Dual effect of the anti-allergic astemizole on Ca2+ fluxes in rat basophilic leukemia (RBL-2H3) cells:: Release of Ca2+ from intracellular stores and inhibition of Ca2+ release-activated Ca2+ influx

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 Ca-45(2+) influx. Here, we present a more detailed study on the effects of astemizole and norastemizole on Ca2+ fluxes. Fura-2-loaded rat basophilic leukemia (RBL-2H3) cells were activated through the high-affinity receptor for IgE (Fc epsilon RI) with antigen or by the endoplasmatic reticulum ATPase inhibitor thapsigargin, bypassing direct Fc epsilon RI-related events. It appeared that astemizole (>15 mu M), in contrast to norastemizole, showed a dual effect on intracellular calcium concentration ([Ca2+](i)): a rise in intracellular calcium concentration was induced, which originated in the release of intracellular Ca2+ stores,whereas Ca2+ influx via store-operated Ca2+ (SOC) channels was inhibited. Ca2+ influx was further characterized using Ba2+ influx, whereas processes in the absence of Ca2+ influx were studied using Ni2+ or EGTA. It was concluded that the drugs most likely affect the store-operated Ca2+ channels in RBL cells directly. The two effects of astemizole on Ca2+ fluxes had opposing influences on exocytosis, thereby accounting for the biphasic effect of increasing astemizole concentration on mediator release in RBL cells. (C) 1998 Elsevier Science Inc.