Effects of the anti-allergics astemizole and norastemizole on FcεRI receptor-mediated signal transduction processes

The non-sedating anti-allergic drug astemizole, apart from its potential to antagonise H 1 receptors, inhibits the release of inflammation mediators from mast cells. To study the mechanism of this inhibition, we investigated the effects of astemizole and one of its active metabolites, norastemizole, on different phases of FcεRI (the high affinity receptor for the immunoglobulin IgE) receptor-activated signal transduction in rat basophilic leukemia cells (RBL-2H3), leading to exocytosis. Cells were stimulated either through antigen, or thapsigargin, or synergistic combinations of FcεRI receptor activation with either adenosine A 3 receptors or integrins, activated by fibronectin adherence. The effects of the drugs on mediator release, inositol 1,4,5-trisphosphate formation, tyrosine phosphorylation of cellular proteins and Ca 2+ fluxes were investigated. Inositol 1,4,5-trisphosphate levels are not affected. Astemizole increased tyrosine phosphorylation in resting cells, especially a 96-kDa protein band. Particularly tyrosine phosphorylation related to post Ca 2+ processes is changed after cell triggering in the presence of astemizole. Both drugs inhibit the influx of 45Ca 2+, with similar dose response curves as for the inhibition of exocytosis. Astemizole but not norastemizole, when used in resting cells, released Ca 2+ from intracellular stores. Astemizole (>15 μM) also induced exocytosis in resting cells. It did not induce additional changes in its inhibiting effect when cells were triggered with synergistic combinations of FcεRI receptor activation with either adenosine A 3 receptors or integrins. Effects on haemolysis of erythrocytes and differential scanning calorimetry in liposomes showed clear differences in membrane perturbation between astemizole and norastemizole. The observed differences, and the role of membrane perturbation in the action on Ca 2+ fluxes, are discussed. © 1997 Elsevier Science B.V. All rights reserved.