EFFECTS OF THE ANTI-ALLERGIES ASTEMIZOLE AND NORASTEMIZOLE ON FC-EPSILON-RI RECEPTOR-MEDIATED SIGNAL-TRANSDUCTION PROCESSES

The non-sedating anti-allergic drug astemizole, apart from its potenti al to antagonise H-1 receptors, inhibits the release of inflammation m ediators from mast cells. To study the mechanism of this inhibition, w e investigated thy effects of astemizole and one of its active metabol ites, norastemizole, on different phases of Fc epsilon RI (the high af finity receptor for the immunoglobulin IgE) receptor-activated signal transduction in rat basophilic leukemia cells (RBL-2H3), leading to ex ocytosis. Cells were stimulated either through antigen, or thapsigargi n, or synergistic combinations of Fc epsilon RI receptor activation wi th either adenosine A(3) receptors or integrins, activated by fibronec tin adherence. The effects of the drugs on mediator release, inositol 1,4,5-trisphosphate formation, tyrosine phosphorylation of cellular pr oteins and Ca2+ fluxes were investigated. Inositol 1,4,5-trisphosphate levels are not affected. Astemizole increased tyrosine phosphorylatio n in resting cells, especially a 96-kDa protein band. Particularly tyr osine phosphorylation related to post Ca2+ processes is changed after cell triggering in the presence of astemizole. Both drugs inhibit the influx of Ca-45(2+), with similar dose response curves as for the inhi bition of exocytosis. Astemizole but not norastemizole, when used in r esting cells, released Ca2+ from intracellular stores. Astemizole (> 1 5 mu M) also induced exocytosis in resting cells. It did not induce ad ditional changes in its inhibiting effect when cells were triggered wi th synergistic combinations of Fc epsilon RI receptor activation with either adenosine A(3) receptors or integrins. Effects on haemolysis of erythrocytes and differential scanning calorimetry in liposomes showe d clear differences in membrane perturbation between astemizole and no rastemizole. The observed differences, and the role of membrane pertur bation in the action on Ca2+ fluxes, are discussed. (C) 1997 Elsevier Science B.V.