Effects of benzodiazepines on serotonin release from rat mast cells

Ro5-4864, diazepam and chlordiazepoxide inhibited the concanavalin A-induced [14C]serotonin release from rat mast cells dose dependently with IC30 values 38, 115 and 160 microM, respectively. They also inhibited concanavalin A-induced 45Ca uptake, with IC50 values 180, 860 and 1800 microM, respectively. Clonazepam slightly inhibited serotonin release, but medazepam did not, and neither compound inhibited the calcium uptake stimulated by concanavalin A. The potencies of benzodiazepines to inhibit concanavalin A-induced serotonin release and 45Ca uptake were correlated with their binding affinities to the peripheral type of benzodiazepine binding sites. At higher concentrations, these benzodiazepines caused release of both serotonin and lactate dehydrogenase, due to their cytotoxicity. The calcium channels of mast cells are probably not voltage-dependent, as the agonists of voltage-dependent calcium channels, Bay k 8644 and YC-170, did not stimulate serotonin release. Moreover, Ro5-4864, diazepam and chlordiazepoxide inhibited A23187-induced serotonin release. Mast cells have high contents of calmodulin (602 +/- 20 ng/10(6) cells), and benzodiazepines inhibited calmodulin. The benzodiazepine inhibitory effects on the serotonin release induced by A23187 seemed to be partly due to their calmodulin-inhibiting activities. These results suggest that inhibition of serotonin release by benzodiazepines in mast cells activated by concanavalin A is mainly due to inhibition of calcium channels, which may be controlled by the peripheral type of benzodiazepine binding sites.