H1-antihistamines and calmodulin antagonists inhibit the ionophore A23187-induced eicosanoid formation by human leukocytes.

The effects of the H1-antihistamines astemizole, oxatomide and pyrilamine, of the calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), on the ionophore A23187 (5 mumol/l)-induced release of cysteinyl-leukotrienes (LT) and thromboxane (TX) B2 from mixed human leukocytes were investigated in comparison to those of the cyclooxygenase inhibitor indomethacin and the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA). In contrast to pyrilamine both astemizole and oxatomide inhibited the release of cysteinyl-LT and TXB2 with IC50 values between 4 and 23 mumol/l. Both astemizole and oxatomide were about twice as effective in inhibiting cysteinyl-LT release as compared to TXB2 release. Similar to astemizole and oxatomide the calmodulin antagonists trifluoperazine and W-7 inhibited the eicosanoid release. W-7 was, however, clearly less effective and in contrast to trifluoperazine no difference was observed in its potency to inhibit cysteinyl-LT or TXB2 release. The H1-antihistamines, astemizole and oxatomide as well as the calmodulin antagonists did not cause intracellular retention of the eicosanoids tested. The reference compounds indomethacin and NDGA proved to be the most potent inhibitors. The results demonstrate that the therapeutic antihistamines astemizole and oxatomide as well as the classical calmodulin antagonists trifluoperazine and W-7 are able to inhibit eicosanoid formation.