Leukotriene D 4 receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma

Abstract

We have tested the hypothesis that leukotriene D 4 (LTD 4) 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 LTD 4 receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV 1 was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE 4; 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 FEV 1 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 LIE 4 excretion was elevated after antigen challenge and was unaffected by administration of the LTD 4 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 LTE 4 excretions. The results suggest that LTD 4 receptor activation plays an important role in antigen-induced asthma.