摘要:

The long-term effects of streptozotocin (30–70 mg/kg) were studied on plasma glucose and insulin levels, islet morphology, and glucose-stimulated insulin secretion in rats. In addition, the protective effect of short-term (7 days) insulin treatment on streptozotocin-induced diabetes was examined. Streptozotocin administration at dose levels exceeding 40 mg/kg resulted in a longterm, stable hyperglycemia with no insulin response to glucose at 3 months and with a marked derangement of islet morphology (few insulin cells, accumulation of glucagon cells). In contrast, at 30 and 40 mg/kg, streptozotocin induced a transient diabetes. Thus, the blood glucose levels, being elevated at days 1-7, returned to normal levels within 10 days after streptozotocin administration and the glucose-induced insulin secretion, being absent at day I, was normal at 3 months. Furthermore, the islet morphology was also normal in these groups at 3 months. Short-term (7 days) insulin treatment normalized the long-term diabetes in rats given 50 mg/kg streptozotocin, but not in rats given 60 or 70 mg/kg streptozotocin. Thus, after insulin treatment, all rats receiving 50 mg/kg streptozotocin returned to normoglycemia within the following 2 weeks, and the glucose-induced insulin secretion was normal after 3 months, as was islet morphology. We conclude that (a) spontaneous recovery after streptozotocin is dose dependent and occurs in rats given 30 or 40 mg/kg of the drug, whereas at 50, 60, or 70 mg/kg, streptozotocin induces a stable diabetes; and (b) a short-term (7 days) insulin treatment turns the diabetes induced by streptozotocin at 50 mg/kg into a transient type, whereas the streptozotocin-induced diabetes at 60 or 70 mg/kg is stable despite insulin treatment.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Cholecystokinin and its analogues such as cerulein, muscarinic cholinergic agonists, and gastrin-releasing peptide (bombesin) bind to distinct receptors on the surface of pancreatic acinar cells and stimulate digestive protein secretion by a calcium-dependent mechanism. The mechanisms of the calcium-dependent secretagogue classes has been assumed to be similar. In this study we have noted that dispersed pancreatic acini secrete comparable maximal rates of amylase in response to cerulein and bombesin; however, the maximal level of phosphatidylinositol 4,5-bisphosphate hydrolysis was less with bombesin than with cerulein. The high agonist dose-inhibited secretion in vitro observed with cerulein was absent with bombesin. In vivo administration of supramaximal secretory stimulating doses of both cerulein and bombesin caused pancreatic edema; however, the increase in serum concentrations of amylase and lipase induced by cerulein treatment was not detected with bombesin. These data indicate that cerulein and bombesin display distinctly different effects on the exocrine pancreas both in vivo and in vitro. That pancreatic edema and elevated serum enzyme levels may be the result of different cellular mechanisms in experimental pancreatitis is strongly suggested.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Recent investigations have suggested that digestive zymogens may become activated within the acinar cell during acute pancreatitis. While the molecular events responsible for intracellular zymogen activation remain unknown, several potential enzymatic pathways require an acidic pH to optimally proceed. We therefore proposed that manipulation of subcellular pH might alter the course of experimental pancreatitis. Chloroquine, a weak base that raises the pH of acidic subcellular compartments, was administered to young female mice in which pancreatitis was induced by a choline-deficient, ethionine- supplemented (CDE) diet. Control animals were maintained on regular laboratory chow. Examination of isolated pancreatic acini using acridine orange cytofluorescence demonstrated expansion of acidic subcellular compartments in animals fed the CDE diet. These compartments were effectively neutralized in animals receiving chloroquine. Animals receiving continuous infusions of high-dose chloroquine demonstrated a significant (p <0.05) decrease in free pancreatic tryptic activity as well as improved survival. These changes were also associated with decreased trypsinogen content in animals treated with high-dose chloroquine, suggesting an additional potential effect of chloroquine on zymogen synthesis and accumulation. One explanation of these findings is that a low-pH compartment may be important in the pathogenesis of diet-induced pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Phospholipase A2(PLA2) has been postulated to play an important role in the pathogenesis of acute pancreatitis. To study the mechanism through which PLA2may cause cellular damage, we used an in vitro model of isolated rat pancreatic acini prepared by collagenase digestion. Newly synthesized proteins were labeled by [35S]methionine. Cellular destruction was measured by the degree of release of radiolabeled proteins. Incubation of pancreatic acini with PLA2alone caused only minor damage when very high concentrations of this enzyme were used. However, when acini were incubated with PLA, in combination with its substrate, lecithin, cells were destroyed in a time- and concentration-dependent manner. Incubating cells with pancreatic homogenates and lecithin caused damage only when there had been prior activation of homogenates with either trypsin or enterokinase. The damage could be simulated by incubating acini with pure lysolecithin. Alcohol and cerulein did not further increase the destruction caused by PLA2and lecithin. When acini were incubated with supernatants from another set of acini to which oleic acid had been added, a similar degree of damage resulted as compared with acini incubated with oleic acid alone. However, adding PLA2to supernatants from acini preincubated with fatty acids significantly increased the degree of cellular necrosis. The destruction by PLA2and lecithin was inhibited by albumin but could not be inhibited by gabexate mesilate, nafamostat mesilate, or cytidine diphosphocholine. We conclude that PLA2could play a role in pancreatic acinar cell damage, especially in the spread of cellular necrosis within the organ, provided that its substrate, lecithin, is present. Lecithin may originate from bile or cellular membranes destroyed by other mechanisms, such as lysis by fatty acids.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Several gastrointestinal peptides inhibit pancreatic secretion in intact animals, but fail to do so in isolated pancreas preparations. Using isolated perfused porcine pancreas with intact innervation, we studied the influence of such peptides (somatostatin, peptide YY, glucagon-like peptide-1, oxyntomodulin, neuropeptide Y, galanin, and calcitonin gene-related peptide) on vagally induced secretion and on release of vasoactive intestinal polypeptide (VIP), a neuropeptide involved in fluid and bicarbonate secretion. In control experiments electrical vagus stimulation increased flow of juice from 0.9 ± 0.1 to 37.3 ± 5.6 ml/h and protein output from 43 ± 5 to 1,244 ± 336 mg/h (mean ± SD). With somatostatin-14 at 10−10mol/L, the fluid response was reduced to 64 ± 11% of controls, protein concentration to 78 3.8%, and protein output to 50 ± 5% (p <0.05). At 10−8Mthe response was almost abolished. VIP release, which in control experiments increased from 0.2 ± 0.05 to 2.1 ± 0.4 pmol/min, was similarly reduced (p <0.01). Galanin at 10−10Minhibited the fluid response to 54 ± 7% of controls, protein output to 51.7 ± 1176, and VIP release to 54 ± 6% (p <0.01). None of the other inhibitory peptides affected vagus responses. It is concluded that somatostatin and galanin inhibit pancreatic secretion through interaction with intrapancreatic ganglia. The other peptides act on extrapancreatic, possibly central sites.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Nude mice bearing xenografts of the MIA PaCa-2 human pancreatic cancer cell line were treated with sustained-release formulations (microcapsules) of luteinizing hormone releasing hormone (LH-RH) agonist [D- Trp6] - LH-NH, somatostatin analogue RC-160 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys- Trp-NH2), or combination of both analogues. Other groups of mice received daily subcutaneous injections of LH-RH antagonist SB-75 [Ac-D-Nal(2)1,D-Phe(4C1)2,D-Pal(3)3,D-Cit6,D-Ala10-LH-RH] or bombesin antagonist RC-3095. At necropsy, in mice given microcapsules releasing 25 kg/day of [D-TrP6]-LH-RH, tumor weight and volume were decreased, but not significantly, as compared with control mice. Microcapsules of RC-160, releasing 25 μg/day, significantly reduced tumor volume, percentage change in tumor volume, and tumor weight. Combination of RC-160 and [D-TrP6I-LH-RH inhibited tumor growth to a somewhat greater extent than RC-160 alone. Bombesin antagonist RC-3095, at a dose of 25 μg/day, did not influence the growth of tumors. In mice receiving 100 μg/day of antagonist SB-75, there was a significant decrease in tumor weight and volume and a significant reduction in the weight of ovaries and uteri. Specific binding of [125I]RC-160 and [125I][D-TrP6]-LH-RH, but not [125I]Tyr4-bombesin, was found on MIA PaCa-2 cells in culture. [D-TrP6]-LH-RH, SB-75, and RC-160 inhibited the growth of MIA PaCa-2 cells in vitro. Neither bombesin nor RC-3095 influenced the growth of MIA PaCa-2 cells in cultures. The results indicate that the LH-RH antagonist SB-75 could be tried for treatment of pancreatic cancer. Our findings confirm the efficacy of somatostatin analogue RC-160 in inhibiting the growth of pancreatic cancers and suggest that the combination of RC-160 and agonist [D-TrP6]-LH-RH might possibly increase the therapeutic response.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The present study investigates the effect of oral pretreatment with the protease inhibitor camostate on the outcome of pancreatitis in three experimental models. In pancreatitis induced by overstimulation with cholecystokinin (CCK) in rats, pancreatic enzymes and the histological degree of pancreatitis were quantified; in pancreatitis induced by a choline-deficient ethionine- supplemented (CDE) diet in mice, the effect on survival was monitored; and in bile-induced pancreatitis in rats, the effect on survival, pancreatic enzymes, and histology was studied. Feeding of camostate (200 mg/kg/day) for 2 weeks worsened the histological degree of pancreatitis induced by overstirnulation with CCK or by injection of taurocholate. The concentration of amylase in the pancreas and in serum was significantly lower after pretreatment with camostate, both in cerulein-induced pancreatitis and in bile-induced pancreatitis, while the concentration of trypsin in the pancreas was significantly increased in the camostate-treated animals. Pretreatment with camostate significantly lowered survival. In pancreatitis induced by a CDE diet, 3 of 20 mice survived the observation period, while 9 of 20 control animals survived (p <0.05). In taurocholate-induced pancreatitis, 5 of 29 rats were alive after 3 days versus 18 of 30 animals in the control group (p <0.001). CCK levels were not elevated in camostate-treated rats, when pancreatitis was induced 24 h after finishing camostate feeding. It is concluded that camostate induced pancreatic hypertrophy and increased concentration of proteolytic enzymes aggravate experimental pancreatitis and that this is not mediated by increased CCK levels.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This study was conducted to investigate the role of humoral factors in pancreatic alterations induced by obstructive jaundice (OJ) in rats. OJ in male Sprague-Dawley rats induced significant increases in pancreatic weight, DNA content, and RNA content of acinar cells. These changes were accompanied by enlargement of eosinophilic granules and compressed nuclei. Protein, amylase, and trypsinogen contents of pancreas were also increased in OJ rats. In addition, plasma levels of bilirubin, cholecystokinin (CCK), and estradiol increased in OJ rats and were correlated positively with each other and with pancreatic weights. Administration of a specific CCK receptor, L-364,718, to OJ rats partly attenuated the changes of the pancreas, indicating that CCK is involved in these changes. These findings suggest that estradiol may be involved in regulating the pancreatic changes induced by OJ in rats.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Involvement of endogenous cholecystokinin (CCK) in the development of acute pancreatitis induced in rats by closed duodenal loop (CDL) was examined, and the effects of the potent and specific CCK receptor antagonist loxiglumide on this model of acute pancreatitis were evaluated. Plasma CCK bioactivity was markedly elevated 3 and 6 h after onset of acute pancreatitis. A single subcutaneous injection of 50 mgkg body wt of loxiglumide 30 min before the induction of acute pancreatitis completely eliminated the hypercholecystokinemia. Loxiglumide given 3 h after the induction of acute pancreatitis suppressed plasma CCK bioactivity, which had risen up to 30-fold over basal value (0 h) at 3 h, to nearly the basal level. Loxiglumide pretreatment, in addition, significantly prevented the rise in serum amylase and lipase activity, as well as the increase in ascitic volume. It also ameliorated histological alterations of hemorrhagic and necrotizing pancreatitis. Reduction of plasma CCK bioactivity by loxiglumide after the onset of pancreatitis slowed the rate of progression of pancreatitis. However, pancreatic wet weight and cellular infiltration were not significantly influenced by loxiglumide treatment. These observations suggest that endogenous CCK is not involved in the initiation of acute hemorrhagic and necrotizing pancreatitis induced by CDL, but is involved in the development of pancreatitis in this model.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

A 72-year-old man with an oncocytic carcinoma of the pancreas of 3 years' duration was treated by pancreatoduodenectomy; 5 and 16 months later, two pulmonary metastases and one subcutaneous metastasis of the thigh were removed. No sign of local recurrence or metastases was present at 20- month follow-up. It is suggested that oncocytic carcinomas of the pancreas have a favorable prognosis if treated surgically.

ISSN:0885-3177    

出版商:OVID    

年代:1993

数据来源: OVID