6-ketoprostaglandin-f1-alpha and diethyl-maleate

The major objective of this study was to determine if a threshold level of glutathione (GSH) depletion is required to elevate plasma prostacyclin (6-ketoPGF1 alpha) in male Sprague-Dawley rats. Rats were treated i.p. with various doses of phorone, diethyl maleate (DEM), or GSH with and without DEM. Similar maximal depletions of hepatic GSH (to 10% of control) and renal GSH (to 50% of control) were observed with DEM and phorone, but lung GSH was depleted maximally by only 30% with phorone compared with a 70% depletion by DEM. Changes in lung GSH, but not kidney GSH, were closely correlated with changes in hepatic GSH 6-KetoPGF1 alpha levels in the lung were 10- to 30-fold higher than in kidney or liver, and there was a stronger correlation between lung and plasma 6-ketoPGF1 alpha than with the other two tissues. The increase in lung 6-ketoPGF1 alpha following GSH depletion did not appear to be due to a shift in prostaglandin metabolite synthesis since reciprocal changes in PGE2 were not observed; lung PGE2 levels were largely unaffected by DEM or phorone. Both DEM and phorone elevated plasma 6-ketoPGF1 alpha but the magnitude of increase for DEM (5- to 6-fold) was much greater than the 2-fold increase for phorone. The increase in plasma 6-ketoPGF1 alpha by 1.0 mL DEM/kg was attenuated by simultaneous administration of 2 mmol GSH/kg. The results indicate that the lung may be responsible for increases in plasma 6-ketoPGF1 alpha following GSH depletion and that a critical level of GSH depletion in the liver and/or lung may be necessary to elevate plasma 6-ketoPGF1 alpha levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Epoprostenol; Glutathione; Ketones; Kidney; Liver; Lung; Male; Maleates; Rats; Rats, Sprague-Dawley

1. Effects of diethyl maleate (DEM) mediated glutathione (GSH) depletion on hepatic and renal cortical blood flow (perfusion), plasma GSH, and portal prostacyclin (6-ketoPGF1 alpha) and thromboxane (TxB2) were determined in anaesthetized swine. 2. Although DEM depleted hepatic GSH to 25% of control, plasma GSH increased 10-fold in comparison to controls. DEM caused a drop in blood pressure and renal cortical perfusion but had no effect on hepatic perfusion or portal 6-ketoPGF1 alpha or TxB2 levels. 3. Possibly, the unexpected rise in plasma GSH may have inhibited prostanoid synthesis, preventing any alterations in tissue perfusion that may have occurred following tissue GSH depletion.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Glutathione; Kidney Cortex; Liver; Male; Maleates; Perfusion; Portal Vein; Swine; Thromboxane B2

1. The effect of glutathione (GSH) depletion on rabbit renal medullary homogenate 6-ketoPGF1 alpha and TxB2 synthesizing capability was investigated. 2. GSH depletion in vivo with diethyl maleate (DEM) produced higher (P less than 0.05) 6-ketoPGF1 alpha and TxB2 renal medullary levels compared to controls. Homogenization and incubation lowered (P less than 0.05) GSH such that there were no differences in GSH between treatments after 5 min of incubation. By 30 min, GSH was lower (P less than 0.05) and 6-ketoPGF1 alpha higher (P less than 0.05) in homogenates from controls in comparison to those from DEM-treated rabbits. 3. The results indicate GSH depletion increased 6-ketoPGF1 alpha levels in rabbit renal medulla in vivo but subsequent GSH catabolism prevented assessing the effect of this GSH depletion on prostanoid synthesizing capability.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Glutathione; In Vitro Techniques; Kidney Medulla; Male; Maleates; Oxidation-Reduction; Rabbits; Radioimmunoassay; Thromboxane B2

Glutathione (GSH) is important in detoxification and regulating cyclooxygenase activity. Since the liver has high levels of GSH, xenobiotic-induced changes in hepatic GSH could affect hepatic tissue blood perfusion (HP) via alterations in prostaglandin synthesis. In anesthetized male New Zealand rabbits, elevating GSH with GSH monoethyl ester had no affect on HP. Treatment of rabbits with diethyl maleate to deplete GSH also had no affect on HP in animals previously given GSH monoethyl ester. However, HP increased within 20 min in rabbits treated with diethyl maleate prior to GSH monoethyl ester. In another experiment, a similar rise in HP following GSH depletion was accompanied by arterial plasma 6-ketoPGF1 alpha (the stable metabolite of prostacyclin) levels that were 4-times higher than in the controls. Plasma TxB2 (the stable metabolite of thromboxane) also increased following diethyl maleate, but only to levels that were 25-times lower than for 6-ketoPGF1 alpha. Since indomethacin blocked the rise in HP, as well as the increases in 6-ketoPGF1 alpha and TxB2, these results indicate changes in HP may occur following GSH depletion as a result of increased synthesis of one or more arachidonic acid metabolites and implicate prostacyclin as a possible mediator of this phenomenon.

Topics: 6-Ketoprostaglandin F1 alpha; Acid-Base Equilibrium; Animals; Blood Pressure; Glutathione; Heart Rate; Indomethacin; Liver; Liver Circulation; Male; Maleates; Rabbits; Thromboxane B2

Exogenous thiol compounds have been reported to protect the stomach from ethanol-induced necrotic lesions. The gastric mucosa contains high levels of an endogenous thiol, glutathion (GSH). Because of the known role of glutathione in protecting against hepatic injury, its role in gastric mucosal cytoprotection was of interest. By use of an animal model for acute gastric injury from ethanol, a close parallel relation between depletion of endogenous mucosal GSH and induction of mucosal protection was demonstrated. Surprisingly, mucosal protection varied inversely with the level of mucosal GSH obtained after treatment with specific GSH-depleting agents (diethyl maleate and cyclohexene-1-one). Depletion of gastric mucosal GSH was associated with an increase in the mucosal content of prostaglandins 6-keto F1 alpha and F2 alpha but not E2. The protective effect induced by GSH-depleting agents was partially reversed by indomethacin in some but not all studies. Although GSH depletors increased gastric juice volume, protection with these agents persisted after the volume and mucosal GSH had returned to control levels and also was not reversed by increasing the dose of ethanol threefold to overcome a possible dilutional effect. We conclude that, contrary to apparent predictions, depletion of endogenous gastric GSH protects the stomach from acute ethanol-induced injury. Although the mechanism of this protection is unknown, a mediation by endogenous release of prostaglandins seems to play a minor role since diethyl maleate was protective even in indomethacin-treated animals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclohexanones; Dinoprost; Dinoprostone; Ethanol; Gastric Mucosa; Glutathione; Indomethacin; Male; Maleates; Necrosis; Prostaglandins E; Prostaglandins F; Rats; Rats, Inbred Strains