Studies on L‐640,035: a novel antagonist of contractile prostanoids in the lung

Abstract

1 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. 2 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), PGF_2α (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 PGF_2α, 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 PGF_2α (pA₂ 6.0), but with some reduction in the maximal contraction. 3 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> 10 mg kg⁻¹) was observed. 4 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> 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⁻¹ significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mg kg⁻¹ 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.