Cook J A, Wise W C, Halushka P V
J Clin Invest. 1980 Jan;65(1):227-30. doi: 10.1172/JCI109655.
The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A(2), in endotoxic shock was investigated in rats. Plasma thromboxane A(2) was determined by radioimmunoassay of its stable metabolite thromboxane B(2). After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B(2) levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054+/-524 pg/ml (n = 8), within 30 min to 2,071+/-429 at 60 min, and decreased to 1,119+/-319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146+/-33 pg/ml in normal controls (n = 5) to 2,161+/-606 pg/ml 30 min after endotoxin (n = 5). In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B(2). Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg), a thromboxane antagonist, reduced mortality from endotoxic shock at 24 h from 100% in control rats to only 50% (P < 0.01). The results suggest that endotoxin induces increased synthesis of thromboxane A(2) that may contribute to the pathogenesis of endotoxic shock.
在大鼠中研究了促聚集血管收缩剂血栓素A₂在内毒素休克中的潜在有害作用。通过对其稳定代谢产物血栓素B₂进行放射免疫测定来确定血浆血栓素A₂。静脉注射肠炎沙门氏菌内毒素（20mg/kg）后，血浆血栓素B₂水平从正常对照大鼠中不可检测的水平（<375pg/ml）在30分钟内升至2054±524pg/ml（n = 8），60分钟时升至2071±429pg/ml，120分钟时降至1119±319pg/ml。血浆前列腺素E水平也从正常对照（n = 5）中的146±33pg/ml在内毒素注射后30分钟升至2161±606pg/ml（n = 5）。与休克对照组相比，用血栓素合成酶抑制剂咪唑预处理的大鼠或缺乏花生四烯酸及其代谢产物的必需脂肪酸缺乏大鼠，血浆血栓素B₂水平未出现显著升高。然而，咪唑并未抑制内毒素诱导的血浆前列腺素E升高。必需脂肪酸缺乏显著降低了致死性内毒素休克的死亡率。在用脂肪酸环氧化酶抑制剂吲哚美辛（10mg/kg）于内毒素注射前30分钟静脉预处理的正常大鼠中可以重现这种难治性。在内毒素前1小时腹腔注射或30分钟静脉注射咪唑（30mg/kg），与24小时时95%的对照死亡率相比，也显著（P < 0.01）将致死性内毒素休克的死亡率降低至40%。同样，用血栓素拮抗剂13-氮杂前列腺酸（30mg/kg）预处理可将24小时内毒素休克的死亡率从对照大鼠的100%降至仅50%（P < 0.01）。结果表明，内毒素诱导血栓素A₂合成增加，这可能有助于内毒素休克的发病机制。
