Inhibition of thromboxane A₂ activity during warm ischemia of the liver

To determine the role of thromboxane A₂ (TxA₂) in ischemic damage of the rat liver, we examined the effects of a TxA₂ synthetase inhibitor (OKY 046) and a TxA₂ receptor antagonist (ONO 3708). Rats were divided into three groups. In group I, a portion of the liver was subjected to 100 min of warm ischemia and the remaining liver resected. In group II, OKY 046 (30 mg/kg, intravenously) was given 5 min before the same procedure. In group III, ONO 3708 (10 mg/kg, intravenous) was given 5 min before ischemia. We then assessed survival, serum biochemistry, extent of histologic necrosis, and the levels of prostaglandin E₂ (PGE₂), TxB₂, and 6-keto-PGF₁-α. Pretreatment with OKY 046 and ONO 3708 significantly improved survival, decreased the tissue water content, and lowered the levels of serum transaminases and the extent of histological liver necrosis compared with the control group. OKY 046 markedly suppressed the level of TxB₂, but not the levels of PGE₂ or 6- keto-PGF₁-α. ONO 3708 did not change the levels of PGE₂, TxB₂, or 6- keto-PGF₁-α. In a liver perfusion model, OKY 046 and ONO 3708 did not suppress the uptake of trypan blue in hepatocytes. Our results demonstrate that either a TxA₂ synthetase inhibitor or a TxA₂ receptor antagonist can protect the liver from an ischemic insult. The effects of these drugs were due to inhibition of TxA₂ synthesis and TxA₂ blockade at the receptor, without modulating PGI₂ or PGE₁. Our results in a perfused rat liver model suggest that these drugs work during reperfusion and prevent postischemic tissue edema.