THROMBOXANE A(2) RECEPTOR ANTAGONIST (ONO-3708) PROTECTS FROM LIVER-DAMAGE INDUCED BY CHOLESTASIS AND ISCHEMIA-REPERFUSION

The effect of a thromboxane (Tx) A(2) 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 mu g/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) F-1 alpha, a stable metabolite of PGI(2) and of TxB(2), a stable metabolite of TxA(2), from the liver. After I-R, cholestasis accelerated the release of TxB(2), but not 6-keto-PGF(1 alpha). I-R also increased the TxB(2)/6-keto-PGF(1 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 TxA(2)/PGI(2) ratio, which predicts cellular damage, and by increasing levels of alpha-tocopherol and glutathione.