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 contraction upon immunological challenge of isolated human bronchi was evaluated. Analysis of picomole amounts of leukotriene C4, D4, 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 responses leukotriene dependent only, the novel 5-lipoxygenase inhibitor 5,6-dihydroxy-2-(N,N-dimethylhydrazino)-1,2,3,4-tetrahydro-naphtalene bromide (CHF 1909) caused a concentration dependent inhibition of the immunologically induced contraction, showing an IC50 value of 13 ± 2.2 μM (mean ± CV). At the concentration of 30 μM, this compound caused more than 90% inhibition of the maximal bronchoconstriction in vitro, and inhibited cysteinyl leukotriene production by 90% as well. Contemporary measurement of immunologically induced contraction and production of cysteinyl leukotrienes in isolated human bronchi provided a direct: correlation between smooth muscle contraction and synthesis of leukotriene C4, D4, and E4.