ono-3708 and Ischemia

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-alpha. 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-alpha. ONO 3708 did not change the levels of PGE2, TxB2, or 6-keto-PGE1-alpha. 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.

Topics: Animals; Blood Glucose; Hot Temperature; Ischemia; Liver; Liver Circulation; Male; Methacrylates; Rats; Rats, Sprague-Dawley; Reperfusion; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Transaminases

Metabolic disturbances in the canine liver during warm ischemia by Pringle's method for 60 minutes and the role of Coenzyme Q10 (CoQ10), Prostaglandin E1 (PGE1) and ONO-3708, TXA2 receptor antagonist, were studied. Mongrel dogs were divided into five groups; control group, group of liver ischemia without drugs, groups of liver ischemia with CoQ10, PGE1 and ONO-3708 pretreatment. Metabolic rates of PGI2, TXA2, insulin, glucagon and glucose and production of lipid peroxides in the five groups were measured at the points before Pringle's procedure, 5 minutes, 60 minutes and 120 minutes after declamping. In the group of ischemia without drug administration, the hepatic metabolism of PGI2, TXA2, insulin and glucose were decreased after declamping. The metabolism of glucagon, however, was not disturbed by warm ischemia. The production of lipid peroxides increased at 5 minutes after declamping. In the groups of CoQ10, PGE1 and ONO-3708 pretreatment, changes of PGI2, TXA2 and insulin metabolism in the liver were improved, and an increased production of lipid peroxides by warm ischemia was normalized. This study suggests that CoQ10, PGE1 and ONO-3708 protect liver damage by warm ischemia as results of improvement of metabolic disturbances of PGI2, TXA2, insulin and suppression of lipid peroxides production.

Topics: Alprostadil; Animals; Body Temperature; Dogs; Epoprostenol; Insulin; Ischemia; Lipid Peroxides; Liver; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Ubiquinone