Ishiura Y, Fujimura M, Myou S, Amemiya T, Nobata K, Liu Q, Yamamori C, Matsuda T
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
Drugs Exp Clin Res. 2000;26(2):33-40.
Beta-adrenoreceptor antagonists, such as propranolol, can provoke severe bronchoconstriction in asthmatic subjects. Recently we developed an animal model of propranolol-induced bronchoconstriction and investigated the involvement of chemical mediators in this reaction. The purpose of this study was to elucidate the role of thromboxane A2 in the development of propranolol-induced bronchoconstriction after allergic bronchoconstriction. Passively sensitized guinea pigs were anesthetized and treated with diphenhydramine hydrochloride and were then artificially ventilated. Propranolol at a concentration of 10 mg/ml was inhaled 20 min after an aerosolized antigen challenge. A potent and selective thromboxane A2 synthase inhibitor, CS-518, in doses of 0.01, 0.1 and 1 mg/kg and vehicle were administered intravenously 15 min after the antigen challenge. Another study was performed in naive guinea pigs; ascending doses of methacholine (12.5, 25, 50, 100 and 200 microg/ml) were inhaled for 20 sec at 5-min intervals, 10 min after intravenous administration of CS-518. Propranolol inhaled 20 min after the antigen challenge caused bronchoconstriction in sensitized guinea pigs. CS-518 administered 15 min after the antigen challenge significantly inhibited propranolol-induced bronchoconstriction in a dose-dependent manner, while CS-518 did not influence the dose-dependent response to inhaled methacholine in naive guinea pigs. We conclude that thromboxane A2 contributes to the development of propranolol-induced bronchoconstriction following allergic reaction in our guinea pig model.
β-肾上腺素受体拮抗剂，如普萘洛尔，可在哮喘患者中引发严重的支气管收缩。最近我们建立了普萘洛尔诱导支气管收缩的动物模型，并研究了化学介质在该反应中的作用。本研究的目的是阐明血栓素A2在变应性支气管收缩后普萘洛尔诱导的支气管收缩发展中的作用。对被动致敏的豚鼠进行麻醉，用盐酸苯海拉明处理，然后进行人工通气。雾化抗原激发后20分钟吸入浓度为10mg/ml的普萘洛尔。在抗原激发后15分钟静脉注射剂量为0.01、0.1和1mg/kg的强效选择性血栓素A2合酶抑制剂CS-518及赋形剂。另一项研究在未致敏的豚鼠中进行；静脉注射CS-518 10分钟后，每隔5分钟吸入递增剂量的乙酰甲胆碱（12.5、25、50、100和200μg/ml），持续20秒。抗原激发后20分钟吸入普萘洛尔可使致敏豚鼠发生支气管收缩。抗原激发后15分钟给予CS-518以剂量依赖的方式显著抑制了普萘洛尔诱导的支气管收缩，而CS-518对未致敏豚鼠吸入乙酰甲胆碱的剂量依赖性反应没有影响。我们得出结论，在我们的豚鼠模型中，血栓素A2在变应性反应后普萘洛尔诱导的支气管收缩发展中起作用。
