6-ketoprostaglandin-f1-alpha and Cholestasis

The effects of OKY-046, a thromboxane A2 synthetase inhibitor, on hepatic dysfunction produced by liver cell ischemia were studied in an experimental model of rats with obstructive jaundice. The experiments were performed 7 days after the rats underwent bile duct ligation. Warm total ischemia of the liver was induced by Pringle's method over a 20-min period and the animals were divided into two groups according to whether or not OKY-046 was administered. The reperfusion time was 30 min in each group. OKY-046 was administered via the femoral vein at a rate of 100 micrograms/kg per min from 15 min before the blockade to the end of the experiment. The level of ATP in the liver tissue of the OKY-046 group was elevated slightly, but not significantly, compared to that of the control group. The ratio TXB2/6-keto PGF1 alpha in the liver tissue was lower in the OKY-046 group than in the control group, and significant differences were found between the two groups in the water content of the liver and the mitochondrial score as examined by transmission electron microscopy. Thus, it was observed that an improvement in the balance of TXA2 and PGI2 associated with OKY-046 administration proctected the cellular structure of the mitochondria in the rat liver.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Alanine Transaminase; Animals; Aspartate Aminotransferases; Cholestasis; Enzyme Inhibitors; Ischemia; Liver; Male; Methacrylates; Microscopy, Electron; Mitochondria, Liver; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase

Advanced cirrhosis is known to be associated with extrahepatic organ dysfunction, but the mechanism for this cirrhosis complication is largely unknown. We measured tissue albumin leakage in rats with biliary cirrhosis or acute cholestasis and tested the hypothesis that arachidonic acid metabolites contribute to the vascular permeability change. Six weeks after bile duct ligation, rats with biliary cirrhosis exhibited increased extravascular leakage of 125I-albumin in lung (p < 0.001) and kidney (p < 0.01) but not in heart or brain. In contrast, in cholestatic rats 10 days after bile duct ligation, only the kidney albumin leak was significantly increased (p < 0.01). Tissue thromboxane B2 levels, measured with an enzyme immunoassay, were increased in lung, kidney and liver of cirrhotic and cholestatic rats. To determine whether thromboxane A2 contributes to the vascular permeability defects in cirrhosis, we pretreated cirrhotic rats with the thromboxane synthase inhibitor dazoxiben (10 mg/kg intraperitoneally every 8 hr) for 20 hr before assessment of vascular permeability. Dazoxiben blocked the increase in thromboxane B2 level in lung but not in kidney and lowered the lung but not the kidney albumin leak index. In cholestatic rats given a higher dose of dazoxiben (40 mg/kg intraperitoneally every 8 hr) for 20 hr, the kidney thromboxane B2 level but not albumin leak was significantly lowered. We conclude that chronic biliary obstruction in rats leads to increased vascular permeability in selected extrahepatic organs and that thromboxane A2 contributes to the vascular permeability increase in the lung. Whether thromboxane A2 plays a role in renal albumin leakage will require further study.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Bile Ducts; Capillary Permeability; Cholestasis; Eicosanoids; Imidazoles; Kidney; Ligation; Liver Cirrhosis, Biliary; Lung; Male; Rats; Rats, Sprague-Dawley; Serum Albumin, Radio-Iodinated; Thromboxane A2; Thromboxane B2

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bile Ducts; Cholestasis; Denervation; Dinoprostone; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Ligation; Male; Prostaglandins; Rats; Rats, Inbred Strains; Sympathetic Nervous System; Thromboxane B2

Endogenous pancreatic prostaglandin production in control and obstructive jaundice was investigated using isolated and perfused dog pancreas. In both groups, spontaneous production of prostaglandin E2 and prostaglandin I2 was recorded, and the levels did not change in both groups. The production of both prostaglandins in jaundice, however, was higher than that in the control on stimulation by 8 x 10(-11) mol of cholecystokinin-octapeptide. Amylase release with cholecystokinin-octapeptide at an amount of 8 x 10(-11) mol in jaundice was higher than in the control. The amylase release in both groups, however, showed further elevation on indomethacin pretreatment. On incubation of pancreatic dispersed cells in both groups, prostaglandin production in jaundiced cells was higher than that in control cells. These data showed that enhanced endogenous prostaglandin in obstructive jaundice might be caused by the characteristic change of pancreatic cells, which increased susceptibility to cholecystokinin-octapeptide because of long-term exposure to abnormal blood components, and enhanced prostaglandins might act as a cytoprotector of acinar cells in the pancreas damaged by cholecystokinin-octapeptide administration.

Topics: 6-Ketoprostaglandin F1 alpha; Amylases; Animals; Cells, Cultured; Cholestasis; Chromatography, High Pressure Liquid; Dinoprostone; Dogs; Female; In Vitro Techniques; Indomethacin; Male; Pancreas; Perfusion; Sincalide

Changes in urinary prostaglandin E2 (PGE2), 6-keto PGF1 alpha, and thromboxane (TXB2) excretion in 12 patients with obstructive jaundice were observed in relation to renal function and the renin-angiotensin (R-A) system. In obstructive jaundice before percutaneous biliary drainage the creatinine clearance (CCr) was significantly lower (p less than 0.001) and the PGE2 and plasma angiotensin II (AII) concentrations were significantly higher (p less than 0.005 and p less than 0.005, respectively) than those in normal subjects. Both 6-keto PGF1 alpha and TXB2 were widely distributed. When CCr returned to normal after drainage, PGE2 and plasma AII also returned to normal, but when CCr decreased after drainage, PGE2 and plasma AII increased. Before drainage, PGE2 correlated negatively with CCr (r = -0.72, p less than 0.01) and positively with plasma AII(r = 0.69, p less than 0.02). 6-Keto PGF1 alpha correlated positively with serum total bilirubin (r = 0.66, p less than 0.02). The percentage change in PGE2 after drainage correlated negatively with that in CCr (r = -0.95, p less than 0.005). The percentage chang in plasma AII correlated positively with that in urine PGE2 (r = 0.94, p less than 0.005) and negatively with that in CCr (r = -0.85, p less than 0.02). These results suggest that PGE2 is closely related to the R-A system and might assist in the maintenance of renal circulation in obstructive jaundice.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Cholestasis; Creatinine; Dinoprostone; Female; Humans; Kidney; Kidney Function Tests; Male; Middle Aged; Prostaglandins; Renin-Angiotensin System; Thromboxane B2

The delayed clearance of endotoxins in obstructive jaundice may cause renal impairment by inducing renal vasoconstriction and glomerular fibrin deposition as a consequence of intravascular coagulation. As endotoxins activate arachidonic acid metabolism we have examined the effects of selective inhibitors on mortality, plasma TXB2 and 6-oxo-PGF1 alpha production and renal fibrin deposition in rats with obstructive jaundice following endotoxin administration. Jaundiced rats had a high mortality following endotoxin--58 per cent at 4 h and 83 per cent at 24 h. Pretreatment with indomethacin 3 mg/kg i.p., dazoxiben 3 mg i.p. or prostacyclin 300 ng/kg i.v. produced significant improvements in survival. Endotoxaemia was associated with significant elevations of plasma TXB2 and early inhibition of plasma 6-oxo-PGF1 alpha generation. Renal fibrin deposition, assessed using indirect immunofluorescence and a 125I-labelled fibrinogen uptake ratio, occurred in jaundiced kidneys following endotoxin and could be prevented using indomethacin, dazoxiben and prostacylin. These results suggest that endotoxin-induced TXA2 production can cause renal fibrin deposition in obstructive jaundice, thus contributing in the pathogenesis of the renal impairment.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholestasis; Endotoxins; Epoprostenol; Escherichia coli; Fibrin; Imidazoles; Indomethacin; Kidney; Male; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2