Ma X L, Karasawa A, Lefer A M
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA.
Methods Find Exp Clin Pharmacol. 1991 Mar;13(2):105-10.
Injection of sodium arachidonate (NaAr) intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits within 3 min. This sudden death is characterized by a precipitous drop in mean blood pressure within 2 min after injection of NaAr, a marked decrease in the circulating platelet count, a significant increase in intratracheal pressure and in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its stable breakdown product, TxB2. Pretreatment with Bay-u-3405, a new specific thromboxane receptor antagonist, at a dose of 1 or 10 mg/kg dramatically protected rabbits against sudden death induced by injection of NaAr. All of the rabbits treated with either of these two doses of Bay-u-3405 survived, and their thrombocytopenia, elevated plasma TxB2 concentration and bronchoconstriction were significantly attenuated. However, administration of 0.1 mg/kg Bay-u-3405 exerted no protective effect in this lethal model. Bay-u-3405 was shown to be a potent and specific inhibitor of thromboxane-mimetic induced platelet aggregation in vitro. Our data clearly show that Bay-u-3405 is a very effective protective agent against NaAr-induced sudden death in rabbits, blocking all of the known deleterious effects of TxA2.
以2毫克/千克的剂量静脉注射花生四烯酸钠（NaAr），在3分钟内可使家兔全部致死。这种猝死的特征是在注射NaAr后2分钟内平均血压急剧下降，循环血小板计数显著减少，气管内压力以及通过对其稳定分解产物血栓素B2（TxB2）进行放射免疫测定所测得的血浆血栓素A2（TxA2）浓度显著升高。用一种新型特异性血栓素受体拮抗剂Bay-u-3405以1或10毫克/千克的剂量进行预处理，可显著保护家兔免受注射NaAr所致的猝死。用这两种剂量的Bay-u-3405治疗的所有家兔均存活，并且它们的血小板减少、血浆TxB2浓度升高和支气管收缩均得到显著减轻。然而，给予0.1毫克/千克的Bay-u-3405在这种致死模型中没有发挥保护作用。在体外实验中，Bay-u-3405被证明是一种有效的、特异性的血栓素模拟物诱导的血小板聚集抑制剂。我们的数据清楚地表明，Bay-u-3405是一种非常有效的抗家兔NaAr诱导猝死的保护剂，可阻断TxA2的所有已知有害作用。
