Bovine pancreatic secretion in the first week of life: potential involvement of intestinal CCK receptors.

The aim of this study was to evaluate pancreatic juice secretion of calves in the first postnatal days, and determine a potential involvement of cholecystokinin (CCK) and intestinal CCK receptor in its regulation. Nine neonatal Friesian calves (five controls and four treated intraduodenally with FK480, a CCK-A receptor antagonist) were surgically fitted with a pancreatic duct catheter and a duodenal cannula before the first colostrum feeding. Collections of pancreatic juice and duodenal luminal pressure recordings were started early after recovery from anaesthesia and continued for 6 days. From day 2 or 3 of life, periodic fluctuations in pancreatic secretions were observed in concert with duodenal myoelectric motor complex (MMC) and variations in plasma pancreatic polypeptide (PP) concentrations. Intraduodenal administration of FK480 reduced pancreatic juice secretion while intravenous infusion of CCK had no effect. Immunocytochemistry indicated an association of mucosal CCK-A and -B receptors with neural components of the small intestine. In conclusion, periodic activity of the exocrine pancreas exists in neonatal calves soon after birth and local neural intestinal CCK-A receptors could be partly responsible for the modulation of neonatal calf pancreatic secretion.     

Effect of nitric oxide synthase inhibitors on the temporal coordination of duodenal contractions and pancreatic exocrine secretion in sheep

The present study evaluated the role of nitric oxide in the regulation of duodenal motility and pancreatic exocrine secretion in conscious sheep. Intravenous infusions of nitric oxide synthase inhibitors, Nω-nitro-l-arginine-methyl ester (l-NAME) and Nω-nitro-l-arginine, induced clusters of duodenal contractions like phase III of migrating motor complexes and simultaneously inhibited flow rate, bicarbonate ion and enzyme outputs of pancreatic juice. The effects of l-NAME were inhibited by simultaneous infusion of l-arginine, but not altered by adrenergic blockade using a combined infusion of phentolamine and propranolol. Inhibition of the pancreatic secretion occurred in coincidence with initiation of the duodenal contractions, while the pancreatic secretion was not inhibited when the premature duodenal contractions were abolished by the l-arginine infusion. The initiation of the cluster of duodenal contractions by l-NAME was not abolished by background infusion of atropine, whereas the amplitude of contractions was significantly inhibited by atropine. These results suggest that intrinsic nitric oxide plays a crucial role in the regulation of duodenal tone and maintenance of continuous secretion by the exocrine pancreas in sheep. These results also implied that inhibition of pancreatic exocrine secretion by the nitric oxide synthase inhibitor is presumably mediated in part through the contractile effect on the duodenum. Accepted: 27 June 2000     

A secretin releasing peptide exists in dog pancreatic juice

Canine pancreatic juice has been shown to stimulate exocrine pancreatic secretion in the dog. In the present study we investigated whether there is a secretin-releasing peptide in canine pancreatic juice. Pancreatic juice was collected from the dogs with Thomas gastric and duodenal cannulas while pancreatic secretion was stimulated by intravenous administration of secretin at 0.5 microg/kg/h and CCK-8 at 0.2 microg/kg/h, respectively. The pancreatic juice was separated into three different molecular weight (MW) fractions (Fr) by ultrafiltration (Fr 1; MW > 10,000, Fr 2; MW=10,000-4,000 and Fr 3; MW < 4,000), respectively. All the fractions were bioassayed in anesthetized rats. Fraction 3 dose-dependently and significantly stimulated pancreatic juice flow volume from 78.0% to 99.4% (p<0.05) and bicarbonate output from 128.9% to 202.1% (p<0.01), respectively. Plasma secretin concentration also increased from 1.2 +/- 0.5 pM to 5.0 +/- 0.8 pM and 6.0 +/- 1.0 pM (p<0.05). None of these fractions increased pancreatic protein secretion or plasma CCK level. The stimulatory effect of Fraction 3 on pancreatic secretion and the release of secretin was completely abolished by treatment with trypsin (1 mg/ml for 60 min at 37 degrees C) but not by heating (100 degrees C, 10 min). Intravenous injection of a rabbit anti-secretin serum, which rendered plasma secretin almost undetectable in rat plasma, also abolished Fr 3-stimulated pancreatic secretion of fluid and bicarbonate secretion. These observations suggest that a secretin-releasing peptide exists in the canine pancreatic juice. It is trypsin-sensitive and heat-resistant. This peptide may play a significant physiological role on the release of secretin and regulation of exocrine pancreatic secretion.     

The role of luminal gastrin in the regulation of pancreatic juice secretion in preruminant calves

The effect of luminal gastrin on the secretion of pancreatic juice was studied in seven conscious preruminant calves employing luminal infusions of gastrin and cholecystokinin (CCK)-9 and pharmacological CCK1 and CCK2 receptor blocks with antagonists. The study was performed in the preprandial and prandial states. Pharmacological blocking of the CCK2 receptor, like that of the CCK1 receptor, resulted in reduction of pancreatic postprandial secretion and increased the duration of the prandial pattern of duodenal electrical activity. Exogenous luminal gastrin, like luminal CCK-9, enhanced the secretion of pancreatic juice proteins, though the overall effect of gastrin was weaker than that of CCK-9. The effect was inhibited by infusion of CCK2 but also by CCK1 receptor antagonist. In conclusion, duodenal luminal gastrin can stimulate exocrine pancreatic secretion by a mechanism that depends on CCK2 receptors in calves. Involvement of the CCK1 receptor in this mechanism needs further investigation. Prandial pancreatic secretory and duodenal motility cycles can be regulated by endogenous gastrin release.     

Role of peptide YY in regulation of duodenal motility during the interdigestive period in sheep

Temporal coordination between duodenal migrating myoelectric complexes (MMC) and pancreatic exocrine secretion, and the effects of porcine peptide YY (PYY) on gastroduodenal motility and pancreatic exocrine secretion were examined during the interdigestive period in conscious mature sheep. Fluid and enzyme secretions from the exocrine pancreas showed a periodic pattern corresponding to the phases of duodenal MMC, although these secretion rates were maintained at a high level during phase II in sheep. Intravenous continuous infusion of PYY at doses ranging from 50 to 200 pmol · kg⁻¹ · h⁻¹ or intravenous bolus infusion of PYY at doses ranging from 50 to 200 pmol · kg⁻¹ showed a tendency to prolong the first cycle of the duodenal MMC and significantly shorten the second cycle. However, there was almost no effect on ruminal contractions from the PYY administration. In the pancreatic exocrine secretion, PYY could inhibit only bicarbonate secretion at only the highest dose of 200 pmol · kg⁻¹. These results imply that endogenous PYY may play a physiological role in the regulation of the duodenal MMC cycles in sheep but not in ruminal contractions. PYY seems unlikely to regulate the pancreatic exocrine secretion in normal sheep, because a supraphysiological dose of PYY was required to inhibit the pancreatic exocrine secretion. Accepted: 3 March 1997     

Biliary and pancreatic exocrine secretions via endogenous secretin by intestinal infusion of propionate and propionate analogues in piglets

1. The secretory responses of hepatic bile and exocrine pancreas by intraduodenal infusion of propionate (PA), 3Cl-PA, 2Cl-PA, 3Br-PA and 2Br-PA solutions were examined in anesthetized piglets. 2. Pancreatic juice and protein secretions were enhanced by infusion of PA and PA analogue solutions of pH 2.0 following increase of plasma secretin level but not pH 7.0. The order of response time was as follows: 3Br-PA greater than 2Cl-PA greater than 2Br-PA greater than 3Cl-PA greater than PA. 3. The response of bile flow depended on endogenous secretin and showed almost the same pattern as that of pancreatic juice secretion. 4. The results suggested that pancreatic exocrine secretion via endogenous secretin was not always dependent on the dissociation constant of weak acids.     

The influence of potato fibre on exocrine pancreatic secretions and on plasma levels of insulin,secretin and cholecystokinin in growing pigs

The effect of a potato fibre preparation on exocrine pancreatic secretions and on gastrointestinal hormone levels in plasma was studied in three 8 weeks old piglets that were surgically fitted with a jugular vein catheter for blood sampling, a pancreatic duct catheter and a T‐shaped duodenal cannula for collection of pancreatic juice. The animals were fed for 2 weeks a control diet (experimental period 1), thereafter for 2 weeks the control diet supplemented with 2% potato fibre (experimental period 2) and for another 2 weeks the control diet again (experimental period 3). Additionally, intraduodenal (i.d.) infusions of the experimental diet, the control diet and potato fibre as well as i.v. infusions of a solution containing cholecystokinin (CCK) and secretin were administered.

Potato fibre in the diet evoked in tendency an increase in the volume of secretion of pancreatic juice and a significant increase both in the mean values of the total protein content and total activities of lipase, trypsin and a‐amylase when compared to the control diet. The i.d. infusion of the control diet, experimental diet and fibre infusate as well as the i.V. administration of the hormone infusate led to a spontaneous secretory response of the exocrine pancreas. Besides gastrointestinal hormones, such as CCK, other factors such as short chain fatty acids may be involved in the regulation of the exocrine pancreas.     

Effect of somatostatin on exocrine pancreatic secretion stimulated by pancreozymin-secretin or by a test meal in the dog

In 4 dogs with chronic duodenal and gastric fistulae, exocrine pancreatic function was assessed by cannulating the pancreatic duct and collecting the duodenal contents. Both methods were applied in each animal. Pancreatic secretion was stimulated by infusion of 2 CHR units of pancreozymin and secretin or by administration of a liquid test meal, injected into the stomach through the gastric fistula. During both experiments 3.5 microgram/kg somatostatin was given as bolus injection followed by an infusion of 3.5 microgram/kg/h. Somatostatin caused a significant reduction in protein and amylase output and in the bicarbonate concentration during stimulation with pancreozymin-secretin. Volume and bicarbonate slightly decreased but not to a significant extent. Duodenal volume and the duodenal activities of trypsin and amylase were significantly reduced during test meal stimulation and somatostatin infusion. Somatostatin is a potent inhibitor of exocrine pancreatic function mainly influencing enzyme secretion.     

Neurotensin stimulates pancreatic exocrine secretion in rats

Neurotensin (NT) stimulates pancreatic exocrine secretion in dogs and humans. The purpose of this study was to examine the effect of exogenous neurotensin on pancreatic exocrine secretion in rats. Five Sprague-Dawley male rats were prepared with pancreatic, gastric and duodenal fistulas. Bile was shunted into the duodenum in order to collect pure pancreatic juice. 24 h later, neurotensin (0.05, 0.1, 0.2, 0.3, 1.0 nmol/kg) was infused intravenously in a random fashion. Pancreatic juice was collected every 10 min, and the volume was recorded and protein and bicarbonate were measured. Neurotensin stimulated, in a dose-related manner, the pancreatic secretion of water, protein and bicarbonate. Neurotensin may be involved in the physiologic control of pancreatic secretion in rats.     

Hepatic bile and pancreatic exocrine secretions evoked by gastrointestinal peptides in sheep

The secretory response of hepatic bile and exocrine pancreas to gastrointestinal peptides has been studied in chronically cannulated sheep. Pancreatic juice flow and protein output were evoked dose dependently by intraportal injection of secretin, CCK-8, caerulein, VIP and neurotensin. However, biliary secretion was evoked by only secretin. Biliary and pancreatic exocrine secretions were enhanced by delivered gastric juice into the duodenum as followed by the increased plasma concentration of immunoreactive secretin (IRS). Results suggest that secretin is the major peptide that regulates pancreatic exocrine secretion and hepatic bile production in the sheep.     

The effect of oleate on pancreatic and bile secretion in the conscious rat

The effects of sodium oleate infused into either the duodenum or the terminal ileum on bile and pancreatic secretion were examined in the conscious rat. Rats were prepared with cannulae draining pure bile and pancreatic juice separately, and with an ileal and two duodenal cannulae. A 40 mM taurocholate solution containing 7 mg/ml bovine trypsin was infused into the duodenum throughout the experiment to replace diverted bile-pancreatic juice to maintain the normal regulation of pancreatic secretion. The intraduodenal infusion of sodium oleate significantly increased pancreatic juice flow, protein, and bicarbonate outputs, whereas it did not affect bile secretion. Intravenous infusion of proglumide (300 mg/kg/hr) did not inhibit pancreatic secretion stimulated by intraduodenal infusion of sodium oleate. An intravenous infusion of atropine (100 micrograms/kg/hr) attenuated protein and fluid secretions but not that of bicarbonate in response to intraduodenal oleate. In contrast, the intraileal infusion of oleate had no effect on pancreatic secretion, whereas it decreased bile flow, bicarbonate, and bile salt outputs. In conclusion, sodium oleate introduced in the duodenum stimulates pancreatic secretion but oleate in the terminal ileum inhibits bile secretion.     

The effect of luminal ghrelin on pancreatic enzyme secretion in the rat

Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 microg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK(1) receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 microg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions.     

Effects of different doses of free 𝛂-linolenic acid infused to the duodenum on the immune function of lactating dairy cows

This study investigated the effect of a duodenal infusion of a C18:3 free fatty acid on the immune function of lactating dairy cows. Four primiparous Chinese Holstein cows fitted with duodenal cannulas received 0, 100, 200, 300, and 400 g/d of α-linolenic acid (LNA) in a two-treatment crossover design. Blood was collected and serum IgA, IgG, IgM, prostaglandin E₂ (PGE₂) and Th1/Th2 cytokines were determined. Results showed that increasing the supply of LNA to the small intestine of dairy cows linearly increased serum IgG and quadratically enhanced interferon-γ (p < 0.05), whereas the concentrations of PGE₂ declined linearly (p < 0.05) and those of interleukin (IL)-4 tended to decrease (p = 0.08). No difference was observed in serum IgA, IgM or other cytokines, such as IL-2, IL-6 and IL-10. This study demonstrated that in dairy cows, a post-ruminal infusion of high doses of LNA has immunomodulatory effects, possibly associated with a predisposition to a Th1-type response.     

Interactions between bile and pancreatic juice diversions on cholecystokinin release and pancreas in conscious rats

Pancreatic exocrine secretion in the conscious rat is regulated by proteases secreted by the pancreas, and cholecystokinin (CCK) is known to be involved in its mechanism. It has also been reported that the absence of either pancreatic juice or bile in the duodenum could stimulate pancreatic secretion. Therefore, differences in CCK release responding to the exclusion of bile, pancreatic juice (PJ), or both bile and pancreatic juice (BPJ) from the intestine were examined by using a bioassay for cholecystokinin. Plasma CCK levels were increased by all three treatments compared with the basal value, the order of their effects being BPJ greater than PJ greater than bile diversion, and CCK concentrations produced by BPJ diversion were much greater than can be explained as simply summed effect of exclusions of bile and PJ. Pancreatic exocrine secretions were significantly increased by PJ and BPJ diversions, but the effect of bile diversion on the pancreas was not statistically significant. An additional infusion of CR-1409 (0.1 mg/rat), one of CCK receptor antagonists, inhibited exocrine function stimulated by BPJ diversion. We conclude (i) BPJ diversion is the strongest endogenous stimulant on CCK release; (ii) the potentiation between bile and PJ diversions is induced on CCK release; (iii) pancreatic protein secretion during BPJ diversion is mainly modulated by CCK.     

Small intestinal and pancreatic microstructures are modified by an intraduodenal CCK-A receptor antagonist administration in neonatal calves

The aim of the present study was to investigate the role of CCK on the upper gut and pancreas microstructure and on pancreatic juice secretion in neonatal calves assessed by a repetitive intraduodenal administration of FK480, a CCK-A receptor antagonist, during the first 6 days of life. The experiment was performed on 10 neonatal calves surgically fitted with a pancreatic accessory duct catheter and duodenal cannulas. Calves were sacrificed on day 7 for tissue sampling. Treatment with FK480 resulted in: reduction of preprandial pancreatic juice secretion at days 1-3, smaller size of pancreatic acini and number of cells per acinus, reduction in intestinal crypt depth (except in the duodenal bulb), numerous modifications of intestinal villi length and width, lower mitotic index of crypt cells, and increased number and size of enterocytes with 'empty vacuoles'. In conclusion, the blockade of CCK-A receptors during early life both reduced pancreatic exocrine secretion and induced complex changes in pancreatic microstructure. The influence of CCK on the upper gut microstructure in neonatal calves could be either direct via activation of CCK-A receptors located in the mucosa of the upper gut or indirect by modulation of the secretion of pancreatic juice.     

Effect of glucagon on canine exocrine pancreatic secretion stimulated by a test meal

The effect of glucagon on exocrine pancreatic secretion stimulated by a test meal was studied in three dogs with a chronic gastric fistula and a modified Thomas duodenal fistula which allows easier collection of pure pancreatic juice after a meal. Glucagon was given by continuous intravenous infusion in doses of 5, 10, 15, or 30 microgram/kg per hour, before and during a test meal. At each dose level glucagon significantly reduced the water and electrolyte secretion of the pancreas. At 15 and 30 microgram/kg per hour glucagon inhibited protein output; this effect was absent at lower doses. These findings demonstrate a dose-dependent inhibition by glucagon of the pancreatic bicarbonate and protein response to a meal. Inhibition of bicarbonate output was more sensitive to glucagon than that of protein output.     

Inhibitory effect of pancreastatin on pancreatic exocrine secretion in the conscious rat

The effect of newly discovered pancreastatin on pancreatic secretion stimulated by a diversion of bile-pancreatic juice (BPJ) from the intestine was examined in the conscious rat. Exogenous pancreastatin infusion (20, 100 and 200 pmol/kg.h) inhibited pancreatic protein and fluid outputs during BPJ diversion in a dose-dependent manner. Pancreastatin did not affect plasma cholecystokinin (CCK) concentrations. Pancreastatin (100 pmol/kg.h) inhibited CCK-stimulated pancreatic secretion, but did not inhibit secretin-stimulated pancreatic secretion. Pancreastatin alone, however, did not affect basal pancreatic secretion. In contrast, pancreastatin (10(-10)-10(-7)M) did not suppress CCK-stimulated amylase release from isolated rat pancreatic acini. These results indicate that pancreastatin has an inhibitory action on exocrine function of the pancreas. This action may not be mediated by direct mechanisms and nor via an inhibition of CCK release. It is suggested that pancreastatin may play a role in the regulation of the intestinal phase of exocrine pancreatic secretion.     

Roles of 5-HT receptors in the release and action of secretin on pancreatic secretion in rats

5-Hydroxytryptamine (serotonin, 5-HT) is a hormone and neurotransmitter regulating gastrointestinal functions. 5-HT receptors are widely distributed in gastrointestinal mucosa and the enteric nervous system. Duodenal acidification stimulates not only the release of both 5-HT and secretin but also pancreatic exocrine secretion. We investigated the effect of 5-HT receptor antagonists on the release of secretin and pancreatic secretion of water and bicarbonate induced by duodenal acidification in anesthetized rats. Both the 5-HT(2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron at 1-100 microg/kg dose-dependently inhibited acid-induced increases in plasma secretin concentration and pancreatic exocrine secretion. Neither the 5-HT(1) receptor antagonists pindolol and 5-HTP-DP nor the 5-HT(4) receptor antagonist SDZ-205,557 affected acid-evoked release of secretin or pancreatic secretion. None of the 5-HT receptor antagonists affected basal pancreatic secretion or plasma secretin concentration. Ketanserin or ondansetron at 10 microg/kg or a combination of both suppressed the pancreatic secretion in response to intravenous secretin at 2.5 and 5 pmol x kg(-1) x h(-1) by 55-75%, but not at 10 pmol x kg(-1) x h(-1). Atropine (50 microg/kg) significantly attenuated the inhibitory effect of ketanserin on pancreatic secretion but not on the release of secretin. These observations suggest that 5-HT(2) and 5-HT(3) receptors mediate duodenal acidification-induced release of secretin and pancreatic secretion of fluid and bicarbonate. Also, regulation of pancreatic exocrine secretion through 5-HT(2) receptors may involve a cholinergic pathway in the rat.     

Guanidinated casein hydrolysate stimulation of cholecystokinin release via pancreatic enzyme- and cholinergic-independent mechanisms in rats.

We had demonstrated that a peptic hydrolysate of guanidinated casein that is made from casein by the conversion of lysine to homoarginine stimulated pancreatic exocrine secretion in rats with chronic bile-pancreatic juice (BPJ) diversion from the proximal small intestine. This modified protein also stimulated cholecystokinin (CCK) release from dispersed rat intestinal cells. In this study, we found that guanidinated casein hydrolysate stimulates CCK release in chronic BPJ-diverted rats with cholinergic control blocked by atropine. Intraduodenal guanidinated casein hydrolysate increased portal plasma CCK concentration and pancreatic secretion in atropine-treated BPJ-diverted rats. In contrast, the portal plasma CCK concentration was not increased by intact casein hydrolysate. We conclude that guanidinated casein hydrolysate directly stimulates CCK release from the intestine via some cholinergic-independent mechanism, and an increase of the pancreatic exocrine secretion is regulated by CCK released by guanidinated casein hydrolysate. A guanidyl residue is likely to be involved in this control.     

Effect of glucagon-(1-21)-peptide on secretin-stimulated pancreatic exocrine secretion in anesthetized dogs

The effects of glucagon-(1-21)-peptide on pancreatic exocrine secretion and plasma glucose levels were studied and compared with those of native glucagon in anesthetized dogs. Intravenous bolus administration of 1 nmol or 10 nmol/kg of glucagon-(1-21)-peptide evoked a significant inhibition of secretin-stimulated pancreatic juice secretion and protein output in a dose-dependent manner, as equimolar doses of glucagon did. Native glucagon induced an immediate and transient increase in pancreatic juice volume, which was followed by a significant inhibition. However, glucagon-(1-21)-peptide showed only the inhibitory action. Glucagon-(1-21)-peptide had no effect on plasma glucose levels even when a dose of 10 nmol/kg was given. The results suggest that the N-terminal amino-acid residues of glucagon play an important role in the inhibition of pancreatic exocrine secretion.