title: MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human.
abstract: MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.
authors.affiliation: Department of Respiratory Diseases, University Hospital, Ghent, Belgium.
authors.forename: J C
authors.initials: JC
authors.lastname: Kips
authors.forename: G F
authors.initials: GF
authors.lastname: Joos
authors.forename: I
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: D J
authors.initials: DJ
authors.lastname: Margolskee
authors.forename: A
authors.initials: A
authors.lastname: Buntinx
authors.forename: R A
authors.initials: RA
authors.lastname: Pauwels
authors.forename: M E
authors.initials: ME
authors.lastname: Van der Straeten
mesh_terms: D000293:Adolescent; D000328:Adult; D000403:Airway Resistance / Q000187:drug effects; D001249:Asthma / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005541:Forced Expiratory Volume; D006801:Humans; D008297:Male; D008875:Middle Aged; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D011422:Propionates; D011804:Quinolines; D013189:SRS-A; C059141:verlukast