Dexamethasone modulates the expression of endothelin-1 and -A receptors in A7r5 vascular smooth muscle cells.
Endothelin-1 (ET-1) is synthesized and released by vascular smooth-muscle cells (VSMCs). Glucocorticoids induce the release of ET-1 from VSMCs into the medium. We investigated whether glucocorticoids modulate ET-1 action by an autocrine production of ET-1 in A7r5 VSMCs. Dexamethasone (100 nM) stimulated the release of ET-1 into the medium. Treatment with 100 nM dexamethasone for 24 h reduced the peak increase of intracellular free Ca2+ induced by ET-1 (100 nM) by 50%, an effect that was dose-dependently inhibited by the specific ET(A)-receptor antagonist FR139317. Scatchard plots of [125I]-ET-1 binding revealed that dexamethasone reduced the number of maximal ET-1 binding sites without altering their binding affinity. FR139317 reversed the decrease in ET-1 binding capacity induced by dexamethasone. Northern blot analysis revealed that dexamethasone increased the level of prepro-ET-1 messenger RNA (mRNA) and decreased the level of ET(A)-receptor mRNA. FR139317 prevented the decrease in the level of ET(A)-receptor mRNA induced by dexamethasone. Results indicate that dexamethasone downregulates ET(A) receptors in A7r5 VSMCs at the mRNA level, in part by the autocrine production of ET-1.
The Third Department of Internal Medicine, Fukui Medical School, Japan.
Y
Y
Koshino
T
T
Hayashi
S
S
Matsukawa
K
K
Asazuma
K
K
Eguchi
H
H
Kato
T
T
Nakai
I
I
Miyamori
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D015536:Down-Regulation; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects* / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017466:Receptors, Endothelin / Q000235:genetics
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005938:Glucocorticoids; D007211:Indoles; D012333:RNA, Messenger; D017466:Receptors, Endothelin; C079574:FR 139317; D003907:Dexamethasone; D002118:Calcium