Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been found earlier that the bradykinin antagonist, icatibant (Hoe 140), prevents the pancreatic oedema and the ensuing hypotension and haemoconcentration, and facilitates the removal of activated enzymes form the tissue during caerulein-induced acute pancreatitis. For a potential therapeutic use of the compound in clinical situations it is essential to investigate whether the associated increase in enzyme activities in the blood serum has any adverse effects on the pancreas itself or on other organs. Normal amylase secretion into the biliopancreatic duct stimulated by a low dose of caerulein (0.4 nmol kg-1 h-1, i.v.) was not affect by icatibant (100 nmol kg-1, s.c.) Acute pancreatitis, induced by a high dose of caerulein (4 nmol kg-1 h-1 for 2 h, i.v.), resulted in elevations in the activities of amylase and lipase in the pancreatic tissue and in the blood serum lasting for at least 4 h after the end of the caerulein infusion. While the rise in enzyme activities in the blood serum was augmented in icatibant-treated rats only at the end of the caerulein-infusion, the enzyme accumulation in the pancreas was significantly reduced by icatibant for at least 4 h after the end of the caerulein infusion. The secretion of amylase and lipase into the biliopancreatic duct was significantly increased only during the first 20 min of acute pancreatitis; in rats pre-treated with icatibant, no significant increase could be observed. Twenty-four hours after induction of pancreatitis, a low-dose caerulein stimulation of the exocrine function of the pancreas led to a reduced but sustained secretion of amylase regardless of whether the animals had received icatibant or not. During the first 45 min of pancreatitis, blood glucose concentrations were significantly reduced, but returned to values not different from those obtained in saline-infused controls. This effect was not affected by icatibant. No changes in the response to an i.v. glucose tolerance test were found on the day after induction of acute pancreatitis. The serum activities of glutamic pyruvic transaminase and gamma-glutamyl transpeptidase determined up to 24 h after induction of pancreatitis were not different from saline controls. icatibant had no effect on the activities of these enzymes. It is concluded that during caerulein-induced acute pancreatitis normal exocrine secretion of pancreatic enzymes into the pancreatic duct ceases almost immediately. Pre-treatment with icatibant significantly reduces the accumulation of activated enzymes in the pancreatic tissue for several hours after induction of pancreatitis while a concomitant augmentation in enzyme activities in the blood serum lasts much shorter. There is no indication of adverse effects on the function of the endocrine or exocrine pancreas and that of the liver, either during the acute stages of pancreatitis or during the recovery period.
 ...
PMID:Effects of the bradykinin antagonist, icatibant (Hoe 140), on pancreas and liver functions during and after caerulein-induced pancreatitis in rats. 875 Oct 86

One of the vasoactive peptides that has been implicated in the progression from edematous to necrotizing pancreatitis is bradykinin. We have investigated the effect of bradykinin administration and bradykinin inhibition on an edematous model of acute pancreatitis in rats (10 micrograms/kg/h of caerulein i.v.). Within six hours i.v. bradykinin reduced circulating serum amylase levels significantly but neither affected tissue edema nor morphology. A bradykinin antagonist (HOE-140), on the other hand, reduced pancreatic edema by 70% and converted edematous pancreatitis into a hemorrhagic and necrotizing variety of the disease. In further experiments we determined the time course and the minimal dosage required for the induction of this severe and non-invasive disease variety. A single dose of caerulein (40 micrograms/kg i.p.) together with a single administration of the bradykinin antagonist HOE-140 (100 micrograms/kg s.c.) consistently resulted in hemorrhagic necrosis of the pancreas within six hours. We conclude that this simple protocol allows for the non-invasive induction of a vascular model of necrotizing pancreatitis and appears ideally suited to study the development of this severe form of the disease.
 ...
PMID:Characterization of a non-invasive, vascular model of acute necrotizing pancreatitis. 877 69

Bradykinin mediates the inflammatory process of acute pancreatitis characterized by an increase of microvascular permeability, vasodilation and leukocyte activation. These phenomena are characteristic also for the ischemia/reperfusion injury of the pancreas, which in time is considered a causative factor in the pathogenesis of acute pancreatitis. The aim of this study was to investigate the influence of the bradykinin B2 receptor antagonist CP-0597. After complete ischemia/reperfusion of the pancreas in rats there is progression from postischemic acute edema to necrotizing pancreatitis over a reperfusion period of 5 days. In 8 Sprague-Dawley rats (treatment group) 18 micrograms/kg/h CP-0597 was administered intraperitoneally over 5 days with an osmotic minipump starting 15 min before release of 2 h ischemia. Animals of the placebo group (n = 8) were identically treated, but received the solvent, phosphate buffer. Animals of a control group (n = 7) underwent sham operation without ischemia. After 5 days the animals were sacrificed for histology. No morphological changes of the pancreatic gland were observed in the control group. Ischemia for 2 h resulted in necrotizing pancreatitis with high mortality (4/8 animals) during the reperfusion period of 5 days. In contrast, all animals in the treatment group survived without clinical or histological signs of necrotizing pancreatitis.
 ...
PMID:The bradykinin antagonist CP-0597 can limit the progression of postischemic pancreatitis. 885 57

The i.v. infusion of a low dose of the cholecystokinin agonist caerulein elicited a sustained secretion of amylase into the biliopancreatic duct of rats. Pretreatment with the bradykinin antagonist icatibant (Hoe-140) had no effect on unstimulated amylase release and did not affect caerulein-induced amylase secretion. An i.v. infusion of bradykinin in doses not producing a pancreatic oedema elicited an increase in pancreatic juice production lasting 20-40 min after the end of the infusion. This pro-secretory effect was also visible at higher doses in captopril-pretreated rats producing an oedema similar to that observed in caerulein-induced pancreatitis. Using the Monastral blue method, it was found that the kininase II blocker captopril induced an opening of endothelial gaps in pancreatic capillaries. This effect was blocked by icatibant suggesting that kinins are formed in the pancreas under basal conditions. Thus, kinins appear not to be involved in the regulation of the production of digestive enzymes. However, kinins may have a modulatory role in the production of pancreatic juice and in the microcirculatory regulation in the pancreas.
 ...
PMID:Pathophysiological and possible physiological roles of kinins in the pancreas. 885 79

During the last 10 years, the role of oxidative stress in pancreatitis and the benefits or otherwise of antioxidants has been the subject of numerous research papers. There is general agreement that glutathione and other sulphydryl compounds are depleted while lipid peroxidation is increased in pancreatic tissue during the development of acute pancreatitis. Treatment with antioxidants has been shown to reduce acinar cell injury and oedema in various animal models of pancreatitis, suggesting that the sustained generation of reactive oxygen species depletes cellular antioxidant defences. Evidence for a role for bradykinin and nitric oxide in pancreatitis has been conflicting with some studies suggesting these agents might ameliorate pancreatic dysfunction by enhancing pancreatic blood flow and secretion in response to bradykinin-stimulated generation of nitric oxide from endothelium, while other studies suggest that nitric oxide potentiates pancreatic oxidative stress. Thus, there is clearly a need for well-designed clinical trials to evaluate the protective role of antioxidant therapy in acute pancreatitis.
 ...
PMID:Role of oxidative stress in the pathogenesis of acute pancreatitis. 886 64

The effect of a potent and long-acting bradykinin B2-receptor antagonist (HOE140) on acute pancreatitis induced by retrograde infusion of trypsin and taurocholate into the pancreatic duct was studied in rats. HOE140 was administered subcutaneously immediately before and 3 h after the induction of pancreatitis and the systemic blood pressure, ascites volume, serum amylase, 24-h survival rate, and pathology of the pancreas were evaluated. Plasma concentrations of bradykinin increased significantly 15 min after the induction of pancreatitis and decreased to basal levels at 90 min. HOE140 (0.1 mg/kg) alleviated hypotension developing immediately after the induction of pancreatitis and reduced the ascites volume. The 24-h survival rate in rats treated with 0.1 mg/kg HOE140 (70.3%) was significantly higher than that in controls (35.6%). Treatment with 0.01, 0.3, 1.0, and 3.0 mg/kg of HOE140, however, had no beneficial effect on the survival rate. Ascites volume, serum amylase, and pathology of the pancreas at 24 h were not improved by treatment with HOE140. These data suggest that HOE140 may improve the survival rate by maintaining hemodynamics in the early stage of experimental acute pancreatitis.
 ...
PMID:Effects of a bradykinin receptor antagonist (HOE140) on taurocholate-induced acute pancreatitis in rats. 888 50

Bradykinin and beta-endorphin increases during acute pancreatitis are thought to contribute to the development of hypotension and myocardial depression in acute pancreatitis. beta-Endorphin release is mediated by trypsin-like enzymes and bradykinin from the pituitary gland. This study was undertaken to investigate the effect of a long-acting bradykinin receptor antagonist on bradykinin and beta-endorphin release and on hemodynamic changes during acute pancreatitis. Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligation of the accessory duct. Serum bradykinin and plasma beta-endorphin levels and cardiovascular function were measured. Twelve dogs (control group) were given 10 ml/kg/h of lactate Ringer's solution intravenously beginning 1 h before the induction of pancreatitis and continuing throughout the experiments. Six dogs received an intravenous infusion of 0.6 mg/kg/h of a new bradykinin receptor antagonist, HOE 140, D-Arg-[Hyp3, Thi5, D-Tic, Oic8]-bradykinin, in lactate Ringer's solution soon after the induction of pancreatitis. Six of twelve dogs in the control group, and none of the six dogs in the bradykinin receptor antagonist group, died during the experiments. Serum bradykinin levels in both groups increased until 1 h after the induction of pancreatitis, but thereafter the levels in the bradykinin receptor antagonist group decreased gradually until 5 h after induction, and levels were significantly lower than those in the control group (p < 0.05). Plasma beta-endorphin levels in the control group increased significantly, to 291.8 pg/ml (+/- 6.6 SEM) 5 h after the induction of pancreatitis, from the mean levels of 47.8 pg/ml before the induction of pancreatitis, while the mean beta-endorphin level in the bradykinin receptor antagonist group did not increase after the induction of pancreatitis. Infusion of the bradykinin receptor antagonist improved survival rates, hypotension, myocardial depression, and plasma lactate, suggesting that the bradykinin receptor antagonist inhibited the release of bradykinin and beta-endorphin, which contributed to the clinical improvement.
 ...
PMID:Effects of bradykinin receptor antagonist on the release of beta-endorphin and bradykinin and on hemodynamic changes in a canine model of experimental acute pancreatitis. 892 25

In order to clarify the derangement of the pancreatic microcirculation in acute pancreatitis, the pancreatic microcirculation in caerulein pancreatitis was monitored intravitally and the roles of bradykinin and nitric oxide were examined using bradkykinin B2 receptor antagonist, HOE140. Under an intravital microscope, the pancreatic microcirculation was observed 2 or 6 hr after the induction of acute pancreatitis. HOE140 was administered 30 min before the induction of acute pancreatitis. The videoimages were taken into the computer, and the value of grayscale was measured with imaging software to quantify the degree of extravasation. Extravasation in the postcapillary venules was remarkable and the velocity in pancreatic terminal arterioles decreased significantly. However, the adherence of leukocytes was not observed until 6 hr after the induction. Both the extension of extravasation and the decrease of velocity were prevented by HOE140. The levels of nitric oxides in the pancreatic tissue declined and this decline was not influenced by HOE140. Bradykinin participates mainly in the regulation of vascular permeability in the early stage of caerulein pancreatitis. Further, the impairment of pancreatic microcirculation may play a key role in the onset and development of acute pancreatitis.
 ...
PMID:Analysis of the derangement of the pancreatic microcirculation in a rat caerulein pancreatitis model using an intravital microscope system. 911 66

The effect of B2 receptor bradykinin antagonist icatibant on postcapillary leukostasis, microcirculatory stasis, and tissue necrosis was studied in acute pancreatitis. In rats, pancreatitis was induced by intraductal injection of sodium taurocholate (ST), intravenous caerulein and intraductal infusion of glucodeoxycholic acid (GDOC), or intravenous caerulein infusion alone. Intravital pancreatic microcirculation was observed. Icatibant or vehicle was given 30 min before induction of pancreatitis. In ST pancreatitis, the number of perfused capillaries increased in icatibant-pretreated rats (77% vs. 0% for controls, P < 0.001). Capillary flow was preserved in icatibant-treated rats; total stasis was observed in controls. Mean venular leukocyte adherence decreased in icatibant-treated rats (26% vs. 74% for controls, P < 0.001), and median histopathologic score was reduced (icatibant vs. controls, 5.0 vs. 12 points, respectively; P < 0.01). Kinase II inhibitor captopril or exogenous bradykinin in addition to an otherwise effective dosage of icatibant resulted in microcirculatory stasis, extensive venular leukocyte adherence, and severe histological damage. With a 100 times greater icatibant dosage, this adverse effect was compensated. The beneficial effects of icatibant were also observed in intermediate pancreatitis (caerulein + GDOC). In ST and intermediate pancreatitis, icatibant preserved microcirculation, reduced venular leukocyte adherence, and prevented pancreatic tissue damage. B2 receptor bradykinin-mediated postcapillary leukostasis plays an important role in the pathogenesis of severe forms of acute pancreatitis.
 ...
PMID:Inhibition of bradykinin B2 receptor preserves microcirculation in experimental pancreatitis in rats. 945 72

The role of oxygen-derived free radicals in pancreatitis after pancreas transplantation was examined in a porcine pancreatic transplantation model. Trypsin activation, protease inhibitor consumption, kininogen consumption, and postoperative graft function were investigated in 24 pigs subjected to whole organ pancreaticoduodenal transplantation. The animals were divided into one control group and two groups treated with free radical scavengers. One group was given allopurinol, and one group was treated with superoxide dismutase in combination with catalase. In the early phase (within 1 hr) after reperfusion, no differences were seen between the groups as to protease activation. Neither trypsin-protease inhibitor imbalance nor any signs of kininogen consumption were seen. In a later phase (1-3 days after the transplantation), the trypsin activation, measured as high molecular weight immunoreactive cationic trypsin in plasma, was significantly less pronounced in allopurinol-treated animals. This finding indicates a less severe form of reperfusion pancreatitis in this group compared with the other groups. A tendency toward better function in the allopurinol-treated group was also seen. We conclude that oxygen-derived free radicals seem to be of importance in the development of reperfusion pancreatitis after pancreas transplantation in the pig. We also conclude that allopurinol, but not superoxide dismutase/catalase, possibly due to the administration regimens used in this series, is able to attenuate the trypsin activation and the development of pancreatitis in the later phase in this model.
 ...
PMID:Role of oxygen-derived free radicals in protease activation after pancreas transplantation in the pig. 948 64


<< Previous 1 2 3 4 5 Next >>