thromboxane-b2 and Pancreatitis

Severe acute pancreatitis is a serious disease, but its detailed mechanism has not yet been elucidated. We aimed to clarify the interaction between neutrophils and platelets in the pathogenesis of acute pancreatitis.. We induced acute pancreatitis in rats by injection of sodium taurocholate into the biliopancreatic duct and killed them over time. We observed the histological changes in pancreatic tissue with special attention to the dynamics of neutrophils and platelets. We also measured the concentrations of neutrophil- and platelet-derived factors in pancreatic tissue and blood samples.. Neutrophils and platelets in the pancreatic tissue showed a similar pattern of migration. They initially spread in the interlobular connective tissue and finally into the lobules. The concentration of myeloperoxidase gradually increased in the inflamed pancreas until 24 hours and the concentration of thromboxane B2, plasminogen activator inhibitor 1, and CD41 also increased with time. Finally, the concentration of serum myeloperoxidase, citrullinated histone H3, and high-mobility group box 1 increased over time.. The interaction between neutrophils and platelets in pancreatic tissue plays an important role in the mechanism of advancing severity in acute pancreatitis. Circulating damage-associated molecular patterns induced by excessive local inflammation may lead to other organ injuries.

Topics: Acute Disease; Animals; Blood Platelets; Cell Communication; Disease Progression; HMGB1 Protein; Leukocyte Count; Male; Neutrophils; Pancreas; Pancreatitis; Peroxidase; Platelet Count; Rats, Wistar; Taurocholic Acid; Thromboxane B2

Arachidonic acid (AA) is generally associated with inflammation in different settings. We assess the molecular mechanisms involved in the inflammatory response exerted by AA on pancreatic acini as an approach to acute pancreatitis (AP). Celecoxib (COX-2 inhibitor), TAK-242 (TLR4 inhibitor) and 15d-PGJ2 (PPARγ agonist) were used to ascertain the signaling pathways. In addition, we examine the effects of TAK-242 and 15d-PGJ2 on AP induced in rats by bile-pancreatic duct obstruction (BPDO). To carry out in vitro studies, acini were isolated from pancreas of control rats. Generation of PGE2 and TXB2, activation of pro-inflammatory pathways (MAPKs, NF-κB, and JAK/STAT3) and overexpression of CCL2 and P-selectin was found in AA-treated acini. In addition, AA up-regulated TLR4 and down-regulated PPARγ expression. Celecoxib prevented the up-regulation of CCL2 and P-selectin but did not show any effect on the AA-mediated changes in TLR4 and PPARγ expression. TAK-242, reduced the generation of AA metabolites and repressed both the cascade of pro-inflammatory events which led to CCL2 and P-selectin overexpression as well as the AA-induced PPARγ down-regulation. Thus, TLR4 acts as upstream activating pro-inflammatory and inhibiting anti-inflammatory pathways. 15d-PGJ2 down-regulated TLR4 expression and hence prevented the synthesis of AA metabolites and the inflammatory response mediated by them. Reciprocal negative cross-talk between TLR4 and PPARγ pathways is evidenced. In vivo experiments showed that TAK-242 and 15d-PGJ2 treatments reduced the inflammatory response in BPDO-induced AP. We conclude that through TLR4-dependent mechanisms, AA up-regulated CCL2 and P-selectin in pancreatic acini, partly mediated by the generation of PGE2 and TXB2, which activated pro-inflammatory pathways, but also directly by down-regulating PPARγ expression with anti-inflammatory activity. In vitro and in vivo studies support the role of TLR4 in AP and the use of TLR4 inhibitors and PPARγ agonists in AP treatment.

Topics: Animals; Arachidonic Acid; Chemokine CCL2; Cholestasis; Dinoprostone; Enzyme Activation; Gene Expression; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; NF-kappa B; P-Selectin; Pancreas, Exocrine; Pancreatitis; PPAR gamma; Rats, Wistar; Receptor Cross-Talk; STAT3 Transcription Factor; Thromboxane B2; Toll-Like Receptor 4

To investigate the therapeutic effects of fluorouracil (5-Fu) and octreotide (Oct) continuous regional arterial infusion (CRAI,) alone or in combination, was administered in a canine model of severe acute pancreatitis (SAP).. The animals were divided into five groups; group A (Sham), group B (SAP), group C (SAP and 5-Fu), group D (SAP and Oct), and group E (SAP and 5-Fu + Oct). Levels of amylase, α-tumor necrosis factor (TNF-α), blood urea nitrogen (BUN), creatinine, thromboxane B2 and 6-keto- prostaglandin F1α were measured both before and after the induction of SAP. Pathologic examination of the pancreas and kidneys was performed after termination of the study.. Pathologic changes noted in the pancreas in SAP significantly improved following CRAI with either single or combined administration of 5-Fu and Oct, where combination therapy demonstrated the lowest injury score. All treatment groups had significantly lower levels of serum TNF-α and amylase activity (P<0.05), though only groups D and E had a lower BUN level as compared to group B. The plasma thromboxane B(2) level increased in SAP, but the ratio of thromboxane B(2)/6-keto- prostaglandin F(1α) decreased in the treatment groups, with the combination therapy (group E) demonstrating the lowest ratio as compared to the other 3 experimental groups (P<0.05).. The findings in the present study demonstrate an attenuation of SAP in a canine model following CRAI administration with 5-Fu or Oct, alone or in combination.

Topics: Amylases; Animals; Antimetabolites; Creatinine; Dogs; Female; Fluorouracil; Gastrointestinal Agents; Infusions, Intra-Arterial; Kidney; Male; Octreotide; Pancreas; Pancreatitis; Thromboxane B2; Tumor Necrosis Factor-alpha

To investigate the effect of bacailin on inflammatory mediators and microcirculation disturbance in severe acute pancreatitis (SAP) rats and explore its therapeutic mechanism.. The rats were randomly divided into SAP group, baicalin-treated group and sham operated group. At 3, 6, and 12 hours after operation, we examined the mortality rate of rats, ascites volume, and pancreatic pathological changes in each group and determined the contents of inflammatory mediators in blood as well as the changes in blood viscosity.. Compared with SAP group, treatment with baicalin is able to improve the pathological damage of the pancreas, reduce the contents of multiple inflammatory mediators in blood, decrease the amount of ascitic fluid, and reduce the mortality rates of SAP rats. The low-shear whole blood viscosity in baicalin-treated group (at 3 hours) as well as the high-shear and low-shear whole blood viscosity in baicalin-treated group (at 12 hours) were significantly lower than that in SAP group.. Baicalin has good prospects in the treatment for SAP because it can exert therapeutic effects on this disease through inhibiting the production of inflammatory mediators, decreasing blood viscosity, improving microcirculation, and mitigating the pathological damage of the pancreas.

Topics: Acute Disease; Amylases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascites; Dinoprostone; Flavonoids; Inflammation Mediators; Interleukin-1beta; Male; Microcirculation; Pancreas; Pancreatitis; Phospholipases A2; Platelet Activating Factor; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

To investigate the changes in plasma endothelin-1 (ET-1) , von Willebrand factor (vWF), serum 6-keto-prostaglandin(1alpha) (PGF(1alpha)) , thromboxane B2 (TXB2), platelet aggregation rate maximum (PAGm) and pancreatic blood flow after reproduction of severe acute pancreatitis (SAP) in rat, and the effect of recombinant staphylokinase (r-Sak) on SAP.. Eighty-one SD rats were divided randomly into the sham-operated group (n=27), the SAP model group (n=27), and the r-Sak treatment group (n=27). SAP was produced by administration of 5% sodium taurocholate into the pancreatic duct. The abdomen of rats was opened at 6, 12 and 18 hours after reproduction of SAP for determining the pancreatic blood flow. Blood was obtained at 6, 12 and 18 hours after reproduction of SAP for determining the concentration of plasma vWF with enzyme-labeled immunosorbent assay (ELISA). The concentration of plasma ET-1 and serum 6-keto-PGF(1alpha), and TXB2 were detected by radioimmunoassay. The PAGm induced by collagen and eicosanoids was assessed.. Pancreatic blood flow in the SAP group appeared to have a decreasing trend at 6,12 and 18 hours after operation and were significantly decreased at all time points after reproduction of the model, compared with those of the sham-operated group (all P<0.05). The PAGm, content of plasma ET-1, vWF, and TXB2 were significantly increased at all time points after reproduction of the model, while 6-keto-PGF(1alpha) was significantly decreased, compared with those of the sham-operated group (all P < 0.05). Compared with SAP model group, PAGm, the content of plasma ET-1, vWF, and serum TXB2 in the r-Sak group were decreased at all time points, however, the content of serum 6-keto-PGF(1alpha) was increased (all P<0.05).. The r-Sak can improve pancreatic microcirculation and enhance pancreatic blood flow in rats with SAP, and may be beneficial in the treatment of SAP.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Endothelin-1; Ischemia; Metalloendopeptidases; Pancreas; Pancreatitis; Platelet Aggregation; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Thromboxane B2; von Willebrand Factor

This work studied the effects of hydrocortisone treatment in experimental acute pancreatitis on cytokines, phospholipase A2, and breakdown products of arachidonic acid and survival. Edematous and necrotizing pancreatitis were induced in Wistar rats by cerulein hyperstimulation and retrograde intraductal infusion of sodium taurocholate, respectively. Hydrocortisone (10 mg/kg) was administered intravenously 10 minutes after induction of acute pancreatitis. Serum was assayed for phospholipase A2; interleukin (IL) 1beta, IL-6, IL-10, thromboxane B2; Prostaglandin E2; and leukotriene B4 at five different time points. A significant release of inflammatory mediators was seen only in the severe model. Hydrocortisone powerfully suppressed arachidonic acid breakdown products and only mildly attenuated the systemic increase of phospholipase A2 and pro- and antiinflammatory cytokines. The mortality rate after 72 hr in the severe model was 86%. Hydrocortisone treatment reduced mortality to 13% (P = 0.001; Fisher's exact test). Hydrocortisone seems to be effective in the treatment of the early systemic inflammatory response syndrome associated with severe acute pancreatitis.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cytokines; Dinoprostone; Disease Models, Animal; Female; Hydrocortisone; Leukotriene B4; Pancreatitis; Rats; Rats, Wistar; Systemic Inflammatory Response Syndrome; Thromboxane B2

Although several pathophysiological sequences, such as protease activation, free radical generation, and inflammatory mediator release, have been described in acute pancreatitis, the precise mechanism by which acute pancreatitis is initiated is unknown. Cellular calcium, a key physiological signaling element in cell function and also a crucial pathological intracellular messenger in cell injury, appears to be involved in the initiation and development of acute pancreatitis. The present study provides several lines of evidence supporting this suggestion. First, verapamil (a calcium channel blocker) administration was associated with a significant protection of rats from acute pancreatitis induced by high doses of cerulein (50 micrograms/kg/hr, subcutaneously), as evidenced both histologically and biochemically. Second, verapamil was found to minimize the increased tissue levels of calcium, platelet-activating factor, and thromboxane B2 detected during acute pancreatitis. Third, acute pancreatitis could be observed in rats with elevated serum calcium levels at low doses of cerulein (5 micrograms/kg/hr, subcutaneously), but could not be observed in rats with normal serum calcium levels treated with low doses of cerulein. It is proposed that cellular calcium, which is a critical signaling component in the synthesis and release of inflammatory mediators and several other events, may be an important factor in the pathogenesis of cerulein-induced acute pancreatitis.

Topics: Acute Disease; Animals; Calcium; Calcium Channel Blockers; Ceruletide; Drug Synergism; Male; Pancreas; Pancreatitis; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Thromboxane B2; Verapamil

The role of liver in the respiratory dysfunction associated with acute pancreatitis has been evaluated. For this purpose, an experimental necrohemorrhagic pancreatitis was induced in rats by intraductal administration of 3.5% sodium taurocholate. Additionally, a portocaval shunt was performed before induction of acute pancreatitis to prevent the initial passage through the liver of substances released by the pancreas. Twelve hours after the induction of pancreatitis, increases in lung prostacyclin and thromboxane B2 synthesis, decreased lung superoxide dismutase activity, and increases in plasma phospholipase A2 activity were found. In addition, inflammatory injury was evidenced in lung by histopathological analysis. The portocaval shunt was able to prevent the metabolic changes and ameliorate the inflammatory process in the lung, suggesting that the liver plays an active role in the systemic inflammatory response to acute pancreatitis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Lipase; Liver; Lung; Male; Pancreas; Pancreatitis; Phospholipases A; Phospholipases A2; Portacaval Shunt, Surgical; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Thromboxane B2

The effect of bradykinin on nitric oxide generation and eicosanoid production in the early stage of an experimental model of acute necrotizing pancreatitis induced by sodium taurocholate has been evaluated. We have compared the effect of administering a long-acting bradykinin antagonist, HOE 140, and an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl esther L-NAME) on pancreatic prostanoid synthesis. Plasma lipase levels were increased after acute pancreatitis induction, and reduced after HOE 140 or L-NAME administration. Nitric oxide production and thromboxane B2 levels were increased after pancreatitis induction and the increases were reduced by L-NAME or HOE 140 administration. In contrast, increased prostacyclin production, reflected as 6-keto-PGF1 alpha levels, was not modified by L-NAME or HOE 140. Bradykinin seems to be involved in nitric oxide and thromboxane synthesis during the initial phases of acute necrohemorrhagic pancreatitis.

Topics: Acute Disease; Animals; Arginine; Bradykinin; Lipase; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pancreas; Pancreatitis; Rats; Rats, Wistar; Taurocholic Acid; Thromboxane B2

The role of nitric oxide in eicosanoid and oxygen-free radical production in the early stages of sodium taurocholate-induced acute necrotizing pancreatitis has been studied. Male Wistar rats were divided into three groups: group I: control group, a volume of 0.1 ml/100 g body wt saline solution was injected at low pressure in the pancreatic duct; group II: acute pancreatitis was induced by administration of 3.5% sodium taurocholate; and group III: intravenous administration of NG-nitro-L-arginine methyl esther (a nitric oxide synthase inhibitor) 5 min before induction of acute pancreatitis as stated for group II. At 5 and 60 min after induction of pancreatitis, blood and pancreas tissue samples were taken for assays. Increases in 6-keto PGF1 alpha, TXB2, PGE2, PGF2 alpha, and 12-HETE were observed in the pancreatic tissue. Lipoperoxidation was also enhanced and remained unaltered after nitric oxide inhibition. The fact that nitric oxide synthase inhibition could only reverse the increases in 6-keto PGF1 alpha and TXB2 levels indicates that in acute pancreatitis endothelial and platelet eicosanoid generation is mediated through an nitric oxide-dependent mechanism. In contrast, nitric oxide appears to be not related with oxygen free radical damage associated with acute pancreatitis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Acute Disease; Animals; Arachidonic Acid; Arginine; Blood Platelets; Endothelium, Vascular; Hydroxyeicosatetraenoic Acids; Lipase; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Organ Size; Pancreas; Pancreatitis; Phospholipases A; Prostaglandins; Rats; Rats, Wistar; Reactive Oxygen Species; Taurocholic Acid; Thromboxane B2

The aim of this work is to establish a relationship between prostanoids and oxygen free radicals in the early stages of acute pancreatitis induced by sodium taurocholate and to study the possible cytoprotective effects of exogenous prostaglandin administration. Tissue prostanoid production (6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2) was studied after induction of an acute pancreatitis by intraductal administration of 3.5% sodium taurocholate (0.1 ml/100 mg). The effect of previous administrations of 16,16-dimethyl prostaglandin E2 (0.5 microgram/kg), indomethacin (20 mg/kg), or superoxide dismutase (13 mg/kg) was evaluated. Early pancreatitis induced significant increases of the three prostanoid levels as soon as 5 min after taurocholate administration. The administration of 16,16-dimethyl prostaglandin E2 was able to maintain the tissue prostanoid production at basal levels while superoxide dismutase treatment only partially prevented the increase of 6-keto-prostaglandin F1 alpha. On the other hand, indomethacin pretreatment, as expected, prevented the taurocholate-induced early prostanoid biosynthesis but increased the mortality, suggesting that endogenous prostanoids play a role in cellular defense mechanisms. The effect of superoxide dismutase suggests that oxygen free radicals are responsible, in part, for prostanoid enhanced biosynthesis in the earlier stages of necrohemorrhagic pancreatitis.

Topics: 16,16-Dimethylprostaglandin E2; 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Dinoprostone; Free Radicals; Indomethacin; Male; Pancreas; Pancreatitis; Prostaglandins; Rats; Rats, Wistar; Superoxide Dismutase; Taurocholic Acid; Thromboxane B2

Pancreatic production of lipid mediators of inflammation, including eicosanoids and platelet-activating factor (PAF), was examined in two models of pancreatitis in the rat. Chronic pancreatitis was induced by ligation of the pancreatic duct and acute pancreatitis by infusion of sodium taurocholate into the pancreatic duct. In the model of chronic pancreatitis, prostaglandin E2 (PGE2), PGD2, 6-keto PGF1 alpha, thromboxane B2 (TXB2), and PAF increased significantly in the pancreas in a similar fashion, whereas leukotriene B4 (LTB4) remained unchanged. BN52021, a PAF antagonist, reduced the accumulation of pancreatic TXB2, 6-keto PGF1 alpha, and PGD2, and did not affect PGE2. In the model of acute pancreatitis, LTB4 increased, whereas PGE2, TXB2, and 6-keto PGF1 alpha decreased significantly; PGD2 changed slightly; and PAF was undetectable. The present results indicate that mild chronic pancreatitis is accompanied by the production and accumulation of a wide spectrum of lipid mediators while LTB4 was the only lipid mediator detected at biologically active concentrations in the model of severe acute pancreatitis. It is suggested that various mediators are involved in establishing a balance between inflammation and the repair of the inflamed pancreatic tissue observed in mild chronic pancreatitis. While both eicosanoids and PAF are involved in such self-limiting responses to inflammatory challenge, PAF seems to play a central role in instigating the production of the various other mediators detected in the model of chronic pancreatitis. In the model of acute pancreatitis while the deficiency of various lipid mediators may render the pancreatic tissue more susceptible to acute damage, enhanced LTB4 appears to contribute to the destructive pathology observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Chronic Disease; Dinoprostone; Diterpenes; Eicosanoids; Ginkgolides; Lactones; Leukotriene B4; Ligation; Male; Masoprocol; Pancreatic Ducts; Pancreatitis; Platelet Activating Factor; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane B2

Systemic prostacyclin and thromboxane A2 production in rat experimental acute pancreatitis has been evaluated by measuring the urinary excretion of the 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2, respectively. Acute pancreatitis was induced by intraductal administration of 4.5% sodium taurocholate (0.1 ml/100 mg body weight) and intravenous cerulein perfusion (5 micrograms/kg/hr) for 6 hr, respectively. Urinary excretion of 2,3-dinor 6-keto prostaglandin F1 alpha and 2,3-dinor thromboxane B2 were much more important in sodium taurocholate- than in cerulein-induced acute pancreatitis. These data confirm an altered prostacyclin and thromboxane metabolism occurring in experimental acute pancreatitis. Phospholipase A2 activity and the effect of gabexate mesilate on the arachidonate metabolism were also evaluated.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Amylases; Animals; Ceruletide; Epoprostenol; Gabexate; Lipase; Male; Pancreatitis; Phospholipases A; Phospholipases A2; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane A2; Thromboxane B2

To evaluate the therapeutic effects and mechanisms of tetramethylpyrazine (TMP), a Chinese herbal medicine, on the lung injury in bile-induced acute haemorrhagic necrotizing pancreatitis (AHNP) in the SD rats, the rats were randomly divided into three groups: sham-operative, untreated and TMP treated. AHNP model were induced by ligation with 5% taurocholate. The changes of lung index, serum lipid peroxide (LPO), TXB2, 6-keto-PGF1 alpha, and lung pathology at light and electron microscope were all investigated at 1, 6, 12 hours after induction of AHNP model. Survival rate of AHNP in rats were recorded also. Results of the study showed that in untreated group, the time-related progressive pancreatic haemorrhage and necrosis, accompanied by pancreatitis-associated lung injury, such as pronounced pulmonary congestion, alveolar and interstitial edema, polymorphonuclear granulocytes infiltration, transparent membrane formation, the density of layer body in type II endothelial cells decreasing, with some vacuole formation, mitochondria, endoplasmic reticulum swollen, basal membrane of endothelial cells rupture were observed. The level of LPO elevated at 1 hour after induction of AHNP and peaked at 12 hours. TXB2 and 6-keto-PGF1 alpha was increased. Using TMP treatment, survival rate increased, and lung at light and electron microscope were much improved and lung index, value of LPO, TXB2 decreased significantly, 6-keto-PGF1 alpha increased slightly, the ratio of TXB2/6-keto-PGF1 alpha was stabilized. It was suggested that TMP has definite therapeutic effects on AHNP-related lung injury in rats, and exerted by scavenging oxygen free radical, inhibiting synthesis of TXA2, augmenting production of PGI2 and maintaining balance between TXA2 and PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Free Radical Scavengers; Lipid Peroxides; Lung; Necrosis; Pancreatitis; Pyrazines; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

Several studies have reported that prostanoids are involved in many of the physiopathological mechanisms underlying acute pancreatitis but their precise role in this disease remains to be established. The objective of this work is to evaluate the variation of local tissue production of prostanoids and lipoxygenase metabolites of arachidonic acid in acute pancreas inflammation induced by intraductal administration of 3.5% sodium taurocholate (0.1 ml/100 mg body weight) in rats. Pancreatic tissue levels of leukotriene B4 (LTB4), 15 hydroxyeicosatetraenoic acid (15-HETE), 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) were determined by HPLC-RIA techniques at 5 and 60 minutes after induction of acute pancreatitis (AP). Prostanoids increased significantly at 5 minutes and LTB4 and 15-HETE at 60 minutes. These data confirm that the prostanoid imbalance could be considered as an early specific response of the pancreas to the inflammatory events characteristic of induced AP while the altered levels of the lipoxygenase products (LTB4 and 15-HETE) would be more of a nonspecific organ response associated to the high cellular infiltration rate and necrosis observed in the late phases of acute pancreatitis.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Dinoprostone; Hemorrhage; Hydroxyeicosatetraenoic Acids; Kinetics; Leukotriene B4; Lipoxygenase; Male; Pancreas; Pancreatitis; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Taurocholic Acid; Thromboxane B2

The effects of a long-acting somatostatin analog (SMS 201-995) were studied in an established model of acute necrotizing pancreatitis in rats. SMS 201-995, when given prior to induction of pancreatitis, decreased the mortality rate from 100% to 40% (P = 0.0001). When treatment was given after induction of pancreatitis, the mortality rate was 75% (P = 0.2). Administration of SMS 201-995 did not influence the serum concentrations of amylase markedly, but the lipase levels were significantly lowered (P less than 0.05). The low levels of serum insulin and the glucose level in whole blood were not influenced. The volume of ascitic fluid was reduced (P less than 0.01). Moreover, less peritoneal fat necrosis was seen, suggesting a reduction in toxic factors in the ascitic fluid. Treatment with SMS 201-995 prior to induction of pancreatitis caused a significant increase in the levels of circulating 6-keto-PGF1 alpha, the stable metabolite of prostaglandin I2 (P less than 0.01). The levels of thromboxane B2 and prostaglandin E2 did not change significantly. The present data support the hypothesis that SMS 201-995 is an activator of prostaglandin I2, thereby modifying the course of the disease.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Amylases; Animals; Dinoprostone; Eicosanoids; Lipase; Male; Necrosis; Octreotide; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane B2

The aim of this study was to investigate the effect of Nafamostat mesilate (FUT-175) on some blood platelet properties during the first hours of acute experimental pancreatitis (AEP) in dogs. A significant decrease in platelet count, hyperaggregability of platelets by ADP and PAF as well as an increased level of TXB2, were found in the early stage of AEP. No changes in platelet aggregation induced with AA were demonstrated. FUT-175 prevented a decrease in platelet number and inhibited platelet aggregation induced with ADP, PAF and AA when it was given immediately after induction of AEP. No evident changes in TXB2 levels in dogs treated with FUT-175 were found. Our results indicate that the positive effect of FUT-175 in AEP in part depends on its antiaggregatory action.

Topics: Acute Disease; Animals; Benzamidines; Blood Platelets; Dogs; Guanidines; Male; Pancreatitis; Platelet Aggregation Inhibitors; Platelet Count; Protease Inhibitors; Thromboxane B2

We studied the effects of the calcium channel blocker, verapamil on experimental acute pancreatitis (AP) in rats. The pancreatic blood flow (PBF) and pancreatic tissue perfusion (PTP) were measured after induction of AP. At the same time, the plasma levels of TXB2 and 6-keto-PGF1 alpha were determined by radioimmunoassay. The survival rate and the mean survival time after induction of AP were determined and the pancreatic histology was examined by light and electron microscopy. The results demonstrated a significant early fall in PBF and PTP, a marked increase in TXB2 levels and a slight increase in 6-keto-PGF1 alpha after induction of AP. Treatment with 0.1 mg/100 g verapamil significantly increased PBF and PTP, and decreased TXB2, resulting in a normalization of TXB2/6-keto-PGF1 alpha ratio. The treated animals also exhibited significant increase in the survival rate and the survival time. They also showed decrease in the severity of pancreatic hemorrhage and necrosis, and in the damage to the cellular ultrastructures. These data suggest that calcium blockade increases PBF and PTP, limits the prostanoid imbalance in the early phase of AP, and may influence the development of experimental acute pancreatitis in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Female; Male; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Regional Blood Flow; Thromboxane B2; Verapamil

The role of blood platelets in the disturbed haemostasis in acute pancreatitis is not fully elucidated. The aim of this study was to evaluate the blood platelet function during the first hours of acute experimental pancreatitis (AEP) in dogs. AEP was induced by the retrograde injection of bile and trypsin into the main pancreatic duct. Platelet count, platelet aggregation induced with ADP, PAF, AA as well as plasma Beta-TG and TXB2 levels were determined. At 30 min after induction of AEP a significant decrease of platelet count was noted; these changes were observed until 4 th hr. At 30 min as well as at 60 min of AEP increased sensitivity of platelet aggregation to ADP was found. After that time evident decrease of platelet aggregation to ADP was shown. Platelets sensitivity to PAF was higher at 30 min of AEP whereas 60 min, 2 and 4 hrs after AEP normalization of platelet aggregation by PAF was observed. The significant increase of plasma Beta-TG and TXB2 concentrations corresponded well to changes of platelet aggregation. These results indicate that AEP affects blood platelet function with the drop of their count.

Topics: Acute Disease; Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Blood Platelets; Dogs; Hemostasis; In Vitro Techniques; Pancreatitis; Platelet Activating Factor; Platelet Aggregation; Platelet Count; Thromboxane B2

In an investigation of the pathogenesis of acute necrotizing pancreatitis (ANP) the plasma levels of TXB2, 6-keto-PGF1 alpha, and PGE2 were measured in rats. After induction of ANP by injection of 5% sodium taurocholate into the pancreatic duct, a marked increase in TXB2 levels and a slight increase in 6-keto-PGF 1 alpha levels were found. PGE2 levels decreased. Mortality was 100% within 30 h. Pretreatment with chloroquine, a phospholipase A2 inhibitor, led to a inhibition of TXB2 production, whereas 6-keto-PGF1 alpha and PGE2 levels showed a surprising slight elevation in the first 6 h. Pretreatment with chloroquine decreased mortality by 30%. Pretreatment with FPL 55712, a leukotriene synthesis blocker, caused an increase in TXB2 and PGE2 levels, whereas the formation of 6-keto-PGF1 alpha remained unaltered. Two out of nine animals survived after pretreatment with FPL 55712. The results of the present study indicate that arachidonate end products are involved in ANP. The significance of the high TXB2 levels, decreased PGE2 levels, and only slightly elevated 6-keto-PGF1 alpha levels during ANP requires further investigation. The thromboxane A2 to prostacyclin ratio may be important.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Chloroquine; Chromones; Dinoprostone; Male; Necrosis; Pancreatitis; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

The possible role of thromboxane A2 (TXA2) in acute necrotizing pancreatitis (ANP) was investigated in rats. After ANP was induced by injecting sodium taurocholate (5% w/v) into the pancreatic duct, the thromboxane B2 (TXB2) levels in plasma increased significantly. The effects of indomethacin, a general blocker of prostaglandin synthesis, on survival time and on plasma TXB2 levels were compared with those of dazoxiben, a more specific blocker of TXA2 synthesis, and Flunarizine, a calcium entry blocker known to inhibit the effects of TXA2. In a test group without any treatment, all animals died within 30 h of ANP induction. Although TXB2 levels were lowered by the administration of indomethacin, dazoxiben, and Flunarizine, survival times were not significantly altered. Indomethacin pretreatment had no beneficial effect, whereas 30% and 40% of the animals survived for 36 h after treatment with Flunarizine and dazoxiben, respectively. The results of the present study indicate that inhibition of TXA2 synthesis alone does not dramatically alter survival time. However, a potential role for other arachidonate metabolites in ANP cannot be ruled out by this study.

Topics: Acute Disease; Animals; Flunarizine; Imidazoles; Indomethacin; Male; Necrosis; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

To study the role of the vasodilatory, antiaggregatory prostacyclin (PGI2) and its endogenous antagonist thromboxane A2 (TxA2) in acute pancreatitis, we measured serum thromboxane B2 (TxB2, which indicates platelet TxA2 production) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, which indicates systemic PGI2 production) from sequential blood samples in trypsin and taurocholate induced acute canine hemorrhagic pancreatitis (AHP). In addition the effect of a prostaglandin synthesis inhibitor, ibuprofen, was studied and systemic (MAP) and pulmonary artery pressure (MPAP) were recorded for 4.5 hr. The animals were divided into a sham-operated group, an AHP group, an ibuprofen prophylaxis group, and an ibuprofen therapy group. In the sham group the parameters remained stable throughout the experiment. In the AHP group MAP decreased steadily and 6-keto-PGF1 alpha rose significantly from 80.0 +/- 7.8 to 956.0 +/- 287.0 pg/ml (P less than 0.001), whereas serum TxB2 and MPAP remained unchanged. Ibuprofen prophylaxis eliminated the initial fall in MAP and the rise of 6-keto-PGF1 alpha. Ibuprofen therapy normalized the initially decreased MAP and depressed the level of 6-keto-PGF1 alpha. We conclude that PGI2 may at least partly mediate the initial hypotension in canine AHP, whereas platelet TxA2 production obviously has a negligible role in the development of hemodynamic changes in AHP.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Blood Pressure; Dogs; Epoprostenol; Hemorrhage; Ibuprofen; Pancreatitis; Thromboxane B2

Evidence suggests that changes in prostaglandins and disseminated intravascular coagulation accompany pancreatitis. Both may induce changes in platelet function. We wished to determine if experimentally induced pancreatitis in the dog was associated with altered platelet number and function, and whether there were concomitant changes in prostaglandins. Evidence for disseminated intravascular coagulation in the dogs with pancreatitis were red blood cell fragmentation, increased platelet turnover indicated by macro-platelets and the transient presence of fibrin degradation products in urine. There were no significant changes in platelet count. The platelets from dogs with pancreatitis showed a functional defect characterized by significantly decreased aggregation in response to adenosine diphosphate, arachidonic acid, and collagen. Release of adenosine triphosphate from platelets was reduced in collagen-stimulated aggregation. There were no changes in the plasma concentrations of thromboxane B2, 6-Keto-PGF1a, and PGE2. This defect may have been due to the generation of fibrin degradation products and platelet "exhaustion".

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Collagen; Dinoprostone; Dogs; Fibrin Fibrinogen Degradation Products; Fluid Therapy; Hematocrit; Pancreatitis; Platelet Aggregation; Platelet Count; Prostaglandins; Prostaglandins E; Thromboxane B2

The behavior of two vasoactive prostanoids was studied in experimental acute pancreatitis (AP) in rats. The stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TXA2), 6-keto-PGF1 alpha and TXB2, respectively, were measured during the course of experimental AP. Blood samples were taken at 3, 6, and 8 h after the induction of AP. In AP both plasma 6-keto-PGF1 alpha plasma TXB2 and serum TXB2 increased up to 6 h simultaneously (6-keto-PGF1 alpha from 271.1 +/- 77.2 pg/ml (mean +/- SD) to 459.4 +/- 192.6 pg/ml, plasma TXB2 from 752 +/- 350 pg/ml to 3640 +/- 2160 pg/ml and serum TXB2 from 22.3 +/- 14.8 micrograms/ml to 140.8 +/- 52.8 micrograms/ml). After 6 h 6-keto-PGF1 alpha remained elevated, whereas serum TXB2 dropped significantly. We suggest that in AP the balance of PGI2 and TXA2 is initially maintained, but later on an imbalance appears to favor vasodilatory PGI2. These agents may contribute to the regulation of the blood flow in the pancreas and thus play a role in the pathophysiology of AP.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Male; Pancreatitis; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Prostacyclin (PGI2), a potent vasodilator with complex effects on the mesenteric circulation, has been found to be elevated in the hemorrhagic ascitic fluid of pigs with hemorrhagic pancreatitis. This investigation was designed to determine if blockage of PGI2 significantly reduces the volume and/or toxicity of hemorrhagic ascitic fluid associated with hemorrhagic pancreatitis in pigs. Fifteen pigs were studied: five received corticosteroids, five received ibuprofen, and five were untreated. The relative toxicity of the hemorrhagic ascitic fluid was assessed by intraperitoneal injections of the fluid from pigs into mice.. (1) hemorrhagic pancreatitis was associated with high levels of PGI2 in blood 15 times and in hemorrhagic ascitic fluid 25 times that of baseline; (2) steroids and ibuprofen blocked PGI2 production (p less than 0.05); (3) neither steroids nor ibuprofen, even when administered as pretreatment, decreased ascites formation; and (4) the mortality rate in mice was significantly reduced (p less than 0.05) in the ibuprofen-treated group as compared with the untreated and steroid-treated groups.. PGI2 does not play a significant role in the volume of ascites formation. There was an absence of toxicity in the hemorrhagic ascitic fluid of the ibuprofen-treated group.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Ascitic Fluid; Biological Assay; Electrolytes; Epoprostenol; Female; Hemorrhage; Hydrogen-Ion Concentration; Ibuprofen; Methylprednisolone; Mice; Osmolar Concentration; Pancreatitis; Swine; Thromboxane B2