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 mu M, 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 mu M), 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.