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.
Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec, Canada.
C S
CS
McFarlane
R
R
Hamel
A W
AW
Ford-Hutchinson
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001200:Ascaris / Q000276:immunology; D001980:Bronchi / Q000187:drug effects; D016859:Lipoxygenase Inhibitors; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D008297:Male; D010640:Phenothiazines / Q000494:pharmacology*; D012453:Saimiri; D013997:Time Factors
D000947:Antigens, Helminth; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; D001091:Arachidonate Lipoxygenases