Randomized, double-blind, placebo-controlled study on effects of raloxifene and hormone replacement therapy on plasma NO concentrations, endothelin-1levels, and endothelium-dependent vasodilation in postmenopausal women

The endothelium is thought to play an important role in the genesis of athe rosclerosis, and several lines of evidence suggest that the effect of an in tervention on endothelial function might predict its involvement in coronar y disease progression and in the rate of cardiovascular events. Estrogen ha s direct effects on the blood vessel wall, indicating that vascular endothe lium may play a key role in the cardiovascular protective effects of hormon e replacement therapy (HRT). Raloxifene relaxes coronary arteries in vitro by an estrogen receptor-dependent and NO-dependent mechanism, thus suggesti ng that this selective estrogen receptor modulator could also have benefici al effects on endothelial function. This study compared the effects of HRT and raloxifene on NO products, endothelin-1 plasma levels, and endothelium- dependent vasodilatation in postmenopausal women. Healthy postmenopausal wo men (n=90) were enrolled in a double-blind, randomized, placebo-controlled, 6-month trial. Women were randomly assigned to receive continuous HRT (1 m g 17 beta -estradiol combined with 0.5 mg norethisterone acetate), raloxife ne (60 mg/d), or placebo for 6 months. Flow-mediated endothelium-dependent vasodilation of the brachial artery, plasma NO concentrations, and endothel in levels were measured at baseline and after 6 months of therapy. The mean baseline level of NO breakdown products was 26.5 +/- 10.7 mu mol/L and inc reased to 36.3+/-11.4 mu mol/L after 6 months of treatment with raloxifene. The mean baseline plasma endothelin level was 17.3+/-8.9 pg/mL and decreas ed to 11.5+/-2.1 pg/mL after 6 months of treatment with the selective estro gen receptor modulator. The mean baseline ratio of NO (breakdown products) to endothelin was also significantly increased at the end of treatment with raloxifene. Postmenopausal women treated with HRT had similar changes in p lasma nitrites/nitrates and endothelin levels as well as in the ratio of NO to endothelin. In contrast, these markers of endothelial function did not change in the placebo-treated women. Flow-mediated endothelium-dependent va sodilation of the brachial artery was 8.3+/-2.1% at baseline and increased to 12.3+/-2.1% after 6 months of treatment with raloxifene. HRT also caused a significant and similar increase in flow-mediated endothelium-dependent vasodilation. No change in flow-mediated vasodilation was observed in the p articipants treated with placebo. We conclude that raloxifene therapy and H RT influence endothelial function and improve flow-mediated endothelium-dep endent vasodilation to a comparable extent in healthy postmenopausal women at least after a 6-month treatment period. However, further investigation i s warranted to enhance our understanding of the mechanisms of the effect of raloxifene on vascular function and to determine whether its effect on end othelial function may contribute to the reduction in cardiovascular-related morbidity and mortality.