Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells.
We studied the inhibitory effects of heparin on basal and agonist-induced endothelin-1 biosynthesis and release from cultured bovine endothelial cells. Heparin dose-dependently and similarly inhibited endothelin-1 release, inositol trisphosphate production, and intracellular free Ca2+ levels stimulated by thrombin. Hirudin fragment had an inhibitory effect on thrombin-induced endothelin-1 release, whereas anti-thrombomodulin antibody had no effect. Heparin completely blocked phorbol ester-induced endothelin-1 release, whereas it had a partial inhibitory effect on endothelin-1 release stimulated by angiotensin and vasopressin. Northern blot analysis using complementary DNA for bovine preproendothelin-1 as a probe revealed that heparin reduced not only the basal but also the stimulated expression of preproendothelin-1 messenger RNA by thrombin and phorbol ester. These data suggest that heparin, in addition to its antithrombin effect, has an inhibitory effect on the biosynthesis and release of endothelin-1, possibly by inhibiting protein kinase C-dependent pathway.
Imai
T
T
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Hirata
Y
Y
Emori
T
T
Marumo
F
F
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016232:Endothelins; D006493:Heparin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate