Bronchodilation with a potent and selective leukotriene D₄ (LTD₄) receptor antagonist (MK-571) in patients with asthma

The sulfidopeptide leukotrienes LTC₄, LTD₄, and LTE₄ can cause airway smooth muscle contraction and have been implicated in the pathophysiology of asthma. MK-571 is a selective, potent LTD₄ receptor antagonist that could attenuate airway obstruction in asthma by inhibiting the actions of sulfidopeptides at the LTD₄ receptor site. The objectives of this study were to investigate the potential for MK-571 to cause bronchodilation in asthma patients with existing airway obstruction and to evaluate its effect on the bronchodilation response to an inhaled beta₂-agonist (albuterol). Twelve male patients (ages 19 to 42 yr) with asthma (baseline FEV₁ 50 to 80% predicted) participated in this placebo-controlled, randomized, two-period, cross-over study. On separate treatment days, each patient received either MK-571 or placebo intravenously for 6 h; inhaled albuterol was administered at the fifth and sixth hour of MK-571/placebo treatment to achieve maximal bronchodilation on that study day. Spirometry (forced expiratory volume in 1 s, FEV₁) was monitored at intervals throughout each study period. MK-571 caused clinically significant bronchodilation; the increase in FEV₁ above baseline, 20 min after the start of the MK-571 infusion, was 22 ± 3.9% compared with 1.3 ± 2.3% for placebo (mean ± SE, p < 0.01). This degree of bronchodilation was maintained throughout the MK-571 infusion. In addition, bronchodilation from inhaled albuterol appeared additive with MK-571. Finally, baseline airway obstruction correlated with the degree of bronchodilation achieved with MK-571 (r = -0.73; p = 0.007). Our observations demonstrate that MK-571 causes significant acute bronchodilation that is additive with inhaled albuterol in patients with airway obstruction from asthma. Based upon our results, we speculate that LTD₄ receptor activation contributes to abnormal airway tone in patients with active asthma, and antagonists to this receptor may provide a new therapeutic approach to asthma.