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.
Department of Medicinal Chemistry, Utrecht Institute for Pharmaceutical Sciences, Faculty of Pharmacy, Utrecht University, The Netherlands. M.J.E.Fischer@far.ruu.nl
M J
MJ
Fischer
J J
JJ
Paulussen
N J
NJ
de Mol
L H
LH
Janssen
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