ceruletide and Body-Weight

Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4. The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed.. Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase. Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.

Topics: Acetylcholinesterase; Acute Disease; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents; Body Weight; Ceruletide; Cytokines; Galantamine; Humans; Mice; Pancreatitis

Severe acute pancreatitis (SAP) is a necrotic pancreatic inflammation associated with high mortality rate (up to 70%). Bone marrow (BM) mesenchymal stem cells (MSCs) have been investigated in pancreatic cellular regeneration, but still their effects are controversial. Therefore, the present study is aimed at examining the enrichment of the stem cells with ascorbic acid (AA) and N-acetylcysteine (NAC) and explore their combined action on the expression of the inflammatory cytokines: interleukin 1

Topics: Acetylcysteine; Animals; Antioxidants; Ascorbic Acid; Blood Glucose; Body Weight; Caspase 3; Cell Proliferation; Ceruletide; Fluorescent Dyes; Insulin; Interleukin-1beta; Islets of Langerhans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; NF-kappa B; Organic Chemicals; Pancreatitis; Proliferating Cell Nuclear Antigen; Rats; Regeneration; Tumor Necrosis Factor-alpha

Nod-like receptor pyrin domain containing 3 (NLRP3) is one of the well characterized inflammasome that controls the maturation of pro-inflammatory cytokines and thereby the inflammation in pancreas which could be a promising target for anti-inflammatory drugs. The present study is aimed to explore whether luteolin can target the NLRP3 inflammasome and modulate its activity through the signaling protein, HSP70 in the ethanol-cerulein model of experimental pancreatitis.. Male albino Wistar rats were divided into four groups. Groups 1 and 2 rats received normal diet. Groups 3 and 4 rats received isocalorically adjusted diet containing ethanol for 5 weeks and cerulein (20 μg/kg body weight i.p., thrice weekly for the last 3 weeks of the experimental period). Additionally, group 2 and 4 rats received 2 mg/kg body weight of luteolin orally from third week.. Luteolin co-administration decreased the serum levels of HSP70, oxidative stress markers, myeloperoxidase, GSH/GSSG and GST with concomitant downregulation in the mRNA expression of HSP70, caspase-1, ASC-NLRP3 and NF-κB. Spearman's rank correlation test showed that serum HSP70 has positive correlation with the expression of ASC-NLRP3, caspase-1, NF-κB and 4-hydroxynonenal and negative correlation with GSH:GSSG ratio.. The modulating effect of luteolin on the expression of HSP70, NF-κB and thereby on ASC-NLRP3 complex may be claimed for its pancreato-protective activity.

Topics: Animals; Apoptosis; Body Weight; Caspase 1; Caspase Activation and Recruitment Domain; Ceruletide; Ethanol; Glutathione Disulfide; HSP70 Heat-Shock Proteins; Inflammasomes; Luteolin; Male; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pancreatitis; Rats; Rats, Wistar

CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas.. We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure.. Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation.. In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein.

Topics: Animals; Animals, Genetically Modified; Body Weight; Carboxylesterase; Ceruletide; Diabetes Mellitus, Type 2; Diet; Disease Models, Animal; Gene Expression; Gene Order; Glucose; Islets of Langerhans; Mice; Mutation; Pancreas, Exocrine; Phenotype

Acute pancreatitis (AP) is a complicated inflammatory disease that has an unknown underlying pathogenesis. Because alpha-pinene can modulate inflammation, we examined whether alpha-pinene plays a role in AP.. Alpha-pinene was administered intraperitoneally 1h prior to the first injection of cerulein. Once AP developed, cerulein, a stable cholecystokinin analog, was injected hourly over a 6-h period. Blood samples were taken 6h later to determine serum amylase and lipase levels. The pancreas and lungs were rapidly removed for morphological examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction. We also isolated the pancreatic acinar cells using a collagenase solution. Cell viability, and cytokine productions were measured in pancreatic acini.. Intraperitoneal administration of alpha-pinene reduced the pancreatic weight (PW) to body weight (BW) ratio and the serum levels of amylase and lipase. Alpha-pinene treatment also reduced histological damage and myeloperoxidase activity in the pancreas and lungs. Furthermore, alpha-pinene pretreatment reduced the production of pancreatic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 during cerulein-induced AP. In vitro, alpha-pinene inhibited cerulein-induced cell death and cytokine production in isolated cerulein-treated pancreatic acinar cells.. These findings suggest that alpha-pinene has an anti-inflammatory effect during cerulein-induced AP.

Topics: Acute Disease; Amylases; Animals; Bicyclic Monoterpenes; Body Weight; Cells, Cultured; Ceruletide; Female; Immunologic Factors; Injections, Intraperitoneal; Lipase; Lung; Mice; Mice, Inbred C57BL; Monoterpenes; Pancreas; Pancreatitis; Peroxidase

Nardostachys jatamansi belonging to the family Valerianaceae has been used as a remedy for stomach and skin ailments in Korea. The effect of N. jatamansi on acute pancreatitis (AP) has not been defined. Therefore, we investigated the effect of N. jatamansi on cerulein-induced AP.. In the pretreatment group, N. jatamansi was administered orally to mice at 10 and 20 mg/kg for 5 days, and the mice were intraperitoneally injected with the stable cholecystokinin analogue cerulein hourly for 6 hours. In the posttreatment group, cerulein was injected hourly for 6 hours, and N. jatamansi was administered at the indicated time (1, 3, and 5 hours after the first cerulein injection) and dose (10 and 20 mg/kg) during the cerulein injection. Blood samples were taken 6 hours later to determine the serum amylase, the lipase, and the cytokine levels. The pancreas and the lung were rapidly removed for morphologic examination, myeloperoxidase assay, and real-time reverse transcription polymerase chain reaction.. Nardostachys jatamansi treatment attenuated the AP, as shown by the histological examination results of the pancreas and the lung, reductions in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and messenger RNA expressions of inflammatory mediators.. These results suggest that N. jatamansi attenuates the severity of AP and pancreatitis-associated lung injury.

Topics: Acute Disease; Amylases; Animals; Body Weight; Cell Survival; Cells, Cultured; Ceruletide; Cytokines; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Female; Lipase; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Nardostachys; Organ Size; Pancreas; Pancreatitis; Peroxidase; Phytotherapy; Plant Extracts; Reverse Transcriptase Polymerase Chain Reaction

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Topics: Acute Disease; Adipokines; Adiponectin; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Chemokines; Cytokines; Disease Models, Animal; Female; Insulin; Leptin; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Pancreas; Pancreatitis; Peroxidase; Severity of Illness Index

To investigate the effect of Gardenia jasminoides (GJ) on cerulein-induced acute pancreatitis (AP) in mice.. C57BL/6 mice weighing 18-20 g were divided into three groups. (1) Normal saline-treated group, (2) treatment with GJ at a dose of 0.1 g/kg, (3) treatment with GJ at a dose of 1 g/kg. GJ was administered orally (n = 6 per group) for 1 wk. Three hours later, the mice were given an intraperitoneal injection of cerulein (50 microg/kg), a stable cholecystokinin (CCK) analogue, every hour for a total of 6 h as described previously. The mice were sacrificed at 6 h after completion of cerulein injections. Blood samples were obtained to determine serum amylase, lipase and cytokine levels. The pancreas was rapidly removed for morphologic examination and scoring. A portion of pancreas was stored at -70 degree and prepared for the measurement of tissue myeloperoxidase (MPO) activity, an indicator of neutrophil sequestration, and for reverse-transcriptase PCR (RT-PCR) and real-time PCR measurements.. Treatment with GJ decreased significantly the severity of pancreatitis and pancreatitis-associated lung injury. Treatment with GJ attenuated the severity of AP compared with saline-treated mice, as shown by reduction in pancreatic edema, neutrophil infiltration, serum amylase and lipase levels, serum cytokine levels, and mRNA expression of multiple inflammatory mediators.. These results suggest that GJ attenuated the severity of AP as well as pancreatitis-associated lung injury.

Topics: Acute Disease; Administration, Oral; Amylases; Animals; Anti-Inflammatory Agents; Body Weight; Ceruletide; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gardenia; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Lipase; Lung; Lung Injury; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Organ Size; Pancreas; Pancreatitis; Peroxidase; Plant Extracts; RNA, Messenger; Tumor Necrosis Factor-alpha

Increase of phosphatidic acid (PA) accumulation in response to caerulein (Cae) and after subtotal pancreatectomy (SP) has been previously described and phospholipase D (PLD) derived PA involvement in pancreatic regeneration was suggested. We also described decrease of Cae stimulated PA accumulation after a single dose of ethanol (both in vitro and in vivo). The present study was undertaken in order to determine the influence of chronic ethanol feeding on basal and Cae stimulated PA accumulation and other parameters of pancreatic regeneration in control and ethanol feed rats. Male rats were pair fed ad libitum with an isocaloric liquid diet (Lieber De Carli) with or without ethanol. In vitro study: pair fed rats were killed after 2 or 6 weeks of feeding, pancreata were dissected out and weighted, dispersed pancreatic acini were then prepared and loaded with 3H myristic acid in order to label the phosphatidylcholine pool. Phosphatidic acid (3H PA) accumulation, in the presence of propranolol, was measured after stimulation with increasing doses of Cae. In vivo study: PA was measured 3 days after SP or sham operation in both groups of rats, and also after 1 h of Cae infusion (0.25 microg/kg/h). Pancreatic weight, amylase, protein, RNA and DNA content were established.. In vitro study 1) Basal PLD activity expressed as PA accumulation was significantly elevated after 6 weeks of ethanol feeding in comparison to the control values (28%). 2) Cae in doses ranging from 100 pM to 5 nM was not able to stimulate PA accumulation in isolated pancreatic acini prepared from ethanol fed rats. In vivo study: 1) Body weight and pancreatic weight were similar in, both the ethanol fed and the control groups, after 2 and 6 weeks. 2) Ethanol feeding significantly decreased total amylase content in the pancreas, but did not change protein, RNA and DNA content. 3) in contrast to the control animals in which SP caused a 71.1% increase of PA accumulation over the sham operation, subtotal pancreatectomy was not able to stimulate PA in rats fed with ethanol. 4) Also Cae infusion did not stimulate PA accumulation in the ethanol fed animals in comparison to the controls. Since the involvement of PLD activation in the early stages of pancreatic regeneration was postulated, our results suggest that chronic ethanol feeding can influence this process by decrease of PA production, probably because of the inhibition of hydrolytic PLD activity in the presence of ethanol. This could be one of the mechanisms responsible for pancreatic injury after chronic ethanol consumption.

Topics: Amylases; Animals; Body Weight; Ceruletide; Chymotrypsin; DNA; Ethanol; Gastrointestinal Agents; Male; Organ Size; Pancreas; Pancreatectomy; Phosphatidic Acids; Proteins; Rats; Rats, Wistar; Regeneration; RNA; Solvents

The present study evaluates long-term effects of the CCK-agonist caerulein and the CCK-A antagonist loxiglumide in obese and lean Zucker rats. Caerulein and loxiglumide altered food intake neither in obese nor in lean rats. By as yet unknown mechanisms, however, weight increase was accelerated by loxiglumide and reduced by caerulein in obese and lean rats. Caerulein increased pancreatic weight only in lean but not in obese rats. Thus, obese rats show a resistance of pancreatic CCK-A receptors. The failure of CCK-agonist and -antagonist to alter food intake suggests that this CCK-resistance is not responsible for obesity in the genetically altered rats.

Topics: Animals; Body Weight; Ceruletide; Cholecystokinin; Drug Resistance; Eating; Female; Male; Obesity; Organ Size; Pancreas; Proglumide; Rats; Rats, Zucker; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Satiety Response

Expression of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) was studied in normal pancreatic tissue and in (pre)neoplastic pancreatic lesions of azaserine-treated rats. They were given either a low fat, high fiber (low caloric) diet, to inhibit carcinogenesis, or a low fat diet combined with injections of the cholecystokinin analog caerulein to enhance carcinogenesis. The control groups, maintained on a low fat diet, were injected with azaserine or were not treated at all. Autopsy was performed at 6 and 15 months after the last azaserine injection. After both 6 and 15 months immunohistochemistry revealed a weak expression of EGF and TGF-alpha peptides in the acinar cells, and a stronger expression in the ductular and centroacinar cells. TGF-alpha peptide expression was reduced in both putative preneoplastic and neoplastic acinar cell lesions, but no differences in EGF peptide expression were observed between the various stages of exocrine pancreatic carcinogenesis. After 16 months an increase in TGF-alpha mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF-alpha mRNA levels in macroscopically isolated tumors were significantly lower, but EGF mRNA levels were significantly higher, than in total pancreatic homogenates from azaserine-treated rats. Furthermore, EGF and TGF-alpha mRNA levels in isolated tumors did not differ significantly from mRNA levels in non-carcinogen-treated rats. Neither with immunohistochemistry nor with PCR were differences in EGF or TGF-alpha expression observed due to either inhibition or stimulation of carcinogenesis. It is concluded that putative preneoplastic acinar cell lesions induced in rat pancreas by azaserine may develop into acinar adenocarcinomas independently of TGF-alpha and EGF. The results suggest involvement of these growth factors at the early stage of the carcinogenic process, during the initiation of normal acinar cells into putative preneoplastic cells. However, modulation of azaserine-induced pancreatic carcinogenesis by cholecystokinin or a low fat, high fiber (caloric restricted) diet appeared not to be regulated by EGF or TGF-alpha.

Topics: Animals; Azaserine; Base Sequence; Body Weight; Carcinogens; Ceruletide; Cocarcinogenesis; Diet, Fat-Restricted; Dietary Fiber; Drug Synergism; Energy Intake; Epidermal Growth Factor; Immunohistochemistry; Male; Molecular Sequence Data; Organ Size; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor alpha

The effects of the cholecystokinin (CCK)-analogue, caerulein, and CCK-receptor antagonist lorglumide (CR-1409) on pancreatic carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) were studied. One hundred thirty rats were divided into the following 10 treatment groups: group 1, DMBA (2-3 mg); group 2, DMBA + caerulein (5 micrograms/kg); group 3, DMBA + caerulein + CR-1409 (12 mg/kg); group 4, caerulein + DMBA; group 5, caerulein + CR-1409 + DMBA; group 6, DMBA + CR-1409; group 7, CR-1409 + DMBA; group 8, caerulein; group 9, CR-1409; and group 10, sham operation + saline. DMBA was surgically implanted into the pancreas. Caerulein and/or CR-1409 was administered twice daily for 15 days after (in groups 2, 3, and 6) or before (in groups 4, 5, and 7) DMBA implantation. Six months after carcinogen administration, all rats were sacrificed and autopsied. The incidence of pancreatic cancer appeared significantly (P < 0.001) increased when caerulein was administered following DMBA implantation. CR-1409 significantly inhibited (P < 0.02) caerulein effects and reduced tumor growth when injected after carcinogen exposure.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adenocarcinoma; Animals; Body Weight; Ceruletide; Chi-Square Distribution; DNA, Neoplasm; Male; Organ Size; Pancreas; Pancreatic Neoplasms; Proglumide; Random Allocation; Rats; Receptors, Cholecystokinin

This study was undertaken to determine the effect of the single and combined administration of caerulein, hydrocortisone, and FOY-305 (camostat) on the regeneration of the remnant pancreas after a 90% pancreatectomy in rats. After undergoing either a sham operation or a 90% pancreatectomy, the rats were administered the three drugs either singly or in combination. After the rats were killed, the pancreas was weighed and examined for tissue amylase activity, tissue protein content and total DNA content. The results were as follows: In the sham operation group, the caerulein among three drugs produced a significant trophic effect. The trophic effect in the combined administration group was greater than that in the single administration group. In the 90% pancreatectomy group, of the three drugs administered, hydrocortisone produced the most significant trophic effect. The trophic effect in the combined administration group was greater than that in the single administration group. These data suggest that the trophic effect of caerulein is significant in mature pancreatic cells while that of hydrocortisone is an immature one and that an additive effect of the three drugs was observed.

Topics: Amylases; Animals; Body Weight; Ceruletide; DNA; Esters; Gabexate; Guanidines; Hydrocortisone; Male; Pancreas; Pancreatectomy; Proteins; Rats; Rats, Wistar; Regeneration; Thymidine; Trypsin Inhibitors

The role of exogenous and endogenous cholecystokinin has been studied in the process of pancreatic regeneration after acute pancreatitis. A mild form of pancreatitis was induced in rats by subcutaneous cerulein at 12 micrograms.kg-1, three times a day for 2 days. After 3 days of rest, the cerulein-treated rats were divided into four groups: rats with acute pancreatitis fed 20% casein, who received no treatment; rats fed 50% casein; rats fed 20% casein supplemented with 1% soybean trypsin inhibitor (SBTI); and rats fed 20% casein who received 1 microgram.kg-1 of subcutaneous cerulein, three times a day. Controls were fed 20% casein plus saline subcutaneously. Rats were killed after 5, 10, or 20 days of treatment. Pancreatitis resulted in significant decreases in pancreatic weight and contents of protein, amylase, chymotrypsin, RNA and DNA. During the regenerative process, 1 microgram.kg-1 of cerulein increased all parameters to control values within 5 days and induced pancreatic growth thereafter. SBTI restored the pancreas to normal after 10 days with cellular hypertrophy; the 50% casein diet gave a response similar to SBTI without hypertrophy. It can be concluded that cerulein and SBTI can accelerate pancreatic regeneration after an attack of acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Body Weight; Ceruletide; Cholecystokinin; Chymotrypsin; Drug Therapy, Combination; Glycine max; Hypertrophy; Male; Nucleic Acids; Organ Size; Pancreas; Pancreatitis; Proteins; Rats; Rats, Inbred Strains; Regeneration; Trypsin Inhibitors

In this study, the effects of chronic water immersion stress on the pancreas were investigated in four groups of rats (each group, n = 9): stress + cerulein group, stress group, cerulein group, and control group. Stress + cerulein rats were treated with water immersion stress for 5 h and two intraperitoneal injections of 20 micrograms/kg body wt of cerulein once a week for 16 weeks. In the macroscopic findings of the pancreas, all rats in the stress+cerulein group exhibited moderate or distinctive congestion of blood vessels, gland atrophy, and fatty changes, while some of them showed bleeding. Microscopically, they all exhibited moderate or severe fibrosis, inflammatory cell infiltration, fatty changes, destruction of lobular architecture, and hemosiderin deposits, while some of them also showed bleeding. The stress group without treatment with cerulein injections showed slight fibrosis, hemosiderin deposits, and bleeding. The cerulein group without stress treatment showed fatty changes, but no inflammatory cell infiltration or fibrosis. In the stress + cerulein group only, the contents of digestive enzymes and protein in the pancreas were approximately 55% lower than those of the control group, whereas those in other groups did not show significant reduction. These findings suggest that stress plays some role in the development of chronic pancreatitis, perhaps by causing circulatory disturbance and blood vessel injury.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Immersion; Male; Organ Size; Pancreas; Pancreatic Elastase; Pancreatitis; Proteins; Rats; Rats, Inbred Strains; Stress, Physiological; Trypsin

The effect of repetitive inductions of pancreatitis by supramaximal doses of cerulein on pancreatic morphology and collagen content was studied in the rat. Pancreatitis was induced nine times at intervals of about 20 days; 3 days after the last injection of cerulein, pancreatitis was still observed, as indicated by pancreatic weight loss, increase of protein-bound hydroxyproline content, acinar-cell destruction, cellular infiltration, and deposition of collagen fibers. However, 6 weeks later, no differences in the parameters mentioned above were observed between control and cerulein-treated animals. Thus, repetitive induction of pancreatitis in the rat, according to the experimental protocol we used, did not result in pancreatic fibrosis.

Topics: Animals; Body Weight; Ceruletide; Collagen; Fibrosis; Male; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains

The effect of dietary protein deficiency and protein concentration of the diet on the pancreatic trophic response to a CCK analogue (cerulein) were studied. Rats were fed for 14 days with semipurified diets containing 5, 30, or 60% casein. During the final 4 days, they received 2 micrograms/kg cerulein or gelatin vehicle subcutaneously three times/day, and the effects on pancreatic weight and pancreatic content of protein, RNA, DNA, amylase, and chymotrypsin were determined. Cerulein failed to increase significantly any pancreatic parameter in rats fed 5% casein, while stimulating significant increases in almost all parameters in rats fed 30 and 60% casein diets. In the absence of cerulein treatment, increases in dietary protein levels caused progressive increases in all pancreatic growth parameters with the exception of amylase. In the presence of cerulein, increases in dietary protein concentrations caused progressive increases in pancreatic growth parameters (except amylase), which were maximal at 30% casein concentration of the diet for most parameters. The results confirm that pancreatic growth is stimulated by increasing protein concentration of the diet and indicate that a low protein diet, acting through a deficiency of dietary nitrogen and essential amino acids, limits the pancreatic trophic response to CCK or analogues. These results explain the failure of trypsin inhibitors to stimulate pancreatic growth in rats fed low levels of dietary protein.

Topics: Animals; Body Weight; Ceruletide; Chymotrypsin; Dietary Proteins; DNA; Male; Organ Size; Pancreas; Proteins; Rats; Rats, Inbred Strains; RNA

The authors investigated whether lorglumide a specific CCK-receptor antagonist affects the pancreatic actions of caerulein in female newborn Wistar rats. Pancreatic secretory response (expressed as the decrease in specific trypsin activity in the pancreas) was studied in 11-day-old rats following acute administration of saline (control), caerulein (0.3, 1, or 3 micrograms/kg s.c.) either without or with lorglumide (10 mg/kg s.c.). Lorglumide was given 15 min before caerulein. In chronic studies rats were treated 3x/day for 10 days from the day of birth (Day 1) with caerulein and lorglumide as above. On Day 11 the rats were decapitated and exsanguinated, their pancreas removed and analyzed. Acute administration of caerulein induced a dose-dependent depletion of specific trypsin activity from the pancreas and this was antagonized by lorglumide. Chronic treatment with each dose of the peptide increased total pancreatic trypsin content. Besides, the 3 micrograms/kg dose caused to increase pancreatic protein, DNA, and amylase content and to increase plasma corticosterone level. Chronic administration of lorglumide did not influence normal pancreatic growth, while it strongly inhibited the increase in trypsin content evoked by caerulein. However, lorglumide, given alone or in combination with caerulein, induced a significant increase in pancreatic amylase content without affecting plasma corticosterone level.

Topics: Amylases; Animals; Animals, Newborn; Body Weight; Ceruletide; Cholecystokinin; Corticosterone; Female; Organ Size; Pancreas; Proglumide; Proteins; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Trypsin

Chronic reserpine treatment of animals, an experimental model for cystic fibrosis (CF), results in generalized exocrinopathy, impaired secretion, and decreased pancreatic content of amylase. However, the mechanisms of altered acinar pancreatic function in both CF patients and reserpine-treated rats are still unknown. The present study was designed to investigate the secretory response of the rat pancreas after reserpine treatment. Rats were given reserpine (1 mg kg-1 day-1 ip) or vehicle, and killed 2, 4, or 7 days later. To distinguish between specific effects of reserpine and those related to secondary malnutrition caused by the drug, secretory response of a group of pair-fed animals to reserpine was also investigated. During reserpine treatment, body weight and food intake were significantly reduced from the 2nd day on. Amylase release from dispersed pancreatic acini, prepared from control pair-fed and from reserpine-treated rats were used to evaluate functional secretory capacity. After 7 days, both chronic reserpine and pair-feeding significantly decreased pancreatic amylase concentration to 75 and 50% of controls, respectively. Reserpine caused desensitization of the pancreatic acini secretory response to carbamylcholine, without altering maximal amylase release. Desensitization occurred gradually and reached a maximum after 7 days. Secretory responses to caerulein and to the phorbol ester 12.0-tetradecanoyl phorbol-13 acetate (TPA) were not altered. These findings indicate that desensitization of amylase release after reserpine was specific to this muscarinic agonist. It may result from increased endogenous acetylcholine release in the course of treatment.

Topics: Acetylcholine; Amylases; Animals; Body Weight; Carbachol; Ceruletide; Cystic Fibrosis; Disease Models, Animal; Eating; Male; Pancreas; Rats; Rats, Inbred Strains; Reserpine; Tetradecanoylphorbol Acetate; Time Factors

We examined whether endogenous cholecystokinin (CCK) is involved in growth of the preweanling rat pancreas. Twice daily for 14 days, 7-day-old neonatal rats received an oral gavage of either 2.5 mg/kg or 5.0 mg/kg of the potent and specific CCK receptor antagonist L-364,718 (the 2.5 mg/kg dose of antagonist was shown in the present study to abolish totally the pancreas growth-promoting effects of exogenously administered caerulein (CR) in neonatal rats). Control pups received oral gavages of the L-364,718 vehicle alone. The final body weights, pancreas weights, total pancreatic DNA contents, and total pancreatic protein contents did not differ significantly between the 21-day-old control pups and the 21-day-old pups that were pretreated for 14 days with either the low or the high doses of L-364,718. These findings suggest that endogenous CCK is not required for growth of the neonatal rat pancreas.

Topics: Amylases; Animals; Animals, Newborn; Benzodiazepinones; Body Weight; Ceruletide; Devazepide; DNA; Organ Size; Pancreas; Proteins; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Weaning

1. The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat. 2. Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investigated after short-term (5 days) administration of the peptides and/or lorglumide. 3. Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration-dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentration-response curves to caerulein to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope not significantly different from unity. The calculated pA2 for lorglumide was 7.31 +/- 0.45. The antagonist, however, was completely ineffective when tested against bombesin-induced amylase release. 4. In vivo experiments confirmed results from in vitro studies since lorglumide (5 and 10 mg kg-1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin. 5. Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10 mg kg-1), administered together with caerulein, reduced the peptide-induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist. 6. These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK-analogue, caerulein, and its inability to affect bombesin-induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK-receptors in the pancreas.

Topics: Amylases; Anesthesia; Animals; Body Weight; Bombesin; Ceruletide; Cholecystokinin; DNA; Glutamine; In Vitro Techniques; Male; Pancreas; Proglumide; Rats; Rats, Inbred Strains; Trypsin

The effect of proglumide and lorglumide, two CCK-receptor antagonists, on caerulein-induced pancreatic secretion and growth was studied in the rat. In anaesthetised animals, caerulein (1 microgram/kg) significantly increased the volume of pancreatic juice and protein output. Lorglumide (5 and 10 mg/kg), administered intraperitoneally 15 min before stimulation, reduced peptide-induced pancreatic exocrine secretion. By contrast, proglumide (100 and 400 mg/kg) was completely ineffective. In experiments dealing with the trophic effect of caerulein, both drugs were administered alone or combined with the peptide (1 microgram/kg) 3 times daily for 5 d. Saline-treated rats served as controls. At the end of the experiment, rats were sacrificed, and growth and composition of pancreatic tissue were determined. Pretreatment of the animals with either proglumide or lorglumide did not affect pancreatic size and composition. Caerulein increased the weight of the pancreas, the total pancreatic protein, trypsin, amylase, and DNA content. After pretreatment with proglumide, all these parameters were not significantly different from those obtained with caerulein alone. In contrast, when lorglumide was given together with caerulein, it significantly reduced caerulein-induced pancreatic growth and decreased enzymatic protein content of the gland. These results show that lorglumide is a much more potent and effective CCK-receptor antagonist than proglumide. Its ability to antagonize the pancreatic secretory and trophic action of a CCK-analogue (i.e. caerulein) supports the view that these physiological actions of CCK are mediated through an interaction of the hormone with specific receptors.

Topics: Amylases; Animals; Body Weight; Ceruletide; DNA; Glutamine; In Vitro Techniques; Organ Size; Pancreas; Pancreatic Juice; Proglumide; Proteins; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Trypsin

The activation of zymogen proteases and lysosomal enzyme cathepsin B in the pancreas was investigated in cerulein-induced pancreatitis in rats. Acute pancreatitis was induced by two intraperitoneal injections of 40 micrograms/kg of body weight of cerulein at intervals of 1 h. After the first cerulein injection, the active trypsin and elastase contents in the pancreas tissues significantly increased, and reached the highest level at 3 h after the first injection, followed by peaks at 5 h in the serum amylase and lipase levels and the pancreas wet weight. Cathepsin B contents in pancreas tissues showed a parallel increase with active zymogen enzymes during the first 3 h of pancreatitis. These findings may suggest that the intracellular activation of trypsinogen is an important step in the development of cerulein-induced acute pancreatitis and that cathepsin B plays a role in the activation of trypsinogen in pancreatic acinar cells.

Topics: Amylases; Animals; Body Weight; Cathepsin B; Ceruletide; Enzyme Precursors; Lipase; Lysosomes; Male; Pancreas; Pancreatic Elastase; Pancreatitis; Peptide Hydrolases; Rats; Rats, Inbred Strains; Trypsin; Trypsinogen

To study the effects of chronic bombesin on pancreatic growth and secretion, rats were injected subcutaneously, 3 times daily for 4 days with either saline or bombesin (10 micrograms/kg). Bombesin significantly increased the pancreatic weight and content in protein and RNA but not in DNA. The ratios of the three former parameters to DNA increased, suggesting cellular hypertrophy. The pancreatic content in enzymes was also elevated, especially for chymotrypsin and to a lesser degree for amylase. However, the volume of pancreatic secretion and the output of enzymes in response to CCK under a continuous infusion of secretin remained unchanged. The in vitro secretory response to caerulein and bombesin was reduced for amylase and lipase. It is concluded that chronic bombesin exerts a trophic action on the rat pancreas but decreases the sensitivity of each cell to hormonal stimulation.

Topics: Animals; Body Weight; Bombesin; Ceruletide; Male; Organ Size; Pancreas; Rats; Rats, Inbred Strains

The secretory function of the exocrine pancreas has been studied in dispersed pancreatic acini from obese and homozygous lean Zucker rats at 6 and 22 wk. No abnormality was found in acini from young rats. Acini from 22 wk obese and lean rats were equally responsive to secretagogues which stimulate cAMP, i.e. vasoactive intestinal peptide (VIP) and secretin. By contrast, there was a reduction in the maximum responsiveness to caerulein and carbamylcholine in acini from obese rats. These latter secretagogues act through mobilization of intracellular Ca2+. Since obese animals are insulin resistant and amylase release is modulated by insulin, the role of insulin resistance in the secretory defect was then investigated. A group of 22 wk obese rats received treatment with Ciglitazone (a drug which reduces insulin resistance in obese laboratory animals) for 4 wk before the secretion study. Despite the expected reduction in insulin resistance there was no improvement of the secretory defect seen with caerulein and carbamylcholine stimulation. Thus, the secretory abnormality in the exocrine pancreas of adult obese Zucker rats does not appear to be directly associated with insulin resistance. Furthermore, the secretory defect is linked to those secretagogues which induce Ca2+-independent phosphoinositide hydrolysis and Ca2+ mobilization in the target cell.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Carbachol; Ceruletide; Female; Homozygote; In Vitro Techniques; Insulin; Kinetics; Obesity; Organ Size; Pancreas; Proteins; Rats; Rats, Zucker

The role of ornithine decarboxylase and of polyamines was investigated on caerulein-induced pancreatic growth through the use of alpha-difluoromethylornithine (DFMO) and putrescine. Caerulein, the cholecystokinin analog, given at a dose of 1 microgram . kg-1 three times a day was associated with pancreatic hyperplasia and hypertrophy after 2 and 4 days of treatment. The present study shows that putrescine, given once daily i.p. at a dose of 300 mumol . kg-1, can reverse the previously observed DFMO inhibition on pancreatic DNA content increments stimulated by caerulein. It was also observed that putrescine inhibits severely the 2-day caerulein-induced pancreatic hypertrophy, yet interferes only moderately with 4 days of caerulein treatment. These data lend further support to the involvement of ornithine decarboxylase and polyamines in induced pancreatic growth.

Topics: Animals; Body Weight; Ceruletide; DNA; DNA Replication; Eflornithine; Male; Organ Size; Ornithine; Ornithine Decarboxylase Inhibitors; Pancreas; Putrescine; Rats; Rats, Inbred Strains

The increases in DNA synthesis and total DNA content after caerulein treatment support the trophic effect of this CCK analog on the pancreas. Over a 15 day caerulein treatment, pancreatic growth plateaued after 5 days and somatostatin is believed to be responsible for this phenomenon. The present study was undertaken to test this possibility. Rats were treated for 2 or 4 days with caerulein (1 microgram X kg-1), somatostatin antiserum plus caerulein or caerulein plus somatostatin (600 micrograms X kg-1). Caerulein increased all parameters studied after 2 and 4 days; pancreatic hyperplasia was established after 2 days. The somatostatin antiserum significantly enhanced the effect of caerulein, especially on DNA synthesis and contents after 2 and 4 days. The trophic effect of caerulein was significantly reduced by somatostatin dramatically so with respect to hyperplasia. The effects of the somatostatin antiserum and those of somatostatin on stimulated pancreatic growth support the hypothesis that somatostatin may be considered an endogenous growth inhibitory factor for the pancreas.

Topics: Animals; Body Weight; Ceruletide; DNA; Growth Inhibitors; Male; Organ Size; Pancreas; Protein Biosynthesis; Rats; Rats, Inbred Strains; RNA; Somatostatin

The study was aimed both at defining normal values of pancreatic function and at looking at variables (age, sex, body weight, height, and body surface) which may influence the range of normality in 271 normal controls evaluated consecutively by duodenal intubation from 1974 to 1981. Frequency distribution of all functional values were consistent with a Gaussian curve. A positive, linear correlation was found between secretory parameters and both volume secretion and output values, while no correlation was detected with bicarbonate and enzymes values. Duodenal fluid secretion and both bicarbonate and enzymes output were approximately 20% higher in males than in females, the difference being statistically significant. Mean values of both bicarbonate and enzyme concentration were not statistically different between sexes. When related to body surface, both volume and outputs values in males were no more different from those observed in females. The study has shown that body size influences pancreatic functional values and, therefore, the values should be related to some parameters of body size as body surface. The difference between males and females in fluid secretion and output values is linked primarily to differences in body size. The normal distribution of all functional parameters implies that normal limits may be calculated with standard parametric statistical analysis.

Topics: Adult; Age Factors; Amylases; Bicarbonates; Body Constitution; Body Height; Body Surface Area; Body Weight; Ceruletide; Chymotrypsin; Duodenum; Female; Humans; Lipase; Male; Middle Aged; Pancreas; Secretin; Sex Factors; Software

Exocrine and endocrine pancreatic function were studied simultaneously in the isolated perfused pancreas from rats fed a normal or an acarbose-containing diet (150 mg/100 g food) for 20 days. Body weight gain of acarbose-treated rats was slightly lower than that of control rats, despite a larger food intake. Basal and caerulein-stimulated flow rates of pancreatic juice from acarbose-treated rat pancreases were similar to those from controls, suggesting that the treated rat pancreas has normal sensitivity and responsiveness to caerulein. On the other hand, amylase output in response to caerulein was significantly decreased in acarbose-treated rat pancreases, though basal output was normal. The addition of acarbose to the diet for 20 days had no effect on the speed of the insulin response to glucose and caerulein, but the magnitude of insulin secretion to glucose stimulation was reduced by 40% and the caerulein-induced additional output of insulin by 30% in the treated group as compared with the control group. The present investigation has demonstrated that inhibition of key enzymes for carbohydrate digestion decreases not only the secretory responsiveness of amylase from acinar cells to caerulein stimulation but also the sensitivity of the insulin-secretory mechanism of pancreatic B cells to glucose and non-glucose stimulation.

Topics: Acarbose; Amylases; Animals; Body Weight; Ceruletide; Eating; Glucose; Hypoglycemic Agents; Insulin; Male; Oligosaccharides; Pancreas; Pancreatic Juice; Perfusion; Rats; Rats, Inbred Strains; Trisaccharides

Oral administration to mice with soybean trypsin inhibitor (SBTI) (27-30 mg/mouse/day) or aprotinin (5500-6000 KIU/mouse/day) for six weeks increased the total pancreatic insulin (IRI). The pancreatic IRI was also increased after sc injections of synthetic caerulein (0.05 microgram/mouse/day divided into 3 daily doses), being 82% above the control levels when expressed per g pancreas. Aprotinin (6000 KIU/mouse/day divided into 3 daily doses) injected sc had no effect on the insulin content. The total glucagon did not change significantly in any of the groups, but the molar ratio of insulin to glucagon was increased in the caerulein- and SBTI-treated mice. Caerulein-treatment led to an increased disappearance rate of glucose with k-values being 7.1 +/- 0.3 compared to 6.0 +/- 0.1 (mean +/- SEM) in the controls (P less than 0.02). In islets isolated by collagenase-digestion of the pancreas and subjected to an overnight incubation, the content of insulin and glucagon was increased in islets from caerulein-treated animals. This corresponded to the results observed in the whole pancreas. The present study suggests that oral administration of proteolytic enzyme inhibitors or treatment with caerulein has a trophic effect on the endocrine pancreas. A difference in specificity seems to exist as SBTI affected both the pancreatic weight and IRI, and aprotinin orally did not influence the pancreatic weight, but increased the total content of IRI. Caerulein led to an increase in IRI, but did not affect the weight of pancreas.

Topics: Animals; Aprotinin; Blood Glucose; Body Weight; Ceruletide; DNA; Glucagon; Glucose Tolerance Test; Insulin; Islets of Langerhans; Male; Mice; Organ Size; Trypsin Inhibitor, Kunitz Soybean; Trypsin Inhibitors

To determine the effects of hydrocortisone and caerulein (separately and in combination) on the exocrine pancreas of suckling, recently weaned, growing, and adult rats, we administered hydrocortisone (0.5 mg/100 g body wt), caerulein (1 microgram/kg), and a combination of these two hormones for 3 days. The rats were killed, and the pancreas was weighed and analyzed for DNA, protein, amylase, and chymotrypsinogen. Caerulein alone was associated with significant decreases in amylase, chymotrypsinogen, and protein concentration in suckling rats; after weaning, it produced significant increases of these same parameters, representative of pancreatic hypertrophy. Hydrocortisone caused significant increases in DNA content and enzyme and protein concentrations in suckling rats; after weaning, the steroid significantly decreased DNA content in 26-day-old rats, but increases in enzyme and protein concentration were observed. Using an increase in DNA content as an index of hyperplasia and cellular mass and enzyme and protein concentrations as indices of hypertrophy, we conclude that over a 3-day period 1) caerulein produced pancreatic hypertrophy after weaning while potentiating the hyperplastic and hypertrophic action of hydrocortisone in suckling rats; and 2) hydrocortisone potentiated the hypertrophic effect of caerulein after weaning. The data suggest that these two hormones may regulate acinar cell proliferation and enzyme synthesis of the exocrine pancreas.

Topics: Aging; Amylases; Animals; Body Weight; Ceruletide; Chymotrypsinogen; DNA; Hydrocortisone; Organ Size; Pancreas; Proteins; Rats

Topics: Adult; Body Weight; Ceruletide; Cholangiography; Cholecystography; Female; Humans; Male; Middle Aged

Rats were given subcutaneous injections of secretin (12.5 microgram kg-1) plus caerulein (0.5 microgram kg-1) in a depot carrier or depot carrier alone every 8 hr for 10 days. Basal pancreatic secretion and responses to secretin and cholecystokinin were then studied while the rats were under urethane anesthesia. In the treated animals, basal secretion of fluid was more than six times greater, basal bicarbonate output more than three times greater, and and basal protein output more than two times greater than in the control rats (P less than 0.01 for each). After subtracting basal values and normalizing for body weight, the treated group means were statistically significantly greater than those of the control for: maximal bicarbonate output (1.81 times control) to secretin; and maximal outputs to cholecystokinin of volume (2.46 times control), bicarbonate (2.69 times control), and protein (2.28 times control). The mean pancreatic weight per kilogram of body weight in the treated group was 1.65 times (P less than 0.01) that of the control group. When normalized for pancreatic weight (basal values subtracted), the increse in maximal protein output (1.37 times control) to cholecystokinin was still statistically significant (P less than 0.05). We conclude that chronic treatment with secretin plus caerulein exerts a trophic effect on the pancreas associated with increased maximal protein output to cholecystokinin and increased maximal bicarbonate output to secretin.

Topics: Animals; Bicarbonates; Body Weight; Ceruletide; Cholecystokinin; Female; Organ Size; Pancreas; Proteins; Rats; Secretin

Prostaglandin (PG) A, E and F compounds applied serosally inhibited net fluid absorption and increased intraluminal pressure in guinea-pig isolated gallbladder. The inhibition was dose-dependent for a given animal body weight but sensitivity varied inversely with animal body weight; relative potencies were PGE2 greater than F2alpha greater than A1. In heavier animals the inhibition was preceded by an apparent increase in fluid absorption, due to fluid extrusion following muscle contraction. Net fluid secretion was observed at higher concentrations of PGE2 or F2alpha in lighter animals. Mucosally applied PGs less potently inhibited absorption, with relative potencies of PGE2 greater than A1 greater than F2beta greater than F2alpha. The spasmogenic effect was estimated by measuring intraluminal pressure (PGE2 greater than F2alpha greater than A1).

Topics: Aging; Animals; Body Fluids; Body Weight; Ceruletide; Gallbladder; Guinea Pigs; In Vitro Techniques; Male; Mucous Membrane; Muscle Contraction; Muscle, Smooth; Pressure; Prostaglandins

Topics: Animals; Body Weight; Ceruletide; Electrophysiology; Guinea Pigs; Humans; In Vitro Techniques; Morphine; Myenteric Plexus; Nicotine; Serotonin; Substance Withdrawal Syndrome; Substance-Related Disorders

Topics: Abnormalities, Drug-Induced; Amylases; Animals; Blood Glucose; Body Weight; Ceruletide; Dogs; Fatty Acids; Female; Gastrointestinal Agents; Injections, Intramuscular; Injections, Intravenous; Injections, Subcutaneous; Lethal Dose 50; Male; Mice; Organ Size; Pancreas; Peptides; Phosphates; Pregnancy; Rabbits; Rats; Rats, Inbred Strains