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Endothelial Function and Menopause: Effects of Raloxifene Administration

Departments of Gynecology and Obstetrics (N.C., F.F.), Geriatric Medicine, and Metabolic Diseases (D.M., M.C., G.P.), Second University of Naples, I-80138 Naples, Italy

Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, IV Internal Medicine, Piazza Miraglia 2, I-80138 Napoli, Italy. E-mail: giuseppe.paolisso{at}unina2.it.

Postmenopausal women have more severe endothelial dysfunction than premenopausal women. In the present study, we evaluated the possible beneficial effect of raloxifene administration, a selective estrogen receptor modulator, on endothelial regulation in postmenopausal women. In a double-blind, randomized vs. placebo trial, 60 healthy postmenopausal women were treated with raloxifene (60 mg/d) or placebo for 4 months to evaluate the effect of raloxifene treatment on endothelial function. Furthermore, in raloxifene-treated subjects (n = 30), the effect of raloxifene was also assessed during the intraarterial infusion of N^G-monomethyl-L-arginine (4 µmol/min). Raloxifene administration vs. placebo was associated with a decrease in plasma low-density lipoprotein cholesterol (P < 0.01), triglyceride (P < 0.05), thiobarbituric acid-reactive substance (P < 0.01), vascular cell adhesion molecule-1 (P < 0.05), intercellular adhesion molecule-1 (P < 0.001), and E-selectin (P < 0.001) levels and with an increase in plasma Trolox equivalent antioxidant capacity (P < 0.001) levels. Indeed, raloxifene treatment was also associated with a significant improvement in endothelial-dependent vasodilatation assessed by brachial reactivity technique. Raloxifene administration had no impact on endothelial-independent vasodilatation. Furthermore, intraarterial infusion of N^G-monomethyl-L-arginine inhibited the significant effect of raloxifene on endothelium-mediated brachial arterial diameter and flow. In conclusion, our results demonstrate that raloxifene administration is associated with a positive modulation of endothelial-dependent vasodilatation likely due to a reduction of risk factors for endothelial damage.

This work was supported by grants from Second University of Naples.

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; eNOS, endothelial NO synthase; HDL, high-density lipoprotein; ICAM-1, intercellular adhesion molecule-1; LDL, low-density lipoprotein; L-NMMA, N^G- monomethyl-L-arginine; NO, nitric oxide; TBARS, thiobarbituric acid-reactive substance; TEAC, Trolox equivalent antioxidant capacity; VCAM-1, vascular cell adhesion molecule-1; WHR, waist to hip ratio.

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