Role of leukotrienes in exercise-induced asthma. Inhibitory effect of ICI 204219, a potent leukotriene D4 receptor antagonist

The sulfidopeptide leukotrienes C4, D4, and E4 are released from mast cells in response to allergen challenge and may be involved in the bronchoconstrictor response to inhaled allergen in asthma. Since mast cell activation may also be implicated in exercise-induced bronchoconstriction, we assessed the inhibitory effects of a potent orally active leukotriene D4 receptor antagonist, ICI 204219 (20 mg), on the bronchoconstrictor response to exercise in eight male asthmatic patients in a placebo-controlled, randomized crossover study. Exercise challenge respiring dry air was performed on a treadmill at constant speed and gradient 2 h after drug administration, and bronchoconstriction was assessed as change in FEV1 over 30 min postexercise. No significant effect on airway caliber, measured as FEV1, was noted 2 h after ICI 204219. The mean maximum percentage fall in FEV1 following exercise was 36.0% following placebo, and reduced to 21.6% after ICI 204219 (p less than 0.01). Analysis of the time course of bronchoconstriction showed that inhibition was most marked over the latter part of the period assessed. These data indicate that the release of sulfidopeptide leukotrienes makes a major contribution to exercise-induced bronchoconstriction.