Carrier R, Cragoe E J, Ethier D, Ford-Hutchinson A W, Girard Y, Hall R A, Hamel P, Rokach J, Share N N, Stone C A
Br J Pharmacol. 1984 Jun;82(2):389-95. doi: 10.1111/j.1476-5381.1984.tb10774.x.
The effects of L-640,035 (3-hydroxymethyl-dibenzo [b,f] thiepin-5,5-dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo. When studied in vitro on guinea-pig tracheal chains, L-640,035 produced significant shifts in the dose-response curves to a prostaglandin (PG) endoperoxide analogue (U-44069) (pA2 7.0), PGF2 alpha (pA2 5.9) and PGD2 (pA2 6.5). L-640,035 produced no significant shift in the dose-response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose-response curve to 5-hydroxytryptamine (5-HT) (pA2 5.2). With the exception of PGF2 alpha, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L-640,035, L-636,499, also produced significant parallel shifts in the dose-response curves to U-44069 (pA2 6.0) and PGF2 alpha (pA2 6.0), but with some reduction in the maximal contraction. When L-640,035 was administered intravenously to guinea-pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U-44069 (ED50 0.16 mg kg-1), leukotriene D4 (ED50 0.25 mg kg-1) and 5-HT (ED50 3.4 mg kg-1) but not histamine (ED50 greater than 10 mg kg-1) was observed. When L-640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U-44069 (ED50 0.85 mg kg-1) but not histamine (ED50 greater than 30 mg kg-1) was observed. 5 When L-640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg- significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mgkg1 i.v.) was observed with a duration of action of > 255 min. 6 It is concluded that L-640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.
已对L - 640,035（3 - 羟甲基 - 二苯并[b,f]硫氮杂䓬 - 5,5 - 二氧化物）在体外和体内对肺平滑肌收缩的作用进行了研究。在豚鼠气管链上进行体外研究时，L - 640,035使对前列腺素（PG）内过氧化物类似物（U - 44069）（pA2 7.0）、前列腺素F2α（pA2 5.9）和前列腺素D2（pA2 6.5）的剂量 - 反应曲线发生显著偏移。L - 640,035对白细胞三烯D4或组胺的剂量 - 反应曲线未产生显著偏移，而对5 - 羟色胺（5 - HT）（pA2 5.2）的剂量 - 反应曲线产生了小但具有统计学意义的偏移。除前列腺素F2α外，Schild分析一般未表明存在竞争性抑制。L - 640,035的主要代谢产物L - 636,499也使对U - 44069（pA2 6.0）和前列腺素F2α（pA2 6.0）的剂量 - 反应曲线发生显著平行偏移，但最大收缩有所降低。当给豚鼠静脉注射L - 640,035时，观察到对U - 44069（ED50 0.16 mg·kg⁻¹）、白细胞三烯D4（ED50 0.25 mg·kg⁻¹）和5 - HT（ED50 3.4 mg·kg⁻¹）诱导的肺阻力增加或吹入压力增加有显著抑制作用，但对组胺（ED50大于10 mg·kg⁻¹）无抑制作用。当给狗静脉注射L - 640,035时，观察到对U - 44069（ED50 0.85 mg·kg⁻¹）诱导的肺阻力增加有显著抑制作用，但对组胺（ED50大于30 mg·kg⁻¹）无抑制作用。当以3和10 mg·kg的剂量经十二指肠途径给狗施用L - 640,03时，观察到对花生四烯酸钠（3 mg·kg⁻¹静脉注射）诱导的肺阻力增加有显著抑制作用，作用持续时间> 255分钟。结论是，L - 640,035是一种新型、相对选择性且口服有效的收缩性前列腺素对肺平滑肌作用的拮抗剂。
