IN-VITRO INHIBITION, BY LORATADINE AND DESCARBOXYETHOXYLORATADINE, OFHISTAMINE-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 meta bolite descarboxyethoxyloratadine upon histamine release was examined on anti-immunoglobulin E (IgE) triggered human basophils and 2,4-dinit rophenyl (DNP) triggered rat basophilic leukemia (RBL-2H3) cells. In b oth experimental systems, dose-dependent inhibition of histamine relea se was observed at descarboxyethoxyloratadine and loratadine doses abo ve 2 and 7 mu M, respectively. In the RBL-2H3 experimental system, inh ibition by loratadine increased when the concentration of extracellula r Ca2+ was reduced from 1.8 to 0.45 mM. We further investigated the ef fect of loratadine and descarboxyethoxyloratadine on the increase in c ytosolic 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 i nto RBL-2H3 cells passively sensitized with DNP-specific IgE. Both dru gs 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 o bserved in both the presence and absence of extracellular Ca2+. Lorata dine also inhibited the Mn2+ influx into these cells, thus reflecting the Ca2+ influx. These results suggest that loratadine and descarboxye thoxyloratadine impair the increase in (Ca2+)(i) following cell activa tion by decreasing both the influx of extracellular Ca2+ and the relea se of Ca2+ from intracellular stores.