Raloxifene acutely stimulates nitric oxide release from human endothelial cells via an activation of endothelial nitric oxide synthase

Raloxifene is a selective estrogen receptor modulator (SERM) clinically eff ective for the prevention of postmenopausal osteoporosis. Estrogen's effect on cardiovascular diseases is mainly dependent on direct actions on the va scular wall. Since raloxifene has an endothelium-dependent relaxing effect, we studied the effects of this molecule on nitric oxide (NO) release from cultured human umbilical vein endothelial cells. Clinically effective conce ntrations of the compound triggered a rapid and dose-dependent release of N O from endothelial cells. Raloxifene-induced NO production was dependent on an estrogen receptor-mediated mechanism, since it was abolished by the pur e estrogen receptor antagonist ICI 182,780. Treatment of endothelial monola yers with raloxifene was not associated with changes in endothelial nitric oxide synthase (eNOS) messenger RNA or protein, showing that raloxifene doe s not increase NO release through a transcriptional increase of eNOS. Indee d, raloxifene-induced NO production is due to an estrogen receptor-dependen t acute stimulation of eNOS enzymatic activity. Tn conclusion, raloxifene a ctivates eNOS in human endothelial cells, exerting a potentially important direct vasculo-protective effect stimulating endothelial NO production.