EFFECTS OF CYCLOSPORINE-A AND DEXAMETHASONE ON HEMOSTATIC AND VASOACTIVE FUNCTIONS OF VASCULAR ENDOTHELIAL-CELLS

Glucocorticoids reduce prostaglandin synthesis in cultured vascular en dothelium, but their effects on other haemostatic functions are unclea r. We examined the effects of dexamethasone and cyclosporin A (CSA) on cultured human umbilical vein endothelial cells (HUVEC). One, 10 and 50 mu g/ml CSA and 1 mu g/ml dexamethasone (Dx) were added to the cult ure 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 tiss ue 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), thrombo spondin (TSP), von Willebrand factor (vWf) and ELISA of plasminogen ac tivator inhibitor 1 (PAI-1). CSA at 1 mu g/ml modestly reduced release of prostacyclin (PGI(2)) but had no reproducible effects on other met abolites. CSA at 10 and 50 mu g/ml inhibited cell growth and thrombin stimulated release of PGI(2) in a time- and dose-dependent manner. Inh ibition of other endothelial metabolites was also observed at CSA 10 > mu g/ml. Dexamethasone 1 mu g/ml reduced both cell number and PGI(2) 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 mu g/ml and dexamethasone 1 mu g/ml together were additive in reducing PGI(2) release and increasing PAI-1 secretion. These observations suggest a role for endothelial dysfunction in the hypertensive and thrombotic co mplications observed in steroid treated patients with CSA potentially contributing to such complications.