Inhibition of antigen-induced contraction of guinea pig trachea by ICI 198,615.
We examined the extent of peptide leukotrienes involvement in ovalbumin-induced contraction of guinea pig trachea isolated from animals passively sensitized with antiovalbumin antibodies. Antigen challenge resulted in a concentration-dependent (EC50 = 10 +/- 3 ng/ml, X +/- S.E.M., n = 6) and prolonged (greater than 60 min) contraction of guinea pig trachea. The maximal contractile response was directly proportional to the quantity of sensitizing antibodies. The maximal response (but not EC50 for ovalbumin) was significantly (P less than 0.01) enhanced by indomethacin (20%), only slightly (10%) inhibited by the histamine H1-antagonist pyrilamine and unaffected by the platelet-activating factor (PAF) antagonist CV-3988. The potent and selective leukotriene antagonist ICI 198,615 partially (45%) inhibited the antigen-induced contraction in a concentration-related fashion (1-300 nM). Even at concentrations that abolish responses to leukotrienes, ICI 198,615 did not further inhibit the response, nor could other leukotriene antagonists (i.e. LY 171883 or FPL 55712) inhibit more than 50% of this response. In contrast, the 5-lipoxygenase inhibitors AA-861 and REV 5901, also a leukotriene antagonist, abolished the contractile response. Taken together, the results suggest that in guinea pig trachea, leukotrienes, in combination with other lipoxygenase metabolites, mediate a major part of the response to antigen. In contrast, PAF, histamine and prostaglandins appear to play only a minor role.
Biomedical Research Department, ICI Pharmaceuticals Group, Wilmington, DE 19897.
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D000818:Animals; D000941:Antigens / Q000276:immunology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology*; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D011738:Pyrilamine / Q000494:pharmacology; D013189:SRS-A / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects
D000941:Antigens; D007191:Indazoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D011720:Pyrazoles; D013189:SRS-A; C054217:ICI 198615; C037913:CV 3988; D010047:Ovalbumin; D011738:Pyrilamine; D007213:Indomethacin