Berthon B, Taudou G, Combettes L, Czarléwski W, Carmi-Leroy A, Marchand F, Weyer A
Unité de Physiologie et de Pharmacologie cellulaire, INSERM U 274, Université Paris-Sud, France.
Biochem Pharmacol. 1994 Mar 2;47(5):789-94. doi: 10.1016/0006-2952(94)90478-2.
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.
研究了H1抗组胺药氯雷他定及其活性代谢物去羧乙氧基氯雷他定对组胺释放的影响，实验对象为抗免疫球蛋白E（IgE）刺激的人嗜碱性粒细胞和2,4-二硝基苯基（DNP）刺激的大鼠嗜碱性白血病（RBL-2H3）细胞。在这两个实验系统中，分别在去羧乙氧基氯雷他定和氯雷他定剂量高于2 microM和7 microM时观察到组胺释放的剂量依赖性抑制。在RBL-2H3实验系统中，当细胞外Ca2+浓度从1.8 mM降至0.45 mM时，氯雷他定的抑制作用增强。我们进一步研究了氯雷他定和去羧乙氧基氯雷他定对胞质钙浓度（Ca2+）i升高的影响，（Ca2+）i升高是导致胞吐作用的生化事件的早期步骤。使用被动致敏于DNP特异性IgE的RBL-2H3细胞中加载的荧光探针fura-2测量这两种药物对（Ca2+）i变化的影响。两种药物均以剂量依赖性方式（2.5 - 25 microM）抑制了致敏RBL细胞中DNP-BSA激发诱导的（Ca2+）i升高，在有和没有细胞外Ca2+的情况下均观察到这一过程。氯雷他定还抑制了Mn2+流入这些细胞，从而反映了Ca2+流入。这些结果表明，氯雷他定和去羧乙氧基氯雷他定通过减少细胞外Ca2+流入和细胞内钙库中Ca2+的释放，损害了细胞活化后（Ca2+）i的升高。
