9 +/- 2.4 vs. 7.0 +/- 0.3 microU/ml, P < 0.001); glucose and bicarbonate were unchanged. Protein outputs during clamp (64 +/- 9 vs. 24 +/- 6 mg/10 min; P < 0.05) and secretin-stimulated (52 +/- 9 vs. 29 +/- 3 mg/10 min; P < 0.05) periods were diminished by atropine but were unaffected by insulin. Secretin-stimulated (90-210 min) bicarbonate output was diminished by insulin (0.03 +/- 0.01 vs. 0.31 +/- 0.05 meq/10 min; P < 0.003) in INN but not DEN animals; this effect was partially reversed by atropine. Dose-response studies demonstrated a threshold for insulin's inhibitory actions between 1.5 and 1.75 mU.kg-1.min-1. These data provide further evidence for exocrine-endocrine regulatory interactions and suggest that insulin may influence secretin's stimulation of ductal cell secretion by a mechanism that is at least partially cholinergic in character.

Effects of KSG-504, a New Cholecystokinin-A-Receptor Antagonist, on Pancreatic Exocrine and Endocrine Secretions in Rats

The effects of KSG-504 ((S)-arginium (R)-4-[N-(3-methoxypropyl)-N-pentylcarbamoyl]-5-(2-naphthylsulf onyl) pentanoate monohydrate), a new cholecystokinin (CCK)-A-receptor antagonist, on pancreatic exocrine secretion in anesthetized rats and endocrine secretion in conscious rats were studied. Intravenous injection of KSG-504 inhibited the pancreatic amylase output stimulated by intravenous infusion of CCK-8 in a dose-dependent manner (ED50: 18 micrograms/kg/min). Moreover, KSG-504 significantly reduced the CCK-8-stimulated increases in pancreatic juice volume and outputs of protein, trypsin and lipase. Intraduodenal infusion of casein increased the plasma CCK concentration and the pancreatic amylase output. KSG-504 significantly inhibited the pancreatic amylase output stimulated by casein. Pancreatic juice volume and bicarbonate output were significantly stimulated by intravenous infusion of secretin, but were not changed by KSG-504. When pancreatic exocrine secretion was stimulated by secretin plus CCK-8, KSG-504 suppressed the increases in juice volume and bicarbonate output to the level stimulated by secretin alone. Basal pancreatic amylase output was decreased by KSG-504. KSG-504 decreased the level of plasma immunoreactive insulin (IRI) stimulated by glucose plus CCK-8, but had no effect on IRI stimulated by glucose alone and the basal IRI. These in vivo studies suggest that KSG-504 has significant inhibitory effects both on the pancreatic exocrine and endocrine secretion stimulated by CCK, but has no effect on the exocrine secretion stimulated by secretin.

Neuronal regulation of the release and action of secretin-releasing peptide and secretin

The acid-stimulated release of secretin is mediated by a secretin-releasing peptide (SRP) in rats. In the present study we investigated to determine whether a neural mechanism(s) is involved in the regulation of release and action of SRP in anesthetized rats. A concentrated acid perfusate (CAP) containing SRP was obtained from donor rats. CAP administered to recipient rats significantly increased pancreatic flow volume (81.6 +/- 18.3%), bicarbonate output (188.7 +/- 15.6%), and plasma secretin level (from 0.9 +/- 0.2 to 4.4 +/- 0.5 pM). However, this effect was attenuated by CAP from donor rats pretreated with tetrodotoxin (TTX), propranolol, bilateral subdiaphragmatic vagotomy (BSV), or systemic and topical administration of capsaicin. In contrast, CAP from donor rats pretreated with phentolamine, atropine, or hexamethonium did not alter the increase in plasma secretin concentration and pancreatic secretion. Moreover, the action of CAP on secretin release was significantly inhibited in the recipient rats pretreated with TTX, BSV, and topical applications of capsaicin but was not suppressed in the recipient rats pretreated with atropine, hexamethonium, or propranolol. Furthermore, perivagal and duodenojejunal mucosal application of capsaicin abolished the pancreatic secretory response to secretin at 5 pmol.kg-1.h-1. In conclusion, the release and action of both SRP and secretin are mediated by a vagal afferent pathway. beta-Adrenergic receptors also play a significant role in the release of SRP.