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 45Ca2+ 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 (FcepsilonRI) with antigen or by the endoplasmatic reticulum ATPase inhibitor thapsigargin, bypassing direct FcepsilonRI-related events. It appeared that astemizole (>15 microM), 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.
Fischer
M J
MJ
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmacy, Utrecht University, The Netherlands. M.J.E.Fischer@far.ruu.nl
Paulussen
J J
JJ
de Mol
N J
NJ
Janssen
L H
LH
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D016589:Astemizole / Q000494:pharmacology*; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects; D015471:Leukemia, Basophilic, Acute; D009532:Nickel / Q000494:pharmacology; D051381:Rats; D017455:Receptors, IgE / Q000187:drug effects; D019284:Thapsigargin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018926:Anti-Allergic Agents; D015220:Calcium Channels; D017455:Receptors, IgE; D001464:Barium; D019284:Thapsigargin; D016589:Astemizole; D009532:Nickel; D002118:Calcium