Endothelin-3 stimulates production of endothelium-derived nitric oxide via phosphoinositide breakdown.
Cultured bovine endothelial cells (EC) have specific receptors for endothelin (ET)-3 functionally coupled to phosphoinositide breakdown. We studied whether ET-3 stimulates synthesis of nitric oxide (NO), an endothelium-derived relaxing factor that activates soluble guanylate cyclase in EC, and whether the ET-3-induced NO formation involves G-proteins. ET-3 dose-dependently stimulated production of intracellular cGMP in EC, of which effects were abolished by pretreatment with NG-monomethyl L-arginine, an inhibitor of NO synthesis, and methylene blue, an inhibitor of soluble guanylate cyclase. The stimulatory effects of ET-3 on cGMP production, inositol trisphosphate formation and increase in cytosolic free Ca2+ concentration were similarly blocked by pretreatment with pertussis toxin (PTX). These data suggest that ET-3 induces synthesis of NO mediated by phosphoinositide breakdown via PTX-sensitive G-protein in EC.
Emori
T
T
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Hirata
Y
Y
Kanno
K
K
Ohta
K
K
Eguchi
S
S
Imai
T
T
Shichiri
M
M
Marumo
F
F
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000008:administration & dosage / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016232:Endothelins; D010716:Phosphatidylinositols; D010566:Virulence Factors, Bordetella; D009569:Nitric Oxide; D015544:Inositol 1,4,5-Trisphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D006152:Cyclic GMP; D002118:Calcium