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-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.
Shirabe
K
K
Department of Surgery, University of Minnesota, Minneapolis, USA.
Kin
S
S
Shinagawa
Y
Y
Chen
S
S
Payne
W D
WD
Sugimachi
K
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D006358:Hot Temperature; D007511:Ischemia / Q000201:enzymology* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008102:Liver Circulation; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D000637:Transaminases / Q000097:blood
D001786:Blood Glucose; D008689:Methacrylates; D013929:Thromboxane B2; D013928:Thromboxane A2; C049855:ONO 3708; D000637:Transaminases; D013930:Thromboxane-A Synthase; C034364:ozagrel