Effect of the administration of monofluorophosphate on alpha-macroglobulin levels and the clinical course of pancreatitis in rats

Clinical course of pancreatitis depends partially on the proteinases-antiproteinases balance. Monofluorophosphate (CAS 10163-15-2, MFP) binds to plasmatic antiproteinase alpha-macroglobulin (AM), modifies its homeostasis and, as a consequence, has potential effects on the progression of pancreatitis and other inflammatory processes. The progress of incomplete closed duodenal loop induced pancreatitis was studied in rats with AM homeostasis perturbed by the oral administration of MFP. Twelve rats received 80 micromol MFP/day orally for one month before the induction of pancreatitis. Controls did not receive MFP. Plasmatic amylase activity and AM levels were measured. The day of death was recorded and histopathology of pancreas was performed. Higher survival and less histopathologic changes were observed in rats treated with MFP previous to pancreatitis compared to rats without MFP. Amylase activities were higher in controls and AM levels decreased significantly in controls respect to MFP-treated animals. Higher survival, lower amylasemia and less pancreatic damage in MFP-treated animals suggest a protective effect of the drug in the clinical course of pancreatitis.     

Hyperlipidemia induced by a cholesterol-rich diet aggravates necrotizing pancreatitis in rats

The aim of the present study was to investigate whether hyperlipidemia can cause acute pancreatitis or alter its severity. Male Wistar rats were fed a 3% cholesterol-enriched diet or a normal diet for 16 weeks. Edematous and necrotizing pancreatitis was induced with 3x75 mug/kg body weight of cholecystokinin s.c. and 2x2 g/kg body weight of L-arginine i.p., respectively, in separate groups of normal and hyperlipidemic rats. The severity of the pancreatitis was assessed. We studied the influence of hyperlipidemia on the formation of oxygen-derived free radicals, endogenous scavengers, nitric oxide synthases (NOS), peroxynitrite (ONOO(-)), heat shock protein 72 (HSP72) and nuclear factor-kappa B (NF-kappaB) activation in the pancreas during acute edematous and necrotizing pancreatitis. Hyperlipidemia did not worsen edematous, but aggravated necrotizing pancreatitis. The cholesterol-enriched diet significantly reduced the catalase and Mn-superoxide dismutase (SOD) and constitutive NOS (cNOS) activities and increased the inducible NOS (iNOS) in the pancreas relative to those in the rats on the normal diet. The pancreatic nitrotyrosine level, as a marker of ONOO(-), and the NF-kappaB DNA-binding activity in the pancreas, were significantly elevated in the cholesterol-fed rats. The pancreatic HSP72 expression during necrotizing pancreatitis was not influenced by the hyperlipidemia. The pancreatic Mn-SOD, Cu, Zn-SOD, glutathione peroxidase, total glutathione and cNOS activities were significantly reduced, while the catalase, iNOS and NF-kappaB DNA-binding activities were significantly increased in the animals with necrotizing pancreatitis on the cholesterol diet as compared with those with pancreatitis and receiving the normal diet. Hyperlipidemia induced with this cholesterol-enriched diet leads to decreases in endogenous scavenger and cNOS activities, results in iNOS and NF-kappaB activation and stimulates ONOO(-) generation in the pancreas, which may be responsible for the aggravation of acute necrotizing pancreatitis.     

Protective effect of the combined treatment of pancreatic and neutrophil elastase inhibitors on acute pancreatitis elicited by lipopolysaccharide in rats given intraductal injection of taurocholate plus trypsin

A severe acute pancreatitis was produced by intraperitoneal injection of lipopolysaccharide (LPS) in rats with preexisting hemorrhagic and necrotizing pancreatitis induced by retrograde injection of a 5% taurocholate plus 1% trypsin solution into the pancreatic duct. Mortality and time-course changes in pancreatic, hepatic, renal and pulmonary functions, and organ myeloperoxidase (MPO) levels were examined in this model. LPS at an intraperitoneal dose of 30 mg/kg, which scarcely caused death and had no marked effect on serum parameters and organ MPO levels in rats without pancreatitis, increased the mortality in rats with taurocholate plus trypsin-induced pancreatitis. Pancreatic weight and ascitic volume increased in rats with taurocholate plus trypsin-induced pancreatitis regardless of the presence or absence of LPS. Serum amylase and lipase levels were also significantly increased in rats with induced pancreatitis, but was higher in the group given LPS. Serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN) and creatinine levels were significantly elevated in LPS-treated rats with induced pancreatitis, whereas levels in rats with induced pancreatitis not given LPS were only slightly elevated. Renal weight was also significantly increased in rats with induced pancreatitis despite the presence or absence of LPS. In LPS-treated rats with induced pancreatitis, the arterial oxygen pressure, pulmonary weight and pulmonary MPO level were significantly elevated. However, the MPO level in the kidney in these rats was not different from that in control rats, indicating that the renal dysfunction was not produced by the infiltration of neutrophils into the kidney. Increase in the pancreatic MPO level was observed in rats with induced pancreatitis, but combination treatment with LPS did not raise it. Protective effects of prophylactic treatment of 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, and trifluoroacetyl-L-lysyl-L-alaninanilide hydrochloride (compound 2), a pancreatic elastase inhibitor, on mortality were also examined in this model. Results were compared with that of the combined treatment of compound 1 and compound 2. In LPS-treated rats with taurocholate plus trypsin-induced pancreatitis, the combined treatment of compound 1 (2 mg/kg/h) and compound 2 (30 mg/kg/h) significantly reduced mortality, whereas single treatment of compound 1 or compound 2 did not show the beneficial effect. These results suggest that marked hepatic and renal dysfunction accompanies pancreatitis in this pancreatitis model rats, which may be good models for acute pancreatitis in humans. It is also suggested that neutrophil and pancreatic elastases may be synergistically involved in the pathogenesis of acute pancreatitis in this model. Received: 24 November 1997 / Accepted: 10 February 1998     

Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

Substance P mediates inflammatory oedema in acute pancreatitis via activation of the neurokinin-1 receptor in rats and mice

Pancreatic oedema occurs early in the development of acute pancreatitis, and the overall extent of fluid loss correlates with disease severity. The tachykinin substance P (SP) is released from sensory nerves, binds to the neurokinin-1 receptor (NK1-R) on endothelial cells and induces plasma extravasation, oedema, and neutrophil infiltration, a process termed neurogenic inflammation. We sought to determine the importance of neurogenic mechanisms in acute pancreatitis. Pancreatic plasma extravasation was measured using the intravascular tracers Evans blue and Monastral blue after administration of specific NK1-R agonists/antagonists in rats and NK1-R(+/+)/(-/-) mice. The effects of NK1-R genetic deletion/antagonism on pancreatic plasma extravasation, amylase, myeloperoxidase (MPO), and histology in cerulein-induced pancreatitis were characterized. In rats, both SP and the NK1-R selective agonist [Sar(9) Met(O(2))(11)]SP stimulated pancreatic plasma extravasation, and this response was blocked by the NK1-R antagonist CP 96,345. Selective agonists of the NK-2 or NK-3 receptors had no effect. In rats, cerulein stimulated pancreatic plasma extravasation and serum amylase. These responses were blocked by the NK1-R antagonist CP 96,345. In wildtype mice, SP induced plasma extravasation while SP had no effect in NK1-R knockout mice. In NK1-R knockout mice, the effects of cerulein on pancreatic plasma extravasation and hyperamylasemia were reduced by 60%, and pancreatic MPO by 75%, as compared to wildtype animals. Neurogenic mechanisms of inflammation are important in the development of inflammatory oedema in acute interstitial pancreatitis.     

异丙酚对重症急性胰腺炎大鼠早期肺损伤的干预作用

目的：探讨异丙酚对重症急性胰腺炎（SAP）大鼠早期肺组织损伤的干预作用。方法：健康成年雄性SD大鼠72只,按随机化原则分成9组,每组8只。即假手术组,重症急性胰腺炎30、60、120、360min组（SAP组：胰胆管逆行注入质量分数为5％牛磺胆酸钠溶液）和异丙酚30、60、120、360min组（造模后立即给予异丙酚150μg·kg^-1·min^-1尾静脉持续注射）。剖杀各组大鼠,分别检测血清淀粉酶（AMY）、脂肪酶（LIP）的含量,计算肺、胰腺组织湿／干重比,并观察胰腺组织和肺组织的病理学改变。结果：异丙酚组大鼠360min时肺组织含水量明显减轻、病理积分明显降低（P均〈0．01）,但大鼠胰腺组织含水量及病理积分无明显改变（P均〉0．05）。结论：异丙酚可减轻重症急性胰腺炎大鼠早期肺组织的损伤程度,但不能减轻重症急性胰腺炎大鼠早期胰腺组织的损伤程度。     

The influence of dopamine receptor agonists and an antagonist on acute pancreatitis in rats

The influence of the dopamine receptor-stimulating agent, bromocriptine, the dopamine-releasing drug, amantadine, and the dopamine antagonist, domperidone, on acute pancreatitis was studied in rats. Acute pancreatitis was induced by ligation of the bile duct at its point of entry into the duodenum. Each drug was applied intraperitoneally 1 h before induction of acute pancreatitis and all the surviving animals were killed 24 h thereafter. The control, saline-pretreated animals exhibited the mortality rate, macroscopical and histological changes, as well as increase of serum amylase levels that were consistent with acute pancreatitis. Domperidone induced a large increase in serum amylase which was significantly reduced by the simultaneous administration of bromocriptine. However, both bromocriptine and amantadine, when given separately did not prevent the increase of serum amylase levels to the control levels. Statistical analysis showed that the difference between the mortality rate in the control and treated groups did not reach the level of significance probably due to the rather limited number of animals used. On the other hand, application of bromocriptine as well as amantadine successfully reduced the onset of acute pancreatitis whereas domperidone, a rather specific peripheral dopamine receptor blocker, had the opposite effect. Both bromocriptine and amantadine significantly reduced the mortality rate from acute pancreatitis in domperidone-pretreated rats. Since the aggravating effect of domperidone was successfully reduced by simultaneous application of bromocriptine, we think that these effects are mediated by peripheral dopamine receptors. However, the mechanisms whereby dopamine receptor-stimulating and dopamine-releasing drugs produce their beneficial effects remain to be elucidated.     

Pinealectomy aggravates acute pancreatitis in the rat

Melatonin, a pineal indoleamine, protects the pancreas against acute damage; however, the involvement of the pineal gland in the pancreatoprotective action of melatonin is unknown. The primary aim of this study was to determine the effects of pinealectomy on the course of acute caerulein-induced pancreatitis (AP) in rats. AP was induced by a subcutaneous infusion of caerulein (25 μg/kg) into pinealectomized or sham-operated animals. Melatonin (5 or 25 mg/kg) was given via intraperitoneal (ip) injection 30 min prior to the induction of AP. The pancreatic content of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal (MDA + 4HNE) and the activity of an antioxidative enzyme, glutathione peroxidase (GSH-Px), were measured in each group of rats. Melatonin blood levels were measured by radioimmunoassay (RIA). In the sham-operated rats, AP was confirmed with histological examination and manifested as pancreatic edema and an increase in the blood lipase level (by 1,500%). In addition, the pancreatic content of MDA+ 4HNE was increased by 200%, and pancreatic glutathione peroxydase (GSH-Px) activity was reduced by 40%. Pinealectomy significantly aggravated the histological manifestations of AP, reduced the GSH-Px activity and markedly augmented the levels of MDA+ 4HNE in the pancreas of rats with or without AP as compared to sham-operated animals. Melatonin was undetectable in the blood of the pinealectomized rats with or without AP. Treatment with melatonin (25 mg/kg, ip) prevented the development of AP in the sham-operated rats and significantly reduced pancreatic inflammation in the animals previously subjected to pinealectomy. In conclusion, pineal melatonin contributes to the pancreatic protection through the activation of the antioxidative defense mechanism in pancreatic tissue as well as its direct antioxidant effects.     

Cholecystokinin fails to promote pancreatic regeneration in diabetic rats following the induction of experimental pancreatitis.

The aim of the present study was to investigate the spontaneous and cholecystokinin-octapeptide (CCK-8)-promoted laboratory changes and morphological alterations in rats with arginine (Arg)-induced pancreatitis in which diabetes had been induced with streptozotocin (STZ). Male Wistar rats were used in our experiments. Pancreatitis was induced by arginine, diabetes by STZ and regeneration was promoted by CCK-8. The serum amylase, glucose and insulin levels, the pancreatic contents of protein, DNA, amylase, trypsinogen and lipase, the pancreatic weight/body- weight ratio (pw/bw) and the plasma glucagon level were examined 1, 3, 7, 14 and 28 days after pancreatitis induction. Pancreatic tissue samples were examined by light microscopy and immunostaining on paraffin-embedded sections. The insulin and glucagon-containing cells were visualized by using monoclonal antibodies. The administration of low doses of CCK-8 accelerated the processes of regeneration following Arg-induced pancreatitis, but in rats that were also diabetic, pancreatic regeneration was not observed. The administration of low doses of CCK-8 seems to reduce the pancreatic beta -cell number and function in diabetic rats. The pancreatic endocrine function was further deteriorated by simultaneous Arg-induced pancreatitis. The diabetic state appeared to shift the normal pancreatic enzyme content (decreased amylase and increased trypsinogen) in this study.     

Restoration of spontaneous exploratory behaviors with an intrathecal NMDA receptor antagonist or a PKC inhibitor in rats with acute pancreatitis

The aim of this study was to determine the influence of a glutamate receptor antagonist or a protein kinase C (PKC) inhibitor on the central visceral nociceptive amplification process present in an experimental pancreatitis model. The acute pancreatitis model was produced by combining intraductal infusion of an irritative bile salt, glycodeoxycholic acid (GDOC), with intraperitoneal injection of a CCK analogue, caerulein, in male Sprague-Dawley rats. Exploratory activities were measured with an automated photobeam activity system and compared among different treatment groups. To confirm the inflammation, the pancreas was weighed and compared histologically with those taken from naive rats. Exploratory activity changed significantly in rats with experimental pancreatitis (i.e., rearing events, rearing time, active time, distance traveled, and total activity all were decreased; whereas resting time was increased). The inflamed pancreatic tissues were edematous, with moderate to marked acinar atrophy and inflammatory infiltrate. Intrathecal administration (at the T7-T9 spinal levels) of an NMDA receptor antagonist (D-AP5, 1 microg) or a selective PKC inhibitor (GF109203X, 0.15 microg) significantly reversed the changes in exploratory activity when compared with the vehicle-treated group of rats with experimental pancreatitis. Our results demonstrate that pancreatitis pain is the result of central pain processes that play a role in the amplification of responses to peripheral visceral input through NMDA receptor activation and PKC phosphorylation signaling pathways.     

Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats

The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. The threshold dose which produced death in rats without pancreatitis was 30 mg/kg. This same dose evoked death in more than 40% of rats with pancreatitis. Time-course changes in serum enzyme and organ myeloperoxidase (MPO) levels were first examined in rats with induced MOF, and the results were compared with those in rats treated with only LPS or cerulein. Pancreatic weight, and serum amylase and lipase levels significantly increased in rats with cerulein-induced pancreatitis despite the presence or absence of LPS, but recovery of these pancreatic dysfunctions was slower in the group given LPS. However, serum GOT, GPT, BUN and creatinine levels were significantly elevated only in MOF rats. In the MOF rats, the MPO level in the lung was significantly elevated and arterial oxygen pressure was decreased, indicating that infiltration of neutrophils into the lung might be involved in pulmonary dysfunction. However, the MPO levels in the pancreas and kidney in the MOF rats were not remarkably different from those in normal rats. The inhibitory effects of YM264 and compound 1 on mortality and organ dysfunction were examined in this MOF model. The 24-h survival rate for rats prophylactically and therapeutically treated with an intravenous infusion of YM264 at 0.1 mg/kg h was significantly higher than that of controls. The 24-h survival rate for rats treated prophylactically by intravenous infusion of 2 mg/kg h of compound 1 was significantly higher than that of control, whereas a beneficial dose of compound 1 was 5 mg/kg h in therapeutically treated rats. Prophylactic treatment with YM264 (0.1 mg/kg h) and compound 1 (2 mg/kg h) ameliorated organ dysfunction in rats with MOF. In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches. Received: 22 December 1997 / Accepted: 6 April 1998     

异丙酚对重症急性胰腺炎大鼠早期肺损伤的干预作用

目的：探讨异丙酚对重症急性胰腺炎（SAP）大鼠早期肺组织损伤的干预作用。方法：健康成年雄性SD大鼠72只,按随机化原则分成9组,每组8只。即假手术组,重症急性胰腺炎30、60、120、360min组（SAP组：胰胆管逆行注入质量分数为5％牛磺胆酸钠溶液）和异丙酚30、60、120、360min组（造模后立即给予异丙酚150μg·kg·min^-1尾静脉持续注射）。剖杀各组大鼠,分别检测血清淀粉酶（AMY）、脂肪酶（LIP）的含量,计算肺、胰腺组织湿／干重比,并观察胰腺组织和肺组织的病理学改变。结果：异丙酚组大鼠360min时肺组织含水量明显减轻、病理积分明显降低（P均〈0．01）,但大鼠胰腺组织含水量及病理积分无明显改变（P均〉0．05）。结论：异丙酚可减轻重症急性胰腺炎大鼠早期肺组织的损伤程度,但不能减轻重症急性胰腺炎大鼠早期胰腺组织的损伤程度。     

Acetyl‐l‐Carnitine Ameliorates Caerulein‐induced Acute Pancreatitis in Rats

Abstract: In the present study, we have addressed the possible protective role of acetyl‐l ‐carnitine in caerulein‐induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 µg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well‐characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione‐S‐transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl‐l ‐carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.     

Enhanced vigilin and anionic trypsinogen expression in experimental chronic pancreatitis

The molecular principles that lead to chronic pancreatitis are incompletely understood. Trypsin(ogen) plays a key role in the development of pancreatitis. Since the production of trypsin(ogen) by acinary pancreatic cells is paralleled by the expression of vigilin we hypothesised that vigilin may be involved in the onset of pancreatitis. Vigilin is a ubiquitous protein and has apparently high affinity to RNA. In the present study experimental pancreatitis was induced in male rats by a single intravenous application of dibutyltin dichloride (DBTC). Sections of rat pancreas were immunostained with an affinity-purified polyclonal antiserum against vigilin or trypsin(ogen). The changes in vigilin and trypsin(ogen) protein expression were determined by immunoblotting and subsequent sequence analysis of the amino acids. Induction of pancreatitis by DBTC caused alterations in the distribution and the amount of both vigilin and trypsin(ogen) as shown by immunohistochemical and immunoblot analysis. Furthermore we could demonstrate that anionic trypsinogen expression is up-regulated in DBTC-induced chronic pancreatitis. The obtained results suggest that vigilin as well as trypsin(ogen) are involved in the pathogenesis of pancreatitis and that the long-time DBTC-induced pancreatitis is a useful model for study of chronic pancreatitis.     

Blockade of bradykinin B(2) receptor suppresses acute pancreatitis induced by obstruction of the pancreaticobiliary duct in rats.

1. The involvement of bradykinin (BK) B(2) receptor in acute pancreatitis induced by pancreaticobiliary duct ligation was investigated in rats. 2. The activities of amylase and lipase in the serum, the water content of the pancreas, and vacuolization of the acinar cells were significantly increased 2 h after obstruction of the duct in Sprague-Dawley rats. 3. Elevated serum amylase activity, increased pancreatic oedema, and damage of the pancreatic tissue were significantly less marked in plasma kininogen-deficient, B/N-Katholiek rats than in the normal strain, B/N-Kitasato rats 2 h after the ligation. 4. Obstruction of the pancreaticobiliary duct augmented the level of (1-5)-BK (Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)), a stable BK metabolite, in the blood from 73.0+/-21.7 pg ml(-1) at 0 h to 149.8+/-38.0 pg ml(-1) at 2 h after the induction of pancreatitis in SD rats. 5. Administration of a BK B(2) receptor antagonist, FR173657 (100 mg kg(-1), p.o.) or Hoe140 (100 nmol kg(-1), s.c.), reduced the elevation of amylase and lipase activities in the serum and of pancreatic water content in a dose-dependent manner. The effective attenuation of oedema formation and vacuolization by the antagonists was also confirmed light-microscopically. In contrast, treatment with gabexate mesilate or indomethacin did not cause significant suppression of the pancreatitis. 6. These findings suggest a possible involvement of kinin B(2) receptor in the present pancreatitis model. Furthermore, they point to the potential usefulness of the B(2) receptor in clinical acute pancreatitis.     

Amelioration of caerulein-induced pancreatitis by restraint stress in the rat

We investigated the influence of restraint stress on caerulein-induced pancreatitis in rats, especially in relation to endogenous glucocorticoids. Pancreatitis was induced by repeated injections of caerulein, and the serum amylase levels, pancreas weight and histological findings were evaluated 6 h later. Restraint stress was performed by immobilizing the animals in Bollman cages from 30 min before the first injection of caerulein, while mifepristone, the glucocorticoid receptor antagonist, was administered s.c. 1 h before. Repeated injections of caerulein produced marked increases in not only the serum amylase levels and pancreas weight but also the intralobular edema of pancreas when determined histologically. Restraint stress significantly reduced the increase in both serum amylase levels and intralobular edema, but not the pancreas weight. The improvement by restraint stress of pancreatitis was totally antagonized by pretreatment with mifepristone. We conclude that restraint stress exerts a beneficial influence on caerulein-induced pancreatitis, mediated by endogenous glucocorticoids.     

The effect of a cholecystokinin receptor antagonist lorglumid on the proteinase-antiproteinase balance in taurocholate acute experimental pancreatitis (AEP) in rats.

The effect of new CCK receptor antagonist, lorglumid on taurocholate AEP in rats was studied. Lorglumid was applied intraperitoneally at a dose of 5.6 mg/kg BW immediately after taurocholate injection into choledochopancreatic duct. Activity of amylase, antithrombin III (AT III), alpha 1 protease inhibitor (alpha 1 PI), alpha 2 antiplasmin (alpha 2 AP) and alpha 2 M) in plasma, trypsin and chymotrypsin in pancreata were measured after 1, 3, 6 h of AEP. In AEP treated by lorglumid serum amylase activity and pancreatic wet weight was significantly reduced. The use of lorglumid prevented the increase of alpha 1 PI and alpha 2 AP compared to not treated animals. AT III and alpha 2 M in plasma and trypsin and chymotrypsin activity in pancreata did not change significantly in all groups. The mortality of the lorglumid treated rats was significantly lower in comparison with control group. It is concluded that lorglumid in taurocholate AEP moderates the changed plasma proteinase-antiproteinase balance. Our results indicate a protective effect of lorglumid in this model of acute experimental pancreatitis.     

Sesamol attenuates oxidative stress-mediated experimental acute pancreatitis in rats

Acute pancreatitis is a potentially fatal disease with no known cure. The initial events in acute pancreatitis may occur within the acinar cells. We examined the effect of sesamol on (i) a cerulein-induced pancreatic acinar cancer cell line, AR42J, and (ii) cerulein-induced experimental acute pancreatitis in rats. Sesamol inhibited amylase activity and increased cell survival. It also inhibited medium lipid peroxidation and 8-hydroxydeoxyguanosine in AR42J cells compared with the cerulein-alone groups. In addition, in cerulein-treated rats, sesamol inhibited serum amylase and lipase levels, pancreatic edema, and lipid peroxidation, but it increased pancreatic glutathione and nitric oxide levels. Thus, we hypothesize that sesamol attenuates cerulein-induced experimental acute pancreatitis by inhibiting the pancreatic acinar cell death associated with oxidative stress in rats.     

Dual, time-dependent deleterious and protective effect of anandamide on the course of cerulein-induced acute pancreatitis. Role of sensory nerves

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.