Stengel P W, Dillard R D, Cho H L, Snyder D W, Spaethe S M, Pechous P A, Obenchain R L, Cockerham S L, Silbaugh S A
Lilly Research Laboratories, Pulmonary Research, Lilly Corporate Center, Indianapolis, Indiana.
J Pharmacol Exp Ther. 1993 Nov;267(2):596-603.
1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), was examined for bronchodilator activity in the guinea pig. In guinea pig tracheal preparations, LY150310 competitively antagonized the contractile effects of exogenous histamine and blocked the histamine-mediated component of contractions produced by ovalbumin challenge. LY150310 had little effect on the nonhistamine component of ovalbumin-induced contractions of lung parenchymal strips, but it enhanced the production of prostaglandin (PG) E2 and PGF2 alpha although it partially inhibited thromboxane B2 formation. In other studies, in which postmortem pulmonary gas trapping was used as an index of in vivo airway obstruction, i.v. LY150310 dose-dependently inhibited the bronchospasm produced by aerosols of the divalent cationic ionophore A23187, histamine, 5-hydroxytryptamine, leukotriene D4, methacholine, ovalbumin or platelet activating factor. LY150310 was equal to or more potent than aminophylline in all test systems. Also, orally administered LY150310 inhibited the airway obstruction produced by selected challenge aerosols. In ex vivo studies, LY150310 elevated PGE2 and tended to decrease thromboxane B2 in sodium arachidonate-stimulated whole blood. However, PGE2 and other cyclooxygenase products did not appear to account for in vivo bronchodilation, because combining LY150310 and piroxicam did not alter inhibition of A23187-induced airway obstruction. Our results demonstrate that LY150310 reduces airway obstruction caused by a variety of bronchoconstrictive agents, including A23187 and ovalbumin. Although this substituted imidazole appears to have activity as a histamine H1-receptor antagonist and can alter prostanoid concentrations in vitro and in vivo, its mode of bronchodilation is unclear.
对1-(1,2,3,4-四氢-1-萘基)-1H-咪唑硝酸盐（LY150310）进行了豚鼠支气管扩张活性研究。在豚鼠气管制备物中，LY150310竞争性拮抗外源性组胺的收缩作用，并阻断卵清蛋白激发所产生收缩的组胺介导成分。LY150310对卵清蛋白诱导的肺实质条收缩的非组胺成分影响很小，但它增强了前列腺素（PG）E2和PGF2α的生成，尽管它部分抑制了血栓素B2的形成。在其他研究中，将死后肺气体潴留用作体内气道阻塞的指标，静脉注射LY150310剂量依赖性地抑制由二价阳离子离子载体A23187、组胺、5-羟色胺、白三烯D4、乙酰甲胆碱、卵清蛋白或血小板活化因子气雾剂所产生的支气管痉挛。在所有测试系统中，LY150310的效力与氨茶碱相当或更强。此外，口服LY150310可抑制选定激发气雾剂所产生的气道阻塞。在体外研究中，LY150310可升高花生四烯酸钠刺激的全血中PGE2水平，并倾向于降低血栓素B2水平。然而，PGE2和其他环氧化酶产物似乎并不能解释其体内支气管扩张作用，因为联合使用LY150310和吡罗昔康并不会改变对A23187诱导的气道阻塞的抑制作用。我们的结果表明，LY150310可减轻由多种支气管收缩剂（包括A23187和卵清蛋白）所引起的气道阻塞。尽管这种取代咪唑似乎具有组胺H1受体拮抗剂活性，并且在体外和体内均可改变类前列腺素浓度，但其支气管扩张模式尚不清楚。
