Thromboxane A₂ Receptor Antagonist (ONO 3708) Protects from Liver Damage Induced by Cholestasis and Ischemia-Reperfusion

Abstract

The effect of a thromboxane (Tx) A₂receptor 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 µg/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 α-tocopherol level between lobes. After induction of I–R, the lipid peroxide level increased and the α-tocopherol level decreased. There was no change in the glutathione level. I–R accelerated the release of 6-keto-prostaglandin (PG) F_1α, 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-PGFι_α. I–R also increased the TxTSyö-keto-PGF_1α 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 α-tocopherol and glutathione.

Role of Thromboxane in Producing Hepatic Injury During Hepatic Stress

“…The plasma TXA 2 /PGI 2 ratio changes in some pathological conditions. 104 It increases during liver ischemia and could influence the extent of hepatic injury 105 and survival rate of animals. 106 Therefore, administration of PGI 2 , which reduces the TXA 2 /PGI 2 ratio, improves the outcome of ischemiareperfusion-induced hepatic injury.…”

Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

“…31 In an animal model of ischemia-reperfusion liver injury, an increase in the level of lipid peroxide and a decrease in the concentration of antioxidant glutathione and alpha-tocopherol have been shown. 39 In this regard, administration of different COX inhibitors, specific TX synthase inhibitors and specific TPR antagonists has been shown to abrogate these negative effects of TXA 2 and protect from severe hepatic injury elicited with various noxious agents 31,[37][38][39] It seems that PGI 2 /TXA 2 ratio is critical for the maintenance of hepatic microcirculation, since its decrease has been observed in several models of liver injury. 24,33,39 PGI 2 antagonizes the effects of TXA 2 by inducing vasodilatation and by inhibiting platelet aggregation.…”

“…39 In this regard, administration of different COX inhibitors, specific TX synthase inhibitors and specific TPR antagonists has been shown to abrogate these negative effects of TXA 2 and protect from severe hepatic injury elicited with various noxious agents 31,[37][38][39] It seems that PGI 2 /TXA 2 ratio is critical for the maintenance of hepatic microcirculation, since its decrease has been observed in several models of liver injury. 24,33,39 PGI 2 antagonizes the effects of TXA 2 by inducing vasodilatation and by inhibiting platelet aggregation. 31 Thus, exogenously applied PGI2 or its stabile agonists significantly increased PGI2/TXA 2 ratioand improved the outcome of liver injury induced by APAP, as well as by other noxious agents, in vivo and in vitro.…”