Antagonism of the in vivo and in vitro effects of leukotriene D4 by SC-39070 in guinea pigs

Abstract

Leukotriene D4 (LTD4) causes contractions of guinea pig isolated ilea, evokes pulmonary bronchoconstriction and induces lesions of the dermal vasculature. In the present study, we assessed the antagonism of these actions by SC-39070 compared to FPL-55712, a known LTD4 receptor antagonist. In guinea pig isolated ileum preparations, SC-39070 displayed selective antagonism of LTD4 with a pA2 = 8.20 +/- 0.06 (S.E.) and a Schild plot slope of -1.20. Administered intravenously to artificially-respired guinea pigs one minute prior to the agonist, SC-39070 antagonized (p less than 0.05) the bronchoconstrictive effect of LTD4 in a dose-dependent manner (0.5-10 mg/kg). At a dose of 2.0 mg/kg, i.v. this activity was retained through a 60 minute pretreatment interval. Similarly, after oral administration of SC-39070, there was a dose-dependent antagonism of the bronchoconstrictive activity of LTD4 (MED50 = 3.8 mg/kg). Antagonism of LTD4-induced bronchoconstriction was evidenced after oral administration of SC-39070 within one hour of treatment and efficacy was retained as long as 20 hours after treatment at a dose of 10 mg/kg. Finally, intravenously administered SC-39070 blocked LTD4-induced dermal permeability in guinea pigs with a minimum effective dose of 1.0 mg/kg. In each assay, the LTD4 antagonism evidenced after treatment with SC-39070 appeared to be equal to or greater than that observed after treatment with FPL-55712.