Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor

Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'A/Q') imbalance. However it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'A/Q disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D-4 inhalation challenge. Gas exchange, including V'A/Q' descriptors were measured at baseline, 3 h after montelukast/placebo pretreatment and 5, 15 and 45 min after the LTD4 challenge. Compared with montelukast, inhalation of LTD4 induced a marked fall in forced expiratory volume in one second (mean +/- SE 33 +/- 2%) and profound V'A/Q' mismatching, reflected by a decreased arterial oxygen tension (from 100 +/- 4 to 75 +/- 3 mmHg) and an increased overall index of V'A/Q' heterogeneity dispersion of retention minus excretion inert gases corrected for dead space (from 4.9 +/- 1.2 to 8.4 +/- 1.1; normal <= 3.0; dimensionless), 5 min after placebo. Following montelukast, LTD4 produced no significant changes in any of the variables. In conclusion, these findings point to the view that leukotriene D-4-induced gas exchange disturbances and bronchoconstriction are both mediated by the cysteinyl-leukotriene, receptor.