Relative potencies of 5-lipoxygenase inhibitors on antigen-induced contractions of guinea pig tracheal strips.
A quantitative method to assess relative potencies (IC50) of 5-lipoxygenase (5-LO) enzyme inhibitors was established in antigen-induced contractions of tracheas isolated from actively sensitized guinea pigs (Schultz-Dale model). The relative potencies of four purported 5-LO inhibitors determined in this tissue assay were compared with those from a crude enzyme preparation isolated from guinea pig neutrophils. All compounds suppressed ovalbumin (OA)-induced tracheal contractions in a concentration-related manner in the presence of indomethacin and pyrilamine. IC50 Values, determined from the percent inhibition values obtained from responses at 30 ng/mL OA of these compounds ranged from 0.56-15 microM. A similar rank order of potency for inhibition of 5-HETE formation from a crude enzyme preparation was observed. This suggested that these agents had a common mechanism of action in the two assay systems and further validated the IC50 values determined in trachea assay. LY171883, an LTD4/LTE4 receptor antagonist, also suppressed OA-induced contractions concentration dependently with an IC50 of 4.9 microM determined by this method. LTD4 concentration-response curves were not altered by any of the four 5-LO inhibitors, ruling out the possibility that these agents were acting as LT receptor antagonists. Results of this study demonstrated that relative potencies of 5-LO inhibitors can be quantitatively assessed using this airway tissue model, which helps in identifying potential therapeutic agents for asthma.
Cho
H L
HL
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Ho
P P
PP
Mihelich
E D
ED
Snyder
D W
DW
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000941:Antigens / Q000276:immunology; D001681:Biological Assay; D006168:Guinea Pigs; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D011971:Receptors, Immunologic / Q000187:drug effects; D018077:Receptors, Leukotriene; D013777:Tetrazoles / Q000494:pharmacology; D014132:Trachea / Q000276:immunology / Q000502:physiology*
D000098:Acetophenones; D000941:Antigens; D016859:Lipoxygenase Inhibitors; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013777:Tetrazoles; C044660:LY 171883; D010047:Ovalbumin