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CARDIOVASCULAR

Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta

Department of Pharmacological Sciences, University of Milan, Milan, Italy (C.P., C.B., P.S., V.P., R.B, A.Co., A.Ci.); and Department of Pharmacology and Anesthesiology, University of Padova, Padova, Italy (P.S., V.P., R.M.G., A.Ci.)

Previous studies reported the ability of raloxifene to acutely relax arterial and venous vessels, but the underlying mechanisms are controversial. Anti-inflammatory effects of the drug have been reported in nonvascular tissues. Therefore, the aim of this study was to investigate the nature of short- and long-term effects of raloxifene on selected aspects of vascular function in rat aorta. Isometric tension changes in response to raloxifene were recorded in aortic rings from ovariectomized female rats that underwent estrogen replacement, whereas long-term experiments were performed in isolated aortic smooth muscle cells (SMCs). Raloxifene (0.1 pM–0.1 µM) induced acute vasorelaxation through endothelium- and nitric oxide (NO)-dependent, prostanoid-independent mechanisms. The relaxant response to raloxifene was significantly weaker than that to 17-estradiol and was sensitive to neither the nonselective estrogen receptor antagonist ICI 182,780 [7,17-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol] nor a selective estrogen receptor (ER) antagonist. This rapid vasorelaxant effect was retained in aortic rings from rats treated with 0.1 mg/kg, but not 1 mg/kg, lipopolysaccharide, 4 h before sacrifice. In cultured aortic SMCs, raloxifene treatment (1 nM–1 µM) for 24 h reduced inducible NO synthase activation in response to cytokines. This effect was prevented by the selective ER antagonist and was associated with up-regulation of ER protein levels, which dropped markedly upon cytokine stimulation. These findings illustrate the relevance of classic ER-dependent pathways to the vascular anti-inflammatory effects rather than to the nongenomic vasorelaxation induced by raloxifene and may assist in the design of novel ER isoform-selective estrogen-receptor modulators targeted to the vascular system.

Address correspondence to: Dr. Andrea Cignarella, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail: andrea.cignarella{at}unimi.it