Effect of BI-L-239, A-64077 and MK-886 on leukotriene B 4 synthesis by chopped guinea pig lung and on antigen-induced tracheal contraction [formula omitted

Abstract

The 5-lipoxygenase (5-LO) inhibitors BI-L-239 and A-64077 were compared with the 5-LO translocation inhibitor MK-886 for the ability to inhibit leukotriene B 4 (LTB 4) biosynthesis by chopped (1 mm 3) guinea pig lung. LTB 4 synthesis by ovalbumin-sensitized chopped lung tissue was determined after stimulation with either calcium ionophore (A23187) or antigen. With A23187 stimulation, MK-886 was more potent (IC 50 = 0.39 ± 0.23 μM, mean ± SEM, p<0.01) than BI-L-239 (IC 50 = 2.48 ± 0.46 μM) or A-64077 (IC 50 = 4.68 ± 0.70 μM) and BI-L-239 was more potent than A64077 (p<0.02). Thus, the order of potency was MK-886 > BI-L-239 > A-64077 for inhibition of calcium ionophore-induced LTB 4 generation. There was no significant differences in potency of the compounds in chopped lung stimulated with antigen: IC 50 for LTB 4 synthesis by A-64077 = 3.31 ± 1.70 μM, for BI-L-239 = 9.06 ± 4.94 μM, and for MK-886 = 13.33 ± 7.91 μM. The ability of these compounds to inhibit contraction of tracheal tissue from actively sensitized guinea pigs in response to antigen was also determined in the presence of indomethacin (15 μg/ml), mepyramine, and atropine (5 μg each/ml). Both 5-LO inhibitors inhibited antigen-induced contraction, with IC 50 values for BI-L-239 and A-64077 of 1.58 and 4.35 μM respectively. MK-886 was ineffective at inhibiting antigen-induced tracheal contraction in vitro at concentrations up to 30 μM. In summary, these compounds inhibit antigen-induced and A23187-induced leukotriene biosynthesis in guinea pig tissue. These 5-LO inhibitors were similarly effective at inhibiting antigen-induced tracheal contraction where MK-886 was ineffective.