Premium
Studies on L‐640,035: a novel antagonist of contractile prostanoids in the lung
Author(s) -
Carrier R.,
Cragoe E.J.,
Ethier D.,
FordHutchinson A.W.,
Girard Y.,
Hall R. A.,
Hamel P.,
Rokach J.,
Share N.N.,
Stone C.A.,
Yusko P.
Publication year - 1984
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1984.tb10774.x
Subject(s) - ed50 , histamine , antagonist , contraction (grammar) , chemistry , in vivo , schild regression , dose–response relationship , prostaglandin , guinea pig , medicine , endocrinology , pharmacology , in vitro , biology , biochemistry , receptor , microbiology and biotechnology
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) (pA 2 7.0), PGF 2α (pA 2 5.9) and PGD 2 (pA 2 6.5). L‐640,035 produced no significant shift in the dose‐response curves to leukotriene D 4 or histamine and produced a small but statistically significant shift in the dose‐response curve to 5‐hydroxytryptamine (5‐HT) (pA 2 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 (pA 2 6.0) and PGF 2α (pA 2 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 (ED 50 0.16 mg kg −1 ), leukotriene D 4 (ED 50 0.25 mg kg −1 ) and 5‐HT (ED 50 3.4 mg kg −1 ) but not histamine (ED 50 > 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 (ED 50 0.85 mg kg −1 ) but not histamine (ED 50 > 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.