Abstract
The antiallergic drugs astemizole and norastemizole inhibit exocytosis in mast cells, which might be relevant for their therapeutic action. From previous studies, it appeared that the drugs inhibited 45Ca 2+ influx. Here, we present a more detailed study on the effects of astemizole and norastemizole on Ca 2+ fluxes. Fura-2-loaded rat basophilic leukemia (RBL-2H3) cells were activated through the high-affinity receptor for IgE (FcϵRI) with antigen or by the endoplasmatic reticulum ATPase inhibitor thapsigargin, bypassing direct FcϵRI-related events. It appeared that astemizole (>15 μM), in contrast to norastemizole, showed a dual effect on intracellular calcium concentration ([Ca 2+] i): a rise in intracellular calcium concentration was induced, which originated in the release of intracellular Ca 2+ stores, whereas Ca 2+ influx via store-operated Ca 2+ (SOC) channels was inhibited. Ca 2+ influx was further characterized using Ba 2+ influx, whereas processes in the absence of Ca 2+ influx were studied using Ni 2+ or EGTA. It was concluded that the drugs most likely affect the store-operated Ca 2+ channels in RBL cells directly. The two effects of astemizole on Ca 2+ fluxes had opposing influences on exocytosis, thereby accounting for the biphasic effect of increasing astemizole concentration on mediator release in RBL cells.
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