Insulin is necessary for the hypertrophic effect of cholecystokinin-octapeptide following acute necrotizing experimental pancreatitis

AIM:In previous experiments we have demonstrated thatby administering low doses of cholecystokinin-octapeptide(CCK-8),the process of regeneration following L-arginine(Arg)-induced pancreatitis is accelerated.In rats that werealso diabetic(induced by streptozotocin,STZ),pancreaticregeneration was not observed.The aim of this study wasto deduce whether the administration of exogenous insulincould in fact restore the hypertrophic effect of CCK-8 indiabetic-pancreatitic rats.METHODS:Male Wistar rats were used for the experiments.Diabetes mellitus was induced by administering 60mg/kgbody mass of STZ intraperitoneally(i.p.),then,on d 8,pancreatitis was induced by 200mg/100 g body mass Argi.p.twice at an interval of 1 h.The animals were injectedsubcutaneously twice daily(at 7 a.m.and 7 p.m.)with1 μg/kg of CCK-8 and/or 2 IU mixed insulin(300g/L short-action and 700g/L intermediate-action insulin) for 14 dafter pancreatitis induction.Following this the animals werekilled and the serum amylase,glucose and insulin levelsas well as the plasma glucagon levels,the pancreaticmass/body mass ratio(pm/bm),the pancreatic contentsof DNA,protein,amylase,lipase and trypsinogen weremeasured.Pancreatic tissue samples were examined bylight microscopy on paraffin-embedded sections.RESULTS:In the diabetic-pancreatitic rats treatment withinsulin and CCK-8 significantly elevated pw/bm and thepancreatic contents of protein,amylase and lipase vs therats receiving only CCK-8 treatment.CCK-8 administeredin combination with insulin also elevated the number ofacinar cells with mitotic activities,whereas CCK-8 alonehad no effect on laboratory parameters or the mitoticactivities in diabetic-pancreatitic rats.CONCLUSION:Despite the hypertrophic effect of CCK-8being absent following acute pancreatitis in diabetic-rats,the simultaneous administration of exogenous insulin restored this effect.Our results clearly demonstrate thatinsulin is necessary for the hypertrophic effect of low-dosesof CCK-8 following acute pancreatitis.     

胰岛β细胞参与急性胰腺炎后胰腺再生过程的研究

目的 探讨胰岛β细胞在实验性急性胰腺炎(AP)后胰腺再生过程中的作用.方法 SD大鼠87只,按数字表法随机分为对照组(15只)、糖尿病组(24只)、AP组(24只)和糖尿病+AP组(24只).采用腹腔注射链脲佐菌素(STZ,60 mg/kg体重)或左旋精氨酸(L-Arg,2.5 g/kg体重,2次)方法分别建立糖尿病和AP模型.术后1、3、5、7d分批处死大鼠.检测血淀粉酶和血糖水平;计算胰腺湿重比;胰腺组织常规病理学检查,计算胰腺坏死面积百分比和组织转化区域百分比;免疫荧光检测胰岛β细胞的再生基因( Reg4)和胰岛素的表达.结果 注射STZ后,大鼠血糖明显升高,注射L-Arg后大鼠胰腺组织水肿、坏死、炎细胞浸润,血淀粉酶明显升高,表明制模成功.制模后第3天糖尿病+ AP组的胰腺坏死面积为(71.6±6.0)％,显著大于AP组的(42.3±4.0)％;第7天的组织转化面积为(45.6±5.4)％,显著小于AP组的(78.5±6.4)％.糖尿病+AP组胰岛β细胞的Reg4和胰岛素表达均较AP组明显减少.结论 STZ破坏了胰岛β细胞,加重精氨酸诱导的AP的损伤,并抑制胰腺的再生过程.     

Pancreatic secretory responses in L-arginine-induced pancreatitis: comparison of diabetic and nondiabetic rats.

The aim of this work was to study cholecystokinin-octapeptide (CCK-8)-stimulated pancreatic secretion after the induction of pancreatitis with L-arginine (ARG) in rats with or without streptozotocin (STZ) diabetes. One, 3, 7, and 14 days after pancreatitis induction, rats were surgically prepared with pancreatic duct and femoral vein cannulae under urethane anesthesia. Graded doses of CCK-8 ranging from 9 to 2,400 ng/kg/30 min were administered intravenously. In the control group, the step-wise increasing doses of CCK-8 resulted in a characteristic dose-response curve for the pancreatic volume, protein and amylase secretion (maximal volume, protein and amylase output at 600 ng/kg/30 min of CCK-8: 157 +/- 20.2 microl/30 min, 28.3 +/- 1.18 mg/30 min, and 3,750 +/- 92 IU/30 min, respectively). In rats with pancreatitis, the pancreatic volume (both basal and maximal) and amylase secretion were significantly elevated on day 1 versus the control group; then on days 3,7, and 14, the pancreatic secretory volume and amylase were progressively and significantly decreased versus the control group. However, the protein output was continuously decreased versus the control group on days 1, 3, 7, and 14. In diabetic rats, the maximal volume and protein and amylase output were all significantly decreased versus the control group throughout the experiment. In the diabetes + pancreatitis group, the maximal volume and protein and amylase output were all significantly increased versus the diabetes group on days 1, 3, 7, and 14. These results indicate that in the early phase of ARG-induced pancreatitis, the pancreatic secretion is characterized by increases in secretory volume and amylase, with a simultaneous decrease in protein output. Simultaneous diabetes seems to moderate the CCK-8-stimulated secretory changes in both the early and late phases after ARG-induced pancreatitis.     

Effect of troglitazone on exocrine pancreas in rats with streptozotocin-induced diabetes mellitus

Abnormality of pancreatic exocrine secretion has been observed in patients with diabetes mellitus. Troglitazone is a novel insulin-sensitizing agent that improves hyperglycemia and hyperinsulinemia in insulin-resistant diabetes mellitus. We investigated the effect of troglitazone on exocrine pancreas in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ (25 mg/kg), and then 0.2% troglitazone containing rat chow was given for 2 weeks. Control diabetic animals received normal rat chow for 2 weeks. Glucose tolerance tests were performed before and after the administration of troglitazone. Pancreas weight, enzyme, protein, and insulin contents in the pancreas were measured. For the exocrine secretory study, pure pancreatic juice was collected hourly. Plasma glucose concentrations stimulated by the oral administration of 2.5 g/kg glucose in the troglitazone-treated group were significantly lower than those in the control group, but not plasma insulin concentrations. Pancreas weight in diabetic rats was less than that in normal rats. Administration of troglitazone resulted in a significant increase in pancreas weight and amylase and trypsin output. However, protein and insulin contents were not affected by the treatment with troglitazone. Both basal and cholecystokinin (CCK-8; 26 pmol/kg/h) stimulated exocrine secretion in juice volume, amylase, and trypsin output were markedly decreased in diabetic rats, compared with those in normal rats. Impaired basal and CCK-stimulated pancreatic exocrine secretion in diabetic rats recovered to the normal levels when troglitazone was given. In conclusion, troglitazone might be effective to restore exocrine pancreatic insufficiency in STZ-diabetic rats.     

Spontaneous and cholecystokinin-octapeptide-promoted regeneration of the pancreas followingl-arginine-induced pancreatitis in rat

Summary Conclusion Inl-arginine (Arg)-induced pancreatitis, evidence of acute inflammation was observed on d 1–3. Continuous tissue atrophy became visible at the sites of previous pancreatic necrosis, with simultaneous regeneration of the pancreas, mainly around the Langerhans islets. Administration of low doses of cholecystokinin-octapeptide (CCK-8) increased the inflammatory signs of pancreatitis in the early phase, but subsequently diminished the level of atrophy and accelerated the processes of regeneration in this model of pancreatitis. Background The aim of this work was to study the regenerative processes following Arg-induced pancreatitis in rats. Besides the spontaneous regeneration, the effects of low doses of CCK-8 on the laboratory and morphologic parameters in this type of experimental pancreatitis were investigated. Methods Male Wistar rats were divided into three groups. In group I, the rats received 200 mg/100 g body weight of Arg ip twice, at an interval of 1 h, and 0.5 mL saline was administered sc twice daily. In group II, besides the same amount of Arg, the rats received 1 μg/kg of CCK-8 sc in 0.5-mL saline twice daily (7am and 7pm). In the control animals (group III), an identical amount of glycine was administered ip instead of Arg at the same times. The rats were examined on d 1, 3, 7, 14, and 28 after pancreatitis induction. The pancreatic weight/body weight ratio (pw/bw) was calculated in each case. The serum levels of amylase, and glucose and the pancreatic contents of soluble protein, trypsin, amylase and DNA were determined, and histologic examinations were performed. Results In groups I and II, both pw/bw (3.5±0.2 mg/g and 4.1±0.28 mg/g, respectively) and the serum amylase level (8900±560 IU/L and 11100±1390 IU/L, respectively) were significantly elevated on d 1 vs group III (2.1±0.06 mg/g and 5562±373 IU/L, respectively). Pw/bw was significantly decreased in groups I (0.96±0.12 mg/g, 0.8±0.1 mg/g, and 1.8±0.1 mg/g, respectively) and II (1.4±0.15 mg/g, 1.7±0.2 mg/g, and 1.95±0.1 mg/g, respectively) on d 7, 14, and 28 vs group III (2.6±0.3 mg/g, 3.1±0.15 mg/g, and 2.7 ±0.1 mg/g, respectively), whereas in group II it was significantly elevated vs. group I on d 7 and 14. The pancreatic contents of soluble protein, DNA, trypsin and amylase were significantly decreased on d 3–14 in groups I and II vs group III. The pancreatic DNA level was significantly elevated in group II (1.23±0.2 mg/pancreas) vs group I (0.7±0.1 mg/pancreas) on d 7. In group II, the soluble protein (73.1±15.5 mg/pancreas) and amylase (1104±160 IU/pancreas) levels were significantly elevated on d 14 as was that of trypsin (27.2±3.1 IU/pancreas) on d 28, vs group I (26.4±5.3 mg/p, 525±111 IU/pancreas, and 16.3±1.1 IU/pancreas, respectively). On histologic sections, the signs of acute inflammation of the pancreas were more pronounced in group II than in group I on d 1–3. After that time, in spite of the progressive atrophy of the pancreas, the signs of tissue repair were more expressed in group II.     

Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide.

BACKGROUND & AIMS: Although alcoholism is a major cause of pancreatitis, the pathogenesis of this disorder remains obscure. Failure to produce experimental alcoholic pancreatitis suggests that ethanol may only increase predisposition to pancreatitis. This study sought to develop a model of ethanol pancreatitis by determining if an ethanol diet sensitizes rats to pancreatitis caused by cholecystokinin octapeptide (CCK-8). METHODS: Rats were fed intragastrically either control or ethanol diet for 2 or 6 weeks. The animals were then infused for 6 hours with either saline or CCK-8 at a dose of 3000 pmol. kg(-1). h(-1), which by itself did not induce pancreatitis. The following parameters were measured: serum amylase and lipase levels, pancreatic weight, inflammatory infiltration, number of apoptotic acinar cells, pancreatic messenger RNA (mRNA) expression of cytokines and chemokines, and nuclear factor (NF)-kappaB activity. RESULTS: All measures of pancreatitis, as well as NF-kappaB activity and mRNA expression for tumor necrosis factor alpha, interleukin 6, monocyte chemotactic protein 1, macrophage inflammatory protein 2, and inducible nitric oxide synthase, were significantly increased only in rats treated with ethanol plus CCK-8. CONCLUSIONS: An ethanol diet sensitizes rats to pancreatitis caused by CCK-8. The combined action of ethanol and CCK-8 results in NF-kappaB activation and up-regulation of proinflammatory cytokines and chemokines in the pancreas. These mechanisms may contribute to the development of alcoholic pancreatitis.     

Pancreatic lipase and colipase activity increase in pancreatic acinar tissue of diabetic rats

We studied the lipase and colipase activity in pancreatic acinar tissue of insulin-deficiency and insulin-resistance obese Zucker rats (fa/fa). After injection of streptozotocin (STX 75 mg/kg) in normal Sprague-Dawley rats, the activity of lipase and colipase in pancreatic acinar tissue was increased by approximately 100%, the increase in colipase occurring 3 days later than that of lipase. At the same time, the amylase activity was decreased by 98%. Injection of alloxan (125 mg/kg) induced a similar change of pancreatic enzyme pattern, with amylase activity strongly reduced by 79% and activity of lipase and colipase increased 20.5 and 18.6%, respectively. Correction of the diabetic state with insulin (1 U/100 g/day) reversed the activity of these enzymes to their prediabetic levels. Administration of insulin (6 U/100 g/day) to normal Sprague-Dawley rats increased the activity of amylase as well as lipase and colipase, whereas injection of glucagon (0.3 mg/100 g/day) decreased the activity of amylase and colipase but had no significant effect on lipase activity. In the obese Zucker rats (fa/fa), the activity of lipase and colipase at onset of obesity (5 weeks of age) was lower than that in their lean littermates (fa/o). Thereafter the activity of the two proteins increased with age, being 40% higher in the fa/fa rat than in the fa/o rat at age 7 weeks. During the same period, amylase activity decreased. These results indicate that pancreatic lipase and colipase activity are increased following either insulin deficiency or insulin resistance in rats by a mechanism related to the changed levels of insulin.     

Effects of CCK-8 in combination with natural or synthetic secretin on amylase, lipase, trypsin, and chymotrypsin secretion in rats

In the present study, we examined the interaction between CCK-8 and natural or synthetic secretin on pancreatic enzyme secretion. On anaesthetized rats, a proximal duodenal segment was continuously perfused with saline and amylase, lipase, trypsin, and chymotrypsin were determined in the perfusate. Neither during iv saline nor during iv secretin (natural or synthetic) at doses of 0.01, 0.05, or 0.1 CU/kg/h, any of the four enzymes changed significantly from basal values over a period of 100 min. Iv CCK-8 at stepwise increasing doses of 5, 10, and 20 pmol/kg/h elicited a significant increase of all four enzymes at the medium dose, with a further increase of amylase and trypsin, but not lipase and chymotrypsin at 20 pmol/kg/h. The addition of secretin at all 3 doses potentiated CCK-induced trypsin output. The effects of natural secretin were more pronounced than those of the synthetic peptide. Secretin significantly increased amylase secretion over basal at the lowest dose of CCK-8 (5 pmol/kg/h) that by itself had no effect on amylase release. Only the higher doses of natural but not synthetic secretin augmented lipase secretion during the lowest dose of CCK-8. Both forms of secretin had no further stimulatory effect on CCK-induced chymotrypsin secretion. The present data demonstrate that, first, in rats a potentiation of CCK-8-induced enzyme secretion by low doses of secretin is different for the four enzymes, which suggests a differential regulatory action of these two intestinal hormones on pancreatic enzyme release. Second, the different effects of natural secretin may represent those of contaminants suggesting that only synthetic secretin should be employed in future studies of this peptide on pancreatic enzyme secretion.     

Alteration of cholecystokinin receptor binding after caerulein-induced pancreatitis in rats.

The alteration of CCK receptor binding on the pancreatic acini in vitro following the induction of pancreatitis was investigated in male rats. Pancreatitis was induced by administering 5 intraperitoneal injections of caerulein, 40 micrograms/kg each at hourly intervals. The uptake of [3H]-thymidine in the pancreatic acini increased on day 7 following caerulein administration. The release of amylase stimulated by CCK-8, and CCK receptor analysis using bioactive [125I]-BH-CCK-8, were performed at regeneration stage, on days 14 and 28 following the injections. The maximal release of amylase stimulated by CCK-8 was reduced on day 14 by about 40% and recovered on day 28. On day 14 there was a decrease of 60% in the number of high-affinity receptors and an increase of 161% in the number of low-affinity receptors. On day 28 there was a 128% increase in the number of low-affinity receptors. Accordingly, we suggest that the CCK receptors of the regenerating cells following caerulein-induced pancreatitis differ from those of the intact cells.     

Effect of buprenorphine on pancreatic enzyme synthesis and secretion in normal rats and rats with acute edematous pancreatitis

Pancreatic enzyme secretion is inhibited during acute pancreatitis, resulting in an increase in acinar zymogen content. Since the premature activation of zymogens has been assigned a central role in the pathogenesis of acute pancreatitis, minimizing the amount of stored zymogens might lead to less severe acute pancreatitis. Inhibition of enzyme synthesis or stimulation of enzyme secretion would result in reduction of zymogen stores. Opiates have a varying effect on pancreatic secretion, depending on the dosage, site of administration, and presence of pancreatic stimulants. The effect of opiates and acute pancreatitis on individual pancreatic enzyme synthesis is unknown. The following study was undertaken in order to examine the effects of an opiate on pancreatic enzyme secretion and synthesis during experimental acute pancreatitis. Four groups of rats were studied. Group I received cerulein (25 µg/kg); group II received an opiate, buprenorphine (BPN, 0.5 mg/kg); and group III received cerulein and BPN. Drugs were dissolved in gelatin/saline and injected subcutaneously. A control group (group IV) received only gelatin/saline. Rats were sacrificed 4 hr after injection, and pancreatic mass was measured. Pancreatic acini were prepared and assayed for amylase and DNA content. Amylase, trypsinogen, chymotrypsinogen and lipase synthesis, and amylase secretion were measured for 2 hr. Results showed that, compared to controls, acini of rats with AP had increased amylase content, a finding consistent with decreasedin vivo amylase secretion. Total protein and individual enzyme synthesis rates were significantly lower in the acini of the rats with AP than in those of the controls. Negative feedback inhibition of enzyme synthesis due to the increased stores of intracellular enzymes may account for these findings. BPN reduced pancreatic edema in rats with acute pancreatitis (AP). Acinar amylase content of rats with AP treated with BPN was significantly lower than in acini of rats with AP. As amylase secretion was lower in the AP + BPN rats, the reduced acinar amylase content was probably solely due to the reduction in enzyme synthesis observed in the AP + BPN rats. The results suggest that BPN may have a moderating effect on the development of AP.This study was supported by a research grant from the South African Medical Research Council.     

Time-course of changes in pancreatic size and enzyme composition in rats during starvation

The effect of starvation for 3, 5, or 7 d on body weight, fat stores, pancreatic weight, and enzyme composition was studied in 300 g rats and was compared with a. 3-d fast in 200 g rats. In the 300 g animals, fasting led to a gradual hypotrophy of the pancreas with a marked, continuous decrease in amylase content. Pancreatic lipase, trypsinogen, chymotrypsinogen, proelastase, and secretory trypsin inhibitor contents increased temporarily, but by d 7, they declined to about the initial values. This decline in enzyme levels coincided with the exhaustion of fat stores. The decrease in amylase content could be related to decreases in circulating insulin levels, whereas the temporary increase in lipase content may be owing to changes in plasma free fatty acid concentrations. In 200 g rats, starvation for 3 d led to exhaustion of fat stores that was accompanied by greater losses of pancreatic weight, protein, and amylase contents. In addition, the levels of trypsinogen and chymotrypsinogen decreased and lipase was unchanged. These findings indicate that during starvation, changes in pancreatic secretory enzymes are time-dependent and vary with the age, body weight, and/or adipose tissue mass of the rats.     

Time-course of changes in pancreatic size and enzyme composition in rats during starvation

The effect of starvation for 3, 5, or 7 d on body weight, fat stores, pancreatic weight, and enzyme composition was studied in 300 g rats and was compared with a 3-d fast in 200 g rats. In the 300 g animals, fasting led to a gradual hypotrophy of the pancreas with a marked, continuous decrease in amylase content. Pancreatic lipase, trypsinogen, chymotrypsinogen, proelastase, and secretory trypsin inhibitor contents increased temporarily, but by d 7, they declined to about the initial values. This decline in enzyme levels coincided with the exhaustion of fat stores. The decrease in amylase content could be related to decreases in circulating insulin levels, whereas the temporary increase in lipase content may be owing to changes in plasma free fatty acid concentrations. In 200 g rats, starvation for 3 d led to exhaustion of fat stores that was accompanied by greater losses of pancreatic weight, protein, and amylase contents. In addition, the levels of trypsinogen and chymotrypsinogen decreased and lipase was unchanged. These findings indicate that during starvation, changes in pancreatic secretory enzymes are time-dependent and vary with the age, body weight, and/or adipose tissue mass of the rats.     

Effects of L-364,718 on pancreatic exocrine and endocrine secretion in the rat.

We examined the inhibitory effect of L-364,718, a nonpeptide cholecystokinin (CCK) antagonist, on CCK stimulation of pancreatic exocrine and endocrine secretion in both the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, L-364,718 inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of 125I-CCK-8 in a dose-dependent manner without appreciable effects on the basal amylase secretion. L-364,718 also inhibited amylase release in response to caerulein and gastrin I, but had no effect on amylase release stimulated by other secretagogues or by agents bypassing receptors. Similarly, binding of N-methylscopolamine to pancreatic acini was not inhibited by L-364,718. In the isolated perfused pancreata, L-364,718 inhibited CCK-8-stimulated pancreatic exocrine secretion and insulin release. The inhibitory effects of L-364,718 were more potent for insulin release than for exocrine secretion and persisted even after the removal of L-364,718 infusion. These results clearly demonstrate that L-364,718 is a specific, potent, and prolonged antagonist of CCK's stimulatory actions on pancreatic acinar and B cells.     

Potentiating effect of secretin on cholecystokinin-stimulated exocrine pancreatic secretion in rats

The potentiating effect of secretin on cholecystokinin (CCK)-stimulated exocrine pancreatic secretion was studied in anesthetized rats. Intravenous infusion of CCK-8 in three different doses of 0.03, 0.06 and 0.12 micrograms/kg-hr increased pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs dose-dependently. Simultaneous infusion of CCK-8 with secretin in a dose of 0.03 CU/kg-hr produced statistically greater pancreatic secretion of volume, bicarbonate, amylase and trypsin outputs than that by CCK-8 alone, and than the sum by secretin alone and CCK-8 alone in each dose. Proglumide (600 mg/kg-hr) significantly suppressed exocrine pancreatic secretion produced by CCK-8 (0.06 micrograms/kg-hr) plus secretin (0.03 CU/kg-hr), to the level induced by secretin alone. These results indicate that CCK-8 increased pancreatic secretion dose-dependently, and secretin in a physiological dose potentiates the stimulating effect of CCK-8 on exocrine pancreatic secretion in rats.     

Essential role of cholecystokinin in pancreatic regeneration after 60% distal resection in rats.

The essential role of cholecystokinin (CCK) in pancreatic regeneration after pancreatitis or resection has been supposed, but not yet clearly demonstrated. In rats, 6-8 weeks after 60% distal resection of the pancreas a gradual increase in pancreatic weight and contents of DNA, protein, trypsin, chymotrypsin and amylase, occurred (there was no increase in lipase); Pancreatic regeneration stopped thereafter. Nonparallel increases in enzyme values were similar to those seen after CCK administration. Indeed, basal CCK levels increased significantly by the 6th week and declined thereafter. A one month s.c. administration of CCK-octapeptide (CCK-8) (3 x 300 ng/kg/d) accelerated regeneration in the first month, but it had almost no effect during the second or third postoperative months. A two week s.c. administration of a specific CCK antagonist, CR 1409 (3 x 4 mg/kg/d) totally prevented regeneration by the fifth and sixth weeks, but did not diminish pancreatic weight or DNA and protein contents during the first two weeks. Alcohol administration (12 g/kg/d) reduced CCK release and prevented pancreatic regeneration during the three-month experimental period. These data indicate that CCK has an essential role in pancreatic regeneration and that the deleterious effect of alcohol on regeneration involves inhibition of CCK release.     

Differing effects of ethanol on in vitro stimulated pancreatic enzyme secretion in ethanol-fed and control rats.

The single most important risk factor for chronic and acute pancreatitis is the abuse of ethanol, which, theoretically, could affect the pancreas by interacting either with some of its cell receptors or with any of its intracellular signal transduction mechanisms. Therefore, we determined in isolated pancreatic acini from 3 month ethanol-fed rats and controls the dose-response effects of secretagogues on enzyme secretion, both in the presence and absence of ethanol in the incubation medium. In ethanol-fed rats, pancreatic amylase activity was decreased by 40%, compared to controls (with identical carbohydrates intakes), whereas lipase and trypsinogen activities were unaffected. With no ethanol in the incubation medium, basal enzyme releases and enzyme dose-response curves to CCK-8, VIP, secretin, bombesin, and bethanechol were essentially unchanged in ethanol-fed rats compared to controls. In contrast, with 0.1 M ethanol present in the medium, enzyme responses to VIP, secretin, and CCK-8 were inhibited and that to CCK-8 also shifted to the right in ethanol-fed rats compared to controls. Hence, if rechallenged to ethanol, acini from ethanol-fed rats show inhibited secretions, in response to two secretagogues acting through the release of cyclic AMP, and an inhibited and right-shifted secretory response to CCK.     

Effect of intrinsic CCK and CCK antagonist on pancreatic growth and pancreatic enzyme secretion in pancreaticobiliary diversion rats

When pancreaticobiliary diversion (PBD) surgery was performed in rats, plasma CCK level increased, the pancreas grew mainly by proliferation, and pancreatic trypsinogen showed a remarkable increase, although amylase and lipase synthesis were somewhat decreased. The sensitivity of amylase release against CCK-8 in the pancreatic acini decreased when plasma CCK level was high. These changes in pancreatic growth and pancreatic enzyme secretion caused by PBD were completely inhibited by the CCK-receptor antagonist loxiglumide. From these results, intrinsic CCK was considered to play an important role in both pancreatic enzyme synthesis and proliferation     

α-Lipoic acid protects against cholecystokinin-induced acute pancreatitis in rats

AIM: α-Lipoic acid (ALA) has been used as an antioxidant.The aim of this study was to investigate the effect of α-lipoic acid on cholecystokinin (CCK)-octapeptide induced acute pancreatitis in rats.METHODS: ALA at 1 mg/kg was intra-peritoneally injected, followed by 75 μg/kg CCK-octapeptide injected thrice subcutaneously after 1, 3, and 5 h. This whole procedure was repeated for 5 d. We checked the pancreatic weight/body weight ratio, the secretion of pro-inflammatory cytokines and the levels of lipase,amylase of serum. Repeated CCK octapeptide treatment resulted in typical laboratory and morphological changes of experimentally induced pancreatitis.RESULTS: ALA significantly decreased the pancreatic weight/body weight ratio and serum amylase and lipase in CCK octapeptide-induced acute pancreatitis. However,the secretion of IL-1β, IL-6, and TNF-α were comparable in CCK octapeptide-induced acute pancreatitis.CONCLUSION: ALA may have a protective effect against CCK octapeptide-induced acute pancreatitis.     

Augmentation of streptozotocin-induced hyperglycemia in mice by prior treatment with complete Freund's adjuvant

The effect of complete Freund's adjuvant (CFA), in combination with streptozotocin (STZ), on pancreatic insulin content, plasma glucose, and pancreatic histopathology were studied in male Balb/c mice. One injection of CFA, followed 24 h later by a single dose of 100 mg/kg of STZ (group I), produced a 92% (p less than 0.01) reduction in pancreatic insulin, a 54% (p less than 0.01) increase in glucagon content, and severe hyperglycemia. The depletion of pancreatic insulin was associated with degranulation, necrosis of beta cells, and reduction of the apparent islet size. Focal pancreatitis, without apparent islet inflammation, occurred in all animals in this group. After treatment with STZ alone (group II), pancreatic insulin content decreased 73% (p less than 0.01), whereas plasma glucose levels, even though being in the hyperglycemic range, were significantly lower (p less than 0.02) than the mice in group I. Although pyknotic and hypertrophic cell nuclei could be observed in several islets of mice from group II, major histopathological changes, such as pancreatitis and extensive beta cell necrosis seen in group I, were absent. The results show that in the Balb/c mouse strain, a nonspecific insult by CFA prior to a cell-specific cytotoxic insult markedly enhanced destruction of beta cells and the development of hyperglycemia.