MK-571, a potent antagonist of leukotriene D₄-induced bronchoconstriction in the human

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.