Stimulation Of Pancreatic Secretion Research Articles

Hollow Microfiber Assembly-Based Endocrine Pancreas-on-a-Chip for Sugar Substitute Evaluation.

With the increasing demand for low-sugar, low-calorie healthy diets, artificial sweeteners have been widely used as substitutes for sugar in the food industry. Therefore, developing models that can better predict the effects of sugar substitutes on the human body is necessary. Here, we developed a new type of endocrine pancreas-on-a-chip based on a microfiber assembly and evaluated its stimulation of pancreatic secretion by glucose or sugar substitutes. This new endocrine pancreas-on-a-chip was assembled using two components: (1) a cell-loaded hollow methacrylate gelatin (GelMA)/calcium alginate (CaA) composite microfiber prepared by microfluidic spinning to achieve vascular simulation and material transport, and (2) a three-dimensional (3D) pancreatic islet culture layer, which also serves as a fiber assembly microchip. Using this established organ chip, we investigated the effects of five sweeteners (glucose, erythritol, xylitol, sodium cyclamate, and sucralose) on pancreatic islet cell viability and insulin and glucagon secretion. The constructed endocrine pancreas-on-a-chip has potential for the safety evaluation of sugar-substituted food additives, which can expand the application of organ chips in the field of food safety and provide a new platform for evaluating various food additives. This article is protected by copyright. All rights reserved.

The role of antisecretory factor in pancreatic exocrine secretion: studies in vivo and in vitro.

What is the central question of this study? Antisecretory factor, an endogenous protein detected in many tissues of the body, is known as an inhibitor of intestinal secretion, but its role in pancreatic exocrine secretory function has not yet been investigated. What is the main finding and its importance? In a rodent model, we show that antisecretory factor reduces pancreatic exocrine secretion, probably via its direct action on the pancreatic acini and via modulation of the enteropancreatic reflexes involving cholecystokinin and sensory nerves. Antisecretory factor (AF) regulates ion and water transport through the intestinal cell membrane. Antisecretory factor inhibits intestinal secretion, but its effect on the exocrine pancreas has not yet been shown. We investigated the effect of AF on pancreatic amylase secretion in vivo and in vitro using pancreatic acini isolated by collagenase digestion. For the in vivo study, Wistar rats were surgically equipped with silicone catheters, inserted into the pancreaticobiliary duct and into the duodenum. Capsaicin was used to deactivate the sensory nerves in turn to assess their involvement in the effects of AF on the exocrine pancreas. Antisecretory factor (1, 3 or 10μgkg(-1) i.p.) was given in basal conditions or following stimulation of pancreatic secretion with diversion of pancreaticobiliary juice. For the in vitro study, rat pancreatic acini were incubated in the presence of increasing doses of AF (from 10(-8) to 10(-5) m) alone or in combination with caerulein (10(-12) m). Cytoplasmic cholecystokinin1 (CCK1 ) receptor protein was detected by Western blot and immunoprecipitation studies. Antisecretory factor markedly reduced the output of pancreatic amylase both in basal conditions and when stimulated by diversion of pancreaticobiliary juice. Deactivation of the sensory nerves with capsaicin completely reversed the inhibitory effects of AF on the exocrine pancreas. Caerulein-induced enzyme secretion from the pancreatic acini was inhibited by AF, whereas basal secretion was unaffected. Administration of AF to the rats significantly diminished the synthesis of CCK1 receptor protein. We conclude that AF inhibits pancreatic exocrine secretion indirectly via sensory nerves and directly decreases amylase release from isolated pancreatic acini. The direct inhibitory action of AF on the exocrine pancreas could be related, at least in part, to a reduction of CCK1 receptors on pancreatic acinar cells.

Effect of osteocalcin on human beta cell proliferation and function and its role on insulin secretion

Effect of osteocalcin on human beta cell proliferation and function and its role on insulin secretion

Ernährung bei akuter Pankreatitis

Nutritional concepts in acute pancreatitis are undergoing a rapid change. An early start of nutrition via nasojejunal tubes is about to replace parenteral nutrition. Yesterday it was believed that the pancreas had to be put at rest. Thus, stimulation of pancreatic secretion by enteral nutrition was believed to be detrimental. However, on comparing the results of enteral with those of parenteral nutrition, the pancreatic infection rates, rate of surgical interventions, days of hospital stay, and costs are found to be significantly reduced. Whether or not enteral nutrition decreases mortality has not been clearly proven. Pancreatitis is associated with the risk of paralytic ileus. Thus, data suggesting that one does not have to feed via a nasojejunal tube but rather via an easier to place nasogastric tube, are provocative. Numerous questions still have to be answered such as composition of tube diet, nutrition in mild to moderate pancreatitis, ways to reduce pain and composition of diet when oral refeeding is started. The nutrition of tomorrow may implicate immunonutrition. There are only a few small studies suggesting beneficial effects by supplementation of tube feeding with MCT/LCT triglycerides, glutamine, arginin, omega-3-fatty acids, nucleotides. So far, these supplements have failed to show efficacy for clinically relevant endpoints. In an recently published study, prebiotics were associated with a high complication rate. In this review, we summarise the current knowledge on nutrition in acute pancreatitis and discuss future developments.

Sensory Signal Transduction in the Vagal Primary Afferent Neurons

The vagal nerve conveys primary afferent information from the intestinal mucosa to the brain stem. Activation of vagal afferent fibers results in inhibition of food intake, gastric emptying, and stimulation of pancreatic secretion. Afferents nerves terminating near to the mucosa are in a position to monitor the composition of the luminal contents. As afferents do not project directly into the lumen, their activation depends on an intermediary step, i.e. neuronal activation by a secondary substance released from within the mucosal epithelium. This review addresses the role for both cholecytokinin (CCK) and serotonin (5-HT) released from enteroendocrine cells and acting as paracrine agents on the terminals of vagal afferents in responses to a number of luminal signals. CCK acted on both high- and low-affinity CCK-A receptors present on distinct vagal primary afferent neurons. Neurons of the nodose ganglia respond to intraduodenal perfusions of maltose, glucose, and hypertonic saline. These neurons were also sensitive to exogenous luminally applied 5-HT at concentrations that mimic physiologic levels. Intravenous administration of a 5-HT3 antagonist blocked these responses suggesting that nodose neuronal responses to luminal osmolarity and to the digestion products of carbohydrates are dependent on the release of endogenous 5-HT from the mucosal enterochromaffin (EC) cells, which acts on the 5-HT3 receptors on vagal afferent fibers to stimulate vagal afferent neurons. Double-labeling studies revealed that nodose neurons responded to 5-HT-dependent luminal stimuli contain mainly glutamate and substance P. Over the past year or so it has become clear that there are multiple possible excitatory inputs to a common vagal afferent route with synergistic interactions being common. The nodose ganglion contains neurons that may possess only high- or low-affinity CCK-A receptors or 5-HT3 receptors. Some neurons that express high-affinity CCK-A receptors also express 5-HT3 receptors and (or) secretin receptors. Pre-exposure to luminal 5-HT may augment the subsequent response to a subthreshold dose of CCK. Synergistic interaction between CCK and secretin also occurs at the nodose ganglia; this is mediated by high affinity CCK-A receptor. This may explain the robust postprandial secretion of enzyme, bicarbonate, and fluid despite the modest increase in CCK after a meal. Some neurons that possess low-affinity CCK-A receptor colocalize with leptin receptors (OB-Rs). These neurons also respond to mechanical distention. Interaction between CCK-A receptor and OB-Rs in these neurons likely facilitates leptin mediation of short-term satiety.

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 μg/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 μg/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 insulin and glucose metabolism on pancreatic exocrine function

Glucose metabolism is highly dependent on hormones secreted by the islets of La ngerhans, and most notably on insulin.Moreover, the endocrine and exocrine pancreas has a complex anatomical and functional interaction. The exocrine part of thepancreas is influenced by the islet hormones mainly through an islet-acinar portal system, for example, the periinsular acinar cellsare larger and contain more zymogen and amylase. The insulo-acinar axis is also indicated by morphological evidences.Hypoinsulinemia causes pancreatic atrophy with fat replacement of the exocrine pancreas in different species. These resultsindirectly show the significant role of insulin on pancreatic exocrine function. However, direct evidence is also available tohighlight the key role of insulin. Both endogenous and exogenous insulin evoke increases in pancreatic enzyme synthesis andgrowth. Insulin is not only important in healthy conditions, but is also involved in the regenerative processes during pancreatitis.Human studies have also proved the necessity of insulin in pancreatic exocrine function. In conclusion, insulin has long termeffects on the regulation of the biosynthesis of pancreatic digestive enzymes and short term effects on the stimulation ofpancreatic secretion. Other peptides, such as pancreatic polypeptide, glucagon and somatostatin seem to inhibit pancreaticsecretion, although more experiments are needed to clarify this hypothesis. Despite our current knowledge, many otherhypotheses and questions remained unanswered concerning the effects of hormones secreted by different cells of the islets ofLangerhans, therefore, it seems to be of great importance to explore the effects of these hormones on pancreatic exocrinefunction.

Neurohumoral control of exocrine pancreatic secretion

Reports over the past year provide significant advances in our knowledge of the neurohumoral control of exocrine pancreatic secretion, especially related to human physiology. Major findings include those demonstrating that human pancreatic acinar cells do not respond to cholecystokinin stimulation and that a major circulating form of cholecystokinin is CCK-58. These findings establish that in humans, cholecystokinin causes pancreatic secretion via a neural circuit after interacting with neural sensory receptors in the mucosa of the intestine and that CCK-58 is the likely form of cholecystokinin that stimulates the neural pathways. Other findings demonstrate significant differences in the pancreatic secretory response in humans as a function of the type of nutrient delivered to the gut, especially the fact the elemental diets and medium-chain triglycerides cause much less stimulation of pancreatic secretion than do complex diets. Finally, convincing evidence demonstrating that pancreatic proteases cause inhibition of pancreatic secretion in humans has been presented. In addition to new insights into the neurohumoral control of pancreatic secretion, these findings provide information relevant to both the pathogenesis of pancreatic disorders and their treatment.

Stimulation of pancreatic secretion by non-sulfated CCK-58 gives insight into neurohormonal regulation of the pancreas

Non-sulfated cbolecystcMmn-58 (CCK-58ns) has been shown to be present m porcine and canine intestine, This form ot cholecystokinin may have been ignored by our laboratory in previous studies because it reacts very poorly in our radioimmunoassay with antibody 5135 (about 10% as potent as CCK-8s. However, it is present in the intestine at about half the concentration of CCK-58s. A maior bi-product from the synthesis and purification of rat CCK-58s is CCK-58ns. Syrabenc CCK-58ns was wall separated from CCK-58s, and was used to stinmlate pancreatic secretion in awake rats. CCK-58ns was as potent and one-half as effacions as CCK.-58s for stimulation ot pancreatic find and protein. CCK-8s was as potent as the CCK-58 peptides for stimulation of prutem, but CCK-8 did not stimulate fluid secretion (Figure). A model that would account tbr these results is one where both the acmar CCK-A receptor and the CCK-A receptor on intrapancreatic nerves regulate pancreatic secretion. The nanral CCK-A receptor is mediated by a neumtransmttter that can be blocked by atropine and it stinmlates both protein and fuid. We propose that this neural receptor is not activated by CCK-8s at any concetrations, possibly because CCK-8s is inactivated by neural endopeptidease before it reaches the neural CCK-A receptor. This is supported by the tact that CCK-58s is resistant to this endopepfidase degradation while CCK-8s is rapidly cleaved. We barther propose that the CCK-A receptor m~ aciuar cells is not activated by CCK-58ns and its inability to react with this receptor causes the decreased efficacy compared to CCK-58s. In conclusion, CCK-58ns is present in intestine and it has a unique pattern for stimulating pancreanc secretion that leads to new hypotheses about regulation of pancreatic secretion.

Cholecystokinin activates specific enteric neurons in the rat small intestine

Cholecystokinin (CCK) is a peptide hormone released from the I-cells of the upper small intestine. CCK evokes a variety of physiological responses, such as stimulation of pancreatic secretion, reduction of food intake and inhibition of gastric emptying. Previously, we reported that CCK activates enteric neurons in the rat. However the specific subpopulations of enteric neurons activated by CCK have not been identified. In the work reported here, we utilized immunohistochemical detection of nuclear Fos, a marker for neuronal activation, and selected phenotypic markers to identify some of the neuronal subpopulations activated by CCK. The phenotypic markers that we examined were: nitric oxide synthase (NOS), neurokinin-1 receptor (NK-1R), calbindin (Cal), Calretinin (Calr), and neurofilament-M (NF-M). We found that in the myenteric plexus of the rat duodenum and jejunum, CCK activated NOS immunoreactive neurons. In the submucosal plexus of duodenum and jejunum, CCK activated Cal, Calr and NF-M immunoreactive neurons. CCK failed to activate NK-1R immunoreactive neurons in either plexus. Our results indicate that CCK activates distinct enteric neurons in the rat upper small intestine. Furthermore the fact that NOS immunoreactive neurons were activated suggests that CCK modulates the activity of inhibitory motor neurons in the myenteric plexus. Expression of Fos immunoreactivity in Calr and Cal immunoreactive neurons is consistent with a role for CCK in modulation of intrinsic sensory and/or secretomotor neuronal activity in the submucosal plexus.

Pathophysiological role of cholecystokinin in humans.

Cholecystokinin (CCK) is a major gastrointestinal hormone that plays an important role in stimulation of pancreatic secretion and gall-bladder contraction, regulation of gastrointestinal motility and induction of satiety. Ingestion of fat and protein induces significant increases in plasma CCK. Intraluminal mediators of CCK secretion, luminal CCK releasing factor and diazepam-binding inhibitor, were purified from rat intestinal secretion. These CCK-releasing factors (RF) are secreted tonically by the small intestine and stimulate CCK release. Another kind of CCK-RF named 'monitor peptide' was purified from the rat pancreatic juice that stimulates CCK secretion when introduced into rat intestine. Bile exclusion from the duodenum causes an increase in basal CCK and enhances stimulated plasma CCK release, and bile salt replacement reverses these effects. Thus, the CCK-RF are spontaneously secreted into the intestinal lumen in humans, while the CCK-producing cells are under constant suppression by intraduodenal bile acids. In acute pancreatitis, plasma CCK levels are high in patients with gallstone pancreatitis, but not in patients with pancreatitis from other causes, such as alcoholic and idiopathic pancreatitis. A transient disturbance of bile flow into the duodenum by stones or oedema of the pancreas together with impairment of pancreatic exocrine function might cause the increase in plasma CCK release in gallstone pancreatitis. Patients with chronic pancreatitis with mild to moderate impairment of exocrine function and abdominal pain, had significantly higher plasma CCK concentrations, whereas patients with pancreatic insufficiency had a significantly lower plasma CCK response to a test meal than the healthy subjects. The increased CCK may further aggravate pancreatitis and worsen the prognosis of pancreatitis by stimulating the injured pancreas, resulting in the vicious circle via endogenous CCK release. The CCK-A receptor antagonist might be therapeutically useful in acute pancreatitis by stopping the vicious circle.

Guanidino group is involved in the stimulation of exocrine pancreatic secretion by protamine in normal and chronic bile-pancreatic juice-diverted rats.

We previously demonstrated that the feeding of guanidinated casein, whose lysine residues are converted to homoarginine, stimulates pancreatic secretion much higher than that of intact casein in chronic bile-pancreatic juice (BPJ)-diverted rats, which suggests that the guanidino group is involved in BPJ-independent enhancement of pancreatic secretion. However, the role of the guanidino group in the protein for the enhancement of pancreatic secretion has not been clarified. In this study, we examined the stimulation of pancreatic secretion by a arginine rich dietary protein, protamine (25, 50 mg/ml), and then determined whether the guanidino group in protamine was responsible for the secretory responses in normal and BPJ-diverted rat by comparison with pancreatic secretion between intact and deguanidinated protamine. The deguanidinated protamine was prepared by converting arginine residues of salmon protamine to ornithine using heated hydrazine (conversion rate of arginine residue was 87%). In normal rats, pancreatic protein and chymotrypsin secretion were stimulated in dose-response fashion after a duodenal instillation of native protamine solution (25, 50 mg in 1 ml). In chronic BPJ-diverted rats, native protamine (25 mg) maximally stimulated pancreatic protein and protease secretion. In contrast, deguanidinated protamine (50 mg in 1 ml) did not stimulate pancreatic secretion in both normal and BPJ-diverted rats. In addition, the duodenal administration of arginine, which is equal to the amount contained in 50 mg of native protamine, had no effect on pancreatic secretion in both rats. These results suggest that a naturally occurring protein, protamine, stimulates pancreatic secretion by a luminal BPJ-independent mechanism and that the guanidino group in this protein is responsible for stimulating pancreatic secretion in BPJ-diverted rats.

Stimulation of exocrine pancreatic secretion by soybean trypsin inhibitor does not depend on the masking of luminal trypsin activity in rats that have bile-pancreatic juice diverted into the ileum.

We reported previously that dietary proteins stimulate pancreatic secretion by a mechanism not involved in masking trypsin activity in rats that have bile-pancreatic juice (BPJ) diverted from the proximal small intestine for 7 days. However, BPJ in the distal small intestine is possibly responsible for the stimulation of pancreatic secretion in chronic BPJ-diverted rats. To examine whether the BPJ-dependent mechanism operates in the distal small intestine of chronic BPJ-diverted rats, we investigated pancreatic responses after inhibition or removal of pancreatic trypsin activity in the distal small intestine of conscious rats. Duodenal instillation of soybean trypsin inhibitor (SBTI), which is a proteinaceous trypsin inhibitor, stimulated pancreatic secretion in the chronic BPJ-diverted rats, whereas a nonpeptidic trypsin inhibitor, FOY 305, did not. Ileal administration of both trypsin inhibitors did not enhance pancreatic secretion in the diverted rats. Exclusion of luminal BPJ from the distal small intestine was also ineffective in causing pancreatic exocrine secretion in the chronic BPJ-diverted rats. These observations reveal that ileal BPJ does not contribute to the stimulation of pancreatic secretion in rats that have BPJ chronically diverted into the ileum, as in intact rats, and that a duodenal instillation of SBTI stimulates pancreatic secretion as a protein, and not as a trypsin inhibitor.

Biology of gut cholecystokinin and gastrin receptors.

1. The stomach hormone gastrin and the intestinal hormone cholecystokinin (CCK) share a common C-terminal pentapeptide sequence but have different biological roles. Gastrin is the major stimulant of gastric acid secretion and has a growth stimulatory effect on the secretory part of the stomach. The physiological roles of CCK are the stimulation of pancreatic secretion and the contraction of the gall-bladder. 2. Several classes of receptors have been defined for peptides of the gastrin/CCK family. The CCKA receptor on pancreatic acini has a greater affinity for sulfated CCK than for gastrin, while the gastrin/CCKB receptor in gastric mucosa and brain has similar affinities for both gastrin and CCK. Potent and selective antagonists have been developed for both receptor classes. 3. The structures of the CCKA and gastrin/CCKB receptors have been deduced from the nucleotide sequences of cloned cDNA. The receptors, which both belong to the family with seven transmembrane segments, control secretion via similar signalling mechanisms. Occupation of either receptor leads to activation of phospholipase C, with resultant increases in intracellular levels of inositol triphosphate and Ca2+. Mitogenic signalling pathways are also being defined. 4. Recent studies have questioned the previous assumption that gastrin precursors are inactive. Glycine-extended gastrin17 has been shown to stimulate mitogenesis in some cell lines and may also have an autocrine role in the growth of colonic cancers. The receptors involved, which are clearly distinct in binding properties from the CCKA and gastrin/CCKB receptors, have not yet been cloned. Specific antagonists for the novel receptors will be required to define their function in further detail.

DIAGNOSIS OF EXOCRINE PANCREATIC INSUFFICIENCY IN CHILDREN BY USE OF PANCREOLAURYL TEST

In adult studies, the urine pancreolauryl test (PLT) is used as an indirect measure of pancreatic exocrine function: the fluorescein dilaurate is cleaved by the pancreas specific cholesterol ester hydrolase and the liberated fluorescein is absorbed and excreted in the urine. Duodenal intubation and stimulation of pancreatic secretion is complicated and unpleasant in children. We present here a modified version of PLT based on plasmatic fluorescein concentration, previously validated in adult patients, in the aim to measure exocrine pancreatic insufficiency (EPI) in children. Methods: 2 capsules containing 174,5 mg of fluorescein dilaurate were ingested with a standard meal. Plasmatic fluorescein concentration was determined spectrophotometrically (492 nm) on blood samples collected through a small catheter at time 0 and every 30 mn during 6 hours. In our adult series PLT has been validated by comparison with the results of duodenal intubation after pancreatic stimulation; 58 patients have been studied: 10 healthy subjects, 7 with chronic digestive disease without pancreatic involvement, 18 patients with moderate EPI and 23 with severe EPI. Calculation of the experimental area under curve (AUC) in mg/ml-1/h showed statistically significant differences (< 0.0001) between controls (57,39 ± 15,67) and EPI (moderate = 19,24 ± 23,93 and severe = 8,05 ± 9,50) and also between digestive diseases (35,75 ± 36,62) and severe EPI. Choosing 30 mg/ml-1/h as the cut off limit: sensitivity was 72% for moderate EPI and specificity was 100% for severe EPI. The PLT was carried out on 18 children (5-16 years): 8 with cystic fibrosis (CF), 2 with Swachman's syndrome (SS). 2 with chronic pancreatitis (CP), 3with chronic diarrhoea (CD),1 with constipation, 1 with failure to thrive, and 1 with recurrent pneumonia. Results: 13 children presented severe EPI (AUC ranging from 0,02 to 0,11): 7 with CF, 2 with SS, 2 with CP and 2 with CD. Fat absorption coefficient was below 90% in 4 of the 9 children tested. The calculated AUC for the child with failure to thrive was 16,95 expressing a moderate EPI and 4 children had normal AUC ranging from 38,08 to 52,63. Conclusion: the modified PLT eliminates the need for timed urine collections. It provides a simple, reliable, and tubeless test of exocrine pancreatic function, more sensitive than the fat absorption coefficient in children. PTL can be used as a diagnostic test to distinguish infants and children with EPI from normal children and those with other causes of diarrhoea and failure to thrive.

A protein less sensitive to trypsin, guanidinated casein, is a potent stimulator of exocrine pancreas in rats.

Previously, we have shown that, in rats that have had bile-pancreatic juice (BPJ) diverted from the proximal small intestine for 7 days, the exocrine pancreatic secretion was enhanced after they were fed a casein, fat-free diet. This demonstrates that the pancreatic secretion is stimulated by dietary protein with a pancreatic protease-independent pathway. To examine the chemical structure of casein responsible for the enhancement of pancreatic secretion, we prepared chemically modified casein in which lysine residues were guanidinated. Secretion of protein, amylase, and chymotrypsin in the chronic BPJ-diverted rat was increased much more after the rats were fed a diet containing guanidinated casein (250 g/kg diet) than after they were fed a diet containing intact casein (250 g/kg diet). In normal rats whose diverted BPJ was returned to the duodenum, the increases in the pancreatic secretion after consuming the guanidinated casein diet were comparable to those after consuming the intact casein diet. In vitro digestibility of guanidinated casein by trypsin and chymotrypsin was much lower than that of intact casein. Also, guanidinated casein inhibited tryptic hydrolysis of benzoyl-L-arginine p-nitroanilide to a lesser extent than did intact casein as determined by an in vitro assay. These results demonstrate that guanidinated casein is less sensitive to trypsin than is intact casein and that the structure that is sensitive to trypsin is not involved in the stimulation of pancreatic secretion in diverted rats. The results evidence that masking luminal trypsin activity does not predominantly contribute to the enhancement of pancreatic secretion in 7-day BPJ-diverted rats. Also, in normal rats, the luminal protease-independent mechanism may play a role partly in increasing the pancreatic secretion by dietary protein.

Gastric acid-independent enhancement of exocrine pancreatic secretion by dietary protein in chronic bile-pancreatic juice diverted rats.

Diversion of bile-pancreatic juice (BPJ) causes exocrine pancreatic hypersecretion in a fasting state, and we demonstrated that a feeding of dietary protein stimulates further secretion of pancreatic enzymes in chronic BPJ-diverted rats. We determined that gastric acid secretion is associated with the stimulatory effect of dietary protein feeding on pancreatic secretion in the diverted rats. BPJ was diverted with a cannula of the common bile-pancreatic duct and returned to the upper ileum for 7 days. The BPJ-diverted rats were administered omeprazole (12 mg/kg body weight) orally and were fed a 25% casein, fat-free diet spontaneously under unrestrained conditions. The volume of BPJ was not changed after administration of omeprazole and feeding the diet. Total protein, amylase, and chymotrypsin secretions were not changed 1 h after omeprazole administration but increased gradually after feeding the diet. The secretion of these enzymes reached peak values 120-150 min after feeding, and these values were two- to threefold higher than those before feeding. We conclude that gastric acid secretion is not responsible for the stimulation of pancreatic secretion that occurs after feeding a dietary protein to chronic BPJ-diverted rats.

Nitric oxide in pancreatic secretion and hormone-induced pancreatitis in rats

The aim of the present study was to determine the role of endogenous nitric oxide (NO) in pancreatic secretion in vivo and amylase release from pancreatic acini in vitro and in caerulein-induced acute pancreatitis in rats. Blockade of NO synthase by NG-nitro-L-arginine (L-NNA) (2.5 mg/kg i.v.) significantly reduced basal pancreatic protein secretion and that induced by the infusion of CCK (0.5 micrograms/kg-h), feeding, and the diversion of pancreatic juice in rats with pancreatic fistula. This inhibitory effect was partially reversed when L-arginine (50 mg/kg-h i.v.) was added to L-NNA. L-Arginine alone (50 mg/kg i.v.) did not affect basal or caerulein-induced pancreatic secretion. L-NNA, L-arginine, or their combination added in various concentrations to the incubation medium of dispersed acini failed to affect basal or secretagogue (caerulein or urecholine) stimulated amylase release. Infusion of caerulein (5 micrograms/kg-h) for 5 h produced histological changes of acute edematous pancreatitis accompanied by a marked increase in pancreatic protein content and about 50% reduction in tissue blood flow. L-NNA alone also reduced the pancreatic blood flow and caused a significant increase in pancreatic weight and protein content. L-NNA significantly potentiated the inflammatory changes in the pancreas caused by caerulein. Addition of L-arginine enhanced the pancreatic blood flow and ameliorated the pancreatitis induced by caerulein alone or that combined with L-NNA. We conclude that NO is involved in the stimulation of pancreatic secretion in vivo and exhibits a beneficial effect on pancreatitis, probably by improving the pancreatic blood flow.

Effects of KRN2391, a novel vasodilator, on pancreatic exocrine secretion in anesthetized dogs

The effects of KRN2391, a newly synthesized vasodilator, on pancreatic exocrine secretion in anesthetized dogs were compared with those of Ki3315, pinacidil and nitroprusside. Graded doses of KRN2391 (0.03–3 μmol/kg) and nitroprusside (0.003–0.3 μmol/kg) injected i.a. produced dose-dependent increases in the secretion of pancreatic juice, with a high concentration of protein and low concentration of bicarbonate, but Ki3315 or pinacidil did not (up to 10 μmol/kg). KRN2391 and nitroprusside increased the cyclic GMP levels in pancreatic tissue together with the increase in pancreatic secretion. Methylene blue decreased pancreatic secretion and cyclic GMP levels stimulated by KRN2391 and nitroprusside, but glibenclamide did not. KRN2391, Ki3315, pinacidil and nitroprusside caused vasodilator actions. These results suggest that KRN2391 has direct secretory properties on pancreatic exocrine glands of the dog and its nitro moiety has an important role in the stimulation of pancreatic secretion, but the K + channel opening action or increasing of blood flow rate does not participate in the secretion.

CRL41405: a drug with a new pharmacological profile on pancreatic exocrine secretion in the rat.

The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7-20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67-200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2-deoxyglucose-induced (but not the acetylcholine-induced) stimulation of pancreatic secretion through an alpha-2 adrenoceptor inhibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha-2 inhibition was suppressed by idazoxan. Under alpha-2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2-deoxyglucose-induced and acetylcholine-induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.