Peptidoleukotrienes may be important mediators of human
bronchial asthma. Accordingly, the effects of a selective
leukotriene (LT) biosynthesis inhibitor (MK-0591) were assessed in allergic dogs characterized by acute bronchoconstriction and subsequent
airway hyperresponsiveness induced by inhaled ragweed
allergen. Peak acute increases in airway resistance (Rrs) induced by ragweed were associated with increased bronchoalveolar lavage
histamine concentration, and neither parameter was inhibited by
MK-0591 (8 micrograms.kg-1.min-1 i.v.). However, the duration of the bronchoconstriction was significantly decreased by
MK-0591, with a reduction in the area under the curve of 40% (P < 0.05). Associated with the acute bronchoconstriction in placebo-treated animals was a fivefold increase in urinary
LTE4 excretion (as seen with allergic asthmatic patients), which was reduced to < 10% of basal values by
MK-0591. Similarly, whole blood
LTB4 biosynthesis was abolished in the MK-0591-treated animals. Bronchial hyperresponsiveness preallergen (measured as the percent concentration of acetylecholine required to increase Rrs by 5 cmH2O.l-1.s) tended to improve with
MK-0591 (0.41 +/- 0.15 vs. 0.23 +/- 0.05%). Five hours after
allergen inhalation, the percent concentration declined substantially in the placebo group (0.07 +/- 0.02%; P < 0.01), revealing an increased airway responsiveness that was significantly blunted by
MK-0591 (0.26 +/- 0.07%; P < 0.001). These data suggest that selective inhibition of LT biosynthesis by novel compounds such as
MK-0591 may modify the airway changes associated with bronchial hyperresponsiveness, as well as offer symptomatic relief in
asthma.