Effects of a 5-lipoxygenase Inhibitor (L-651,392) on Primary and Late Pulmonary Responses to Ascaris Antigen in the Squirrel Monkey

Allergic squirrel monkeys when exposed to an aerosol of Ascaris suum either develop a reproducible, immediate bronchoconstriction or an immediate bronchoconstriction followed by a reproducible late response. Pretreatment of ascaris-challenged squirrel monkeys with a potent, selective, orally active 5-lipoxygenase inhibitor, L-651,392 (4-bromo-2,7-dimethoxy-3,4-phenothizin-3-one), at a dose of 5 mg/kg p.o. resulted in near complete inhibition of the increases in pulmonary resistance (RL) and decreases in dynamic compliance (Cdyn) normally observed following exposure to the antigen. A lower dose (1 mg/kg p.o.) of L-651-392 produced only a significant inhibition of the decreases in Cdyn. In monkeys known to develop dual responses to antigen, L-651,392 (5 mg/kg p.o.) significantly attenuated the immediate response and markedly inhibited the late response. These results suggest an important role for leukotrienes in primary and late phase allergen-induced bronchoconstriction.