DEXAMETHASONE MODULATES THE EXPRESSION OF ENDOTHELIN-1 AND ENDOTHELIN-A RECEPTORS IN A7R5 VASCULAR SMOOTH-MUSCLE CELLS

Endothelin-l (ET-1) is synthesized and released by vascular smooth-mus cle cells (VSMCs). Glucocorticoids induce the release of ET-1 from VSM Cs into the medium. We investigated whether glucocorticoids modulate E T-1 action by an autocrine production of ET-1 in A7r5 VSMCs. Dexametha sone (100 nM) stimulated the release of ET-1 into the medium. Treatmen t with 100 nM dexamethasone for 24 h reduced the peak increase of intr acellular free Ca2+ induced by ET-1 (100 nM) by 50%, an effect that wa s dose-dependently inhibited by the specific ETA-receptor antagonist F R139317. Scatchard plots of [(125)]-ET-1 binding revealed that dexamet hasone reduced the number of maximal ET-1 binding sites without alteri ng their binding affinity. FR139317 reversed the decrease in ET-1 bind ing capacity induced by dexamethasone. Northern blot analysis revealed that dexamethasone increased the level of prepro-ET-l messenger RNA ( mRNA) and decreased the level of ETA-receptor mRNA. FR139317 prevented the decrease in the level of ETA-receptor mRNA induced by dexamethaso ne. Results indicate that dexamethasone downregulates ETA receptors in A7r5 VSMCs at the mRNA level, in part by the autocrine production of ET-1.