Inhibition of exercise-induced bronchoconstriction by mk-571, a potent leukotriene D₄–receptor antagonist

Background. Exercise is a common stimulus of bronchoconstriction in subjects with asthma, who also have bronchoconstriction after inhaling the sulfidopeptide leukotriene D₄ (LTD₄). The purpose of this study was to investigate the importance of LTD₄ as a mediator of exercise-induced bronchoconstriction. Methods. In a double-blind, randomized, crossover study, 12 subjects with stable asthma were treated intravenously with MK-571 (160 mg), a selective and potent LTD₄-receptor antagonist, or placebo, 20 minutes before each of two challenges involving exercise at a level previously demonstrated to cause a fall of at least 20 percent in the forced expiratory volume in one second (FEV₁). The two exercise challenges were separated by one week. The results of the challenges were expressed as both the maximal fall in FEV₁ after exercise and the time to recovery from bronchoconstriction. Results. Treatment with MK-571 attenuated exercise-induced bronchoconstriction in all the subjects. The mean (±SEM) maximal percent decrease in FEV₁ after exercise was 25.2±3.5 percent in the subjects taking placebo and 9.2±2.5 percent in the subjects taking MK-571 (P<0.001). Conclusions. The mean percent inhibition for the entire group was 69.5 percent. The mean time to recovery after exercise was 33.4±4.0 minutes in the placebo group and 8.4±2.5 minutes in the MK-571 group (P<0.001). This study demonstrates that pretreatment with a potent and selective LTD₄ antagonist markedly attenuates exercise-induced bronchoconstriction, and it suggests that LTD₄ is a major mediator of this type of bronchoconstriction. (N Engl J Med 1990; 323: 1736–9.).