thromboxane-a2 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

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion. 2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats. 3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 +/- 0.05 (SEM) as compared with 1.06 +/- 0.09 ml min-1 g-1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats. 4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 +/- 22.3 versus 56.8 +/- 10.2 pmol 24 h-1 100 g-1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 +/- 2.0 versus 6.4 +/- 0.9 pmol h-1 mg-1 protein (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Blood Pressure; Body Weight; Cholestasis; Female; Kidney; Kidney Glomerulus; Ligation; Organ Size; Phenylacetates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2

The effect of a thromboxane (Tx) A2 receptor antagonist, ONO 3708, on cholestasis and injury related to ischemia and subsequent reperfusion (I-R) was investigated in the dog liver by assessing changes in insulin and glucagon metabolism. The left hepatic duct was ligated for 4 weeks to create a cholestatic lobe. Sixty-minute ischemia was induced by Pringle's procedure. ONO 3708 (200 micrograms/kg/min) was initiated 60 min before induction of ischemia and continued throughout the experiment. The rate of insulin metabolism was higher in the right noncholestatic lobe than in the left cholestatic lobe. There was no significant difference in the rate of glucagon metabolism between the right and left lobes. After induction of I-R, the rate of insulin metabolism, but not glucagon metabolism, decreased. The lipid peroxide level was higher and the glutathione level was lower in the cholestatic lobe than in the noncholestatic lobe. There was no significant difference in the alpha-tocopherol level between lobes. After induction of I-R, the lipid peroxide level increased and the alpha-tocopherol level decreased. There was no change in the glutathione level. I-R accelerated the release of 6-keto-prostaglandin (PG) F1 alpha, a stable metabolite of PGI2, and of TxB2, a stable metabolite of TxA2, from the liver. After I-R, cholestasis accelerated the release of TxB2, but not 6-keto-PGF1 alpha. I-R also increased the TxB2/6-keto-PGF1 alpha ratio. ONO 3708 reduced these metabolic changes in the cholestasis and after I-R. These findings suggest that ONO 3708 protects liver function, especially in the cholestatic lobe, from I-R-related injury by reducing peroxidation of lipids and the TxA2/PGI2 ratio, which predicts cellular damage, and by increasing levels of alpha-tocopherol and glutathione.

Topics: Animals; Cholestasis; Dogs; Glucagon; Glutathione; Insulin; Lipid Peroxides; Liver; Liver Circulation; Receptors, Thromboxane; Reperfusion Injury; Thromboxane A2; Vitamin E

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