Leukotriene D₄ receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma

We have tested the hypothesis that leukotriene D₄ (LTD₄) receptor activation is involved in the development of antigen-induced bronchoconstriction. In two studies, patients with asthma received infusions of placebo or MAT-571, a potent and specific LTD₄ receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV₁ was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE₄; plasma samples were drawn repeatedly for assay of MK-571. MK-571 infusions inhibited both immediate (0 to 3 hours) and late (3 to 10 hours) asthmatic responses. For the high MK-571 dose, the extent of inhibition, as assessed by the area under the curve of FEV₁ versus time was 88% (p = 0.01) and 63% (p = 0.01), for immediate and late responses, respectively. The low MK-571 dose also inhibited both responses but to a minor extent. Mean urinary LIE₄ excretion was elevated after antigen challenge and was unaffected by administration of the LTD₄ receptor antagonist. The present study demonstrates that MK-571 inhibits antigen-induced asthma in a dose-related fashion; it had no effect on antigen-induced increases in urinary LTE₄ excretions. The results suggest that LTD₄ receptor activation plays an important role in antigen-induced asthma.