5-Lipoxygenase inhibitors and allergic conjunctivitis reactions in the guinea-pig.
The role of leukotrienes as mediators of microvascular permeability changes (assessed through the accumulation of [99mTc]albumin) associated with immediate hypersensitivity reactions in the guinea-pig conjunctiva was investigated by means of two novel, structurally dissimilar 5-lipoxygenase inhibitors, L-651,392 and L-651,896. Both compounds, when applied topically in vivo to the eyes of sensitized guinea-pigs as a 0.1% suspension significantly inhibited 5-lipoxygenase in the conjunctiva as assessed by ex vivo challenge with either antigen or ionophore A23187 and measurement of the release of leukotriene B4-immunoreactive material. Topical application of antigen (either single challenge or 2 challenges separated by 24 h) to the eyes of sensitized guinea-pigs produced changes in conjunctival permeability which were blocked in part by either mepyramine (H1-receptor antagonist) or the 5-lipoxygenase inhibitors. Combinations of mepyramine and L-651,896 resulted in near complete suppression of the permeability response, suggesting that the reaction is mediated only by histamine and leukotrienes.
Garceau
D
D
Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec, Canada.
Ford-Hutchinson
A W
AW
Charleson
S
S
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D003233:Conjunctivitis, Allergic / Q000276:immunology / Q000503:physiopathology*; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000502:physiology*; D016859:Lipoxygenase Inhibitors; D008297:Male; D010640:Phenothiazines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D013189:SRS-A / Q000502:physiology*
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; D013189:SRS-A; D007975:Leukotriene B4; D000001:Calcimycin; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one; C053727:L 651896; D001091:Arachidonate Lipoxygenases; D011738:Pyrilamine