Inhibition of allergen-induced bronchoconstriction in hyperreactive rats as a model for testing 5-lipoxygenase inhibitors and leukotriene D4 receptor antagonists.
Sensitized inbred hyperreactive rats showed reproducible episodes of dyspnea when exposed to aerosols of antigen. Following inhibition of the serotonin component of the response by pretreatment with methysergide, the model was shown to be useful for studying the oral activity of compounds that affect the production or action of leukotrienes. This was shown through inhibition of the duration of dyspnea by two selective 5-lipoxygenase inhibitors, L-651,392 and L-615,919, and two selective leukotriene D4 receptor antagonists, L-647,438 and L-649,923. Selectivity of the compounds could be demonstrated by reducing inhibition of the antigen response in the absence of methysergide and failure to inhibit serotonin-induced dyspnea. It is concluded that the model provides a reproducible method for screening large numbers of leukotriene inhibitors and antagonists and gives a measurement of their duration of biological activity.
Piechuta
H
H
Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec, Canada.
Ford-Hutchinson
A W
AW
Letts
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LG
D000485:Allergens / Q000276:immunology; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004417:Dyspnea / Q000503:physiopathology; D006967:Hypersensitivity / Q000276:immunology*; D016859:Lipoxygenase Inhibitors; D008784:Methysergide / Q000494:pharmacology; D051381:Rats; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects*
D000485:Allergens; D001993:Bronchodilator Agents; D016859:Lipoxygenase Inhibitors; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D001091:Arachidonate Lipoxygenases; D008784:Methysergide