title: Studies on L-640,035: a novel antagonist of contractile prostanoids in the lung.
abstract: 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.
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects; D003988:Dibenzothiepins / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008168:Lung / Q000187:drug effects*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013189:SRS-A / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
chemical_list: D001095:Arachidonic Acids; D003988:Dibenzothiepins; D011448:Prostaglandin Antagonists; D011450:Prostaglandin Endoperoxides, Synthetic; D013189:SRS-A; D016718:Arachidonic Acid; C028429:U 44069; C041107:L 640035; D006632:Histamine