Leukotriene-associated toxic oxygen metabolites induce airway hyperreactivity.
The effect of toxic oxygen metabolite scavengers was examined in a guinea pig trachealis model of leukotriene (LTD4)-induced synergism upon histamine contractures. Under both physiologic (2.5 mM) and low (OmM) extracellular calcium conditions, LTD4 (10(-7) to 10(-9) M) potentiated histamine isometric tension responses. This LTD4-induced histamine hyperresponse was inhibited by pretreatment with superoxide dismutase. Inhibition of LTD4 receptor binding by FPL 55712 (10(-5) M) also aborted this interaction. Actual trachealis superoxide anion (O2-) generation by LTD4 was observed with a maximal release of 15 nM O2-/CPK unit X 10(-2) over 60 min. Phorbol myristate acetate (PMA) also generated O2- in this preparation. Trachealis muscle hyperreactivity to histamine induced by 10(-8) M LTD4 assayed in OmM (Ca++)E was not induced by PMA. It is concluded that exogenous LTD4 activates toxic oxygen metabolites which interact to induce an acquired hyperreactivity to agonist histamine in trachealis smooth muscle.
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D010100:Oxygen / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000209:etiology* / Q000503:physiopathology; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000633:toxicity; D013481:Superoxides / Q000633:toxicity; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002867:Chromones; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D013481:Superoxides; D006632:Histamine; C006312:FPL 55712; D013482:Superoxide Dismutase; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen