Endothelin receptor regulation by endothelin synthesis in vascular smooth muscle cells: effects of dexamethasone and phosphoramidon.
One of the major biological effects of the endothelium-derived peptide endothelin-1 (ET-1) is its receptor-mediated constrictive action on vascular smooth muscle. In this study, we have examined the effects on the ET-1 pathway of 18 h exposure at 37 degrees C of cultured rat aortic smooth muscle cells to dexamethasone (DEX) and phosphoramidon. ET-1 synthesis was evaluated by radioimmunoassay, ET-1 binding characteristics were determined with [125I]iodo-ET-1, and ET-1-induced intracellular calcium mobilization was measured using fura-2-loaded cells. DEX (100 nM) led to a 2- to 3-fold-increase of ET-1 production, it down-regulated ET-1 receptors and reduced ET-1-stimulated calcium mobilization by 70%. In contrast, phosphoramidon (100 microM) inhibited ET-1 production by 60%, up-regulated ET-1 receptors and potentiated ET-1-induced calcium mobilization by 75%. These results indicate that the regulatory effects of DEX and phosphoramidon on ET-1 receptors are mediated via ET-1 production by the cells. This suggests an autocrine control of ET-1 receptors by endogenous ET-1 synthesis in vascular smooth muscle cells.
Institut Henri Beaufour, Les Ulis, France.
P
P
Roubert
I
I
Viossat
M O
MO
Lonchampt
M
M
Chapelat
J
J
Schulz
P
P
Plas
V
V
Gillard-Roubert
P E
PE
Chabrier
P
P
Braquet
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D016232:Endothelins / Q000096:biosynthesis* / Q000502:physiology; D005246:Feedback; D006020:Glycopeptides / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism*
D016232:Endothelins; D006020:Glycopeptides; D017466:Receptors, Endothelin; D003907:Dexamethasone; D002118:Calcium; C008890:phosphoramidon