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, o n cholestasis and injury related to ischemia and subsequent reperfusio n (I-R) was investigated in the dog liver by assessing changes in insu lin and glucagon metabolism. The left hepatic duct was ligated for 4 w eeks to create a cholestatic lobe. Sixty-minute ischemia was induced b y 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 diff erence in the rate of glucagon metabolism between the right and left l obes. After induction of I-R, the rate of insulin metabolism, but not glucagon metabolism, decreased. The lipid peroxide level was higher an d 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 pero xide level increased and the alpha-tocopherol level decreased. There w as 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 al pha). I-R also increased the TxB(2)/6-keto-PGF(1 alpha) ratio. ONO 370 8 reduced these metabolic changes in the cholestasis and after I-R. Th ese findings suggest that ONO 3708 protects liver function, especially in the cholestatic lobe, from I-R-related injury by reducing peroxida tion of lipids and the TxA(2)/PGI(2) ratio, which predicts cellular da mage, and by increasing levels of alpha-tocopherol and glutathione.