In vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (RBL-2H3).
The effect of the H1-antihistamine drug loratadine and its active metabolite descarboxyethoxyloratadine upon histamine release was examined on anti-immunoglobulin E (IgE) triggered human basophils and 2,4-dinitrophenyl (DNP) triggered rat basophilic leukemia (RBL-2H3) cells. In both experimental systems, dose-dependent inhibition of histamine release was observed at descarboxyethoxyloratadine and loratadine doses above 2 and 7 microM, respectively. In the RBL-2H3 experimental system, inhibition by loratadine increased when the concentration of extracellular Ca2+ was reduced from 1.8 to 0.45 mM. We further investigated the effect of loratadine and descarboxyethoxyloratadine on the increase in cytosolic calcium concentration (Ca2+)i, an early step in biochemical events leading to exocytosis. The effect of these two drugs upon (Ca2+)i changes was measured using the fluorescent probe fura-2 loaded into RBL-2H3 cells passively sensitized with DNP-specific IgE. Both drugs inhibited, in a dose-dependent manner (2.5-25 microM), the (Ca2+)i rise induced by DNP-BSA challenge in sensitized RBL cells, a process observed in both the presence and absence of extracellular Ca2+. Loratadine also inhibited the Mn2+ influx into these cells, thus reflecting the Ca2+ influx. These results suggest that loratadine and descarboxyethoxyloratadine impair the increase in (Ca2+)i following cell activation by decreasing both the influx of extracellular Ca2+ and the release of Ca2+ from intracellular stores.
Berthon
B
B
Unité de Physiologie et de Pharmacologie cellulaire, INSERM U 274, Université Paris-Sud, France.
Taudou
G
G
Combettes
L
L
Czarléwski
W
W
Carmi-Leroy
A
A
Marchand
F
F
Weyer
A
A
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D004136:Dinitrobenzenes / Q000494:pharmacology; D004140:Dinitrophenols / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D066298:In Vitro Techniques; D015471:Leukemia, Basophilic, Acute / Q000378:metabolism*; D017336:Loratadine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C045618:2,4-dinitrophenyl-IgG; D000888:Antibodies, Anti-Idiotypic; D004136:Dinitrobenzenes; D004140:Dinitrophenols; D007074:Immunoglobulin G; C026408:anti-IgE antibodies; C086094:des(ethoxycarbonyl)loratadine; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D017336:Loratadine; D002118:Calcium