Effects of cyclosporin A and dexamethasone on haemostatic and vasoactive functions of vascular endothelial cells.
Glucocorticoids reduce prostaglandin synthesis in cultured vascular endothelium, but their effects on other haemostatic functions are unclear. We examined the effects of dexamethasone and cyclosporin A (CSA) on cultured human umbilical vein endothelial cells (HUVEC). One, 10 and 50 micrograms/ml CSA and 1 microgram/ml dexamethasone (Dx) were added to the culture medium for 3 h, 3 days and 6 days and compared with HUVEC cultured in medium and serum alone. After assay of accumulated release of tissue type plasminogen activator (t-PA) and endothelin 1 (ET), cells were stimulated with 1 U/ml of human thrombin for 1 h and medium collected for RIA of 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), thrombospondin (TSP), von Willebrand factor (vWf) and ELISA of plasminogen activator inhibitor 1 (PAI-1). CSA at 1 microgram/ml modestly reduced release of prostacyclin (PGI2) but had no reproducible effects on other metabolites. CSA at 10 and 50 micrograms/ml inhibited cell growth and thrombin stimulated release of PGI2 in a time- and dose-dependent manner. Inhibition of other endothelial metabolites was also observed at CSA 10 > micrograms/ml. Dexamethasone 1 microgram/ml reduced both cell number and PGI2 release and increased thrombin stimulated release of vWf, TSP and PAI-1 with increases in t-PA and endothelin 1 in the medium. CSA 1 microgram/ml and dexamethasone 1 microgram/ml together were additive in reducing PGI2 release and increasing PAI-1 secretion. These observations suggest a role for endothelial dysfunction in the hypertensive and thrombotic complications observed in steroid treated patients with CSA potentially contributing to such complications.
Huang
L Q
LQ
Department of Medicine, St George Hospital, NSW, Australia.
Whitworth
J A
JA
Chesterman
C N
CN
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016572:Cyclosporine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D011464:Epoprostenol / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D019699:Thrombospondins; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014471:Umbilical Veins; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism
D015815:Cell Adhesion Molecules; D017077:Culture Media, Conditioned; D016232:Endothelins; D008562:Membrane Glycoproteins; D017395:Plasminogen Activator Inhibitor 1; D019699:Thrombospondins; D014841:von Willebrand Factor; D015121:6-Ketoprostaglandin F1 alpha; D003907:Dexamethasone; D016572:Cyclosporine; D011464:Epoprostenol; D013917:Thrombin; D010959:Tissue Plasminogen Activator