Dexamethasone potentiates production of inositol trisphosphate evoked by endothelin-1 in vascular smooth muscle cells.

To investigate the possibility of participation of glucocorticoids in the action of endothelin-1 (ET-1), the effect of glucocorticoids on ET-1-induced inositol trisphosphate (IP3) production was studied in cultured vascular smooth muscle cells (VSMC). ET-1 transiently increased IP3 in a dose-dependent manner. Pretreatment with 1 microM dexamethasone for 48 h shifted the dose-response curve of ET-1-induced IP3 production to the left; i.e., it significantly reduced the half-maximal effective concentration of ET-1 (from 50 to 10 nM). This action of dexamethasone required a minimum of 12 h of incubation. A glucocorticoid antagonist, RU 38486, completely blocked this effect. To elucidate the interaction with prostaglandin, we used indomethacin, a potent inhibitor of prostaglandin synthesis. Treatment with 1 microM indomethacin shifted the dose-response curve of ET-1-induced IP3 production to the left, but this shift was significantly less than that observed after treatment with dexamethasone and no additive effect between indomethacin and dexamethasone was noted. Glucocorticoids potentiate the IP3 production response to ET-1 in cultured VSMC, and this action of glucocorticoids depends partially on prostaglandin inhibition. These results suggest that glucocorticoids play an important role in modulation of ET-1 action.