COMPARATIVE-ANALYSIS OF ISOLATED HUMAN BRONCHI CONTRACTION AND BIOSYNTHESIS OF CYSTEINYL LEUKOTRIENES USING A DIRECT 5-LIPOXYGENASE INHIBITOR

Quantitation of cysteinyl leukotriene production and smooth muscle con traction upon immunological challenge of isolated human bronchi was ev aluated. Analysis of picomole amounts of leukotriene C-4, D-4, and E4 was achieved using HPLC separation and enzyme immunoassay quantitative determination. The aim of the study was to correlate the contraction of airway smooth muscle and cysteinyl leukotriene production with and without 5-lipoxygenase inhibition. In human isolated bronchial tissue treated with indomethacin and pyrilamine to make their contractile res ponses leukotriene dependent only, the novel 5-lipoxygenase inhibitor N-Dimethylhydrazino)-1,2,3,4-tetrahydro-naphtalene bromide (CHF 1909) caused a concentration-dependent inhibition of the immunologically ind uced contraction, showing an IC50 value of 13 +/- 2.2 mu M (mean +/- C V). At the concentration of 30 mu M, this compound caused more than 90 % inhibition of the maximal bronchoconstriction in vitro, and inhibite d cysteinyl leukotriene production by 90% as well. Contemporary measur ement of immunologically induced contraction and production of cystein yl leukotrienes in isolated human bronchi provided a direct correlatio n between smooth muscle contraction and synthesis of leukotriene C-4, D-4, and E-4.