Vascular mechanism of action of endothelin-1: effect of Ca2+ antagonists.
The vasoconstrictive properties of the endothelium-derived peptide, endothelin-1 (ET-1), were investigated on rat isolated aorta and on cultured rat aortic smooth muscle cells. In rat isolated aorta, endothelin-1 induced a slow and sustained contraction in a Ca2+-free medium; after calcium readmission, an additional sustained contraction was elicited. In vascular smooth muscle cells, endothelin-1 provoked a dose-dependent Ca2+ influx that was not inhibited by calcium entry blockers (nifedipine, D 600, or diltiazem). In these cells, [125I]-endothelin-1 bound to a specific, saturable, and high affinity recognition site (Kd about 10(-9) M and Bmax = 52 +/- 2 fmol/10(6) cells). The binding was not reversible and not affected by calcium antagonists. These data do not support the hypothesis that endothelin-1 acts as an endogenous agonist of the voltage-dependent Ca2+ channels. The action of endothelin-1 can be separated into two components: one dependent on Ca2+ influx but insensitive to calcium antagonists and another independent of extracellular Ca2+. The irreversible binding of endothelin-1 may reflect an internalization of the ligand inside the cell membrane, leading to multiple contractile events.
Chabrier
P E
PE
Institut Henri Beaufour, Les Ulis, France.
Auguet
M
M
Roubert
P
P
Lonchampt
M O
MO
Gillard
V
V
Guillon
J M
JM
Delaflotte
S
S
Braquet
P
P
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002132:Calcium Radioisotopes; D002478:Cells, Cultured; D016232:Endothelins; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D016232:Endothelins; D007457:Iodine Radioisotopes; D010455:Peptides; D002118:Calcium