Comparative effects of estrogen, raloxifene and tamoxifen on endothelial dysfunction, inflammatory markers and oxidative stress in ovariectomized rats.

AIM: Endothelial dysfunction is considered a premature indication of atherosclerosis and vessel damage and is present in the postmenopausal period. This study compares the influence of estrogen, raloxifene and tamoxifen on factors that affect endothelial function in ovariectomized (OVX) rats. MAIN METHODS: The rats were divided into: SHAM; OVX; OVX+estrogen (0.5 µg/kg/day); OVX+raloxifene (2 mg/kg/day) and OVX+tamoxifen (1 mg/kg/day) groups. The acetylcholine vasorelaxation response was evaluated in the mesenteric vascular bed. The vascular oxidative stress and serum inflammatory cytokine levels were monitored, and analyses of eNOS and iNOS were performed. KEY FINDINGS: The acetylcholine-induced responses obtained in the OVX were lower than those obtained in the SHAM, and all treatments restored this response. l-NAME reduced and equalized the acetylcholine-induced response in all groups. The attenuation of the acetylcholine-induced responses by aminoguanidine was greater in the OVX. Endothelial dysfunction in OVX was associated with oxidative stress and an increase in iNOS and decrease in eNOS expression. Except for the production of reactive oxidative species (ROS) in the OVX+tamoxifen, treatments improved the nitric oxide component of the relaxation response and normalized both the oxidative stress and the expression of those signaling pathway enzymes. Serum levels of TNF-α and IL-6 were increased in OVX, and treatments normalized these levels. SIGNIFICANCE: Raloxifene and tamoxifen have similar anti-inflammatory effects that may be important in improving vascular dysfunction. Tamoxifen did not affect the ROS but improved endothelial dysfunction. The protective effect on endothelial function by these treatments provides evidence of their potential cardiovascular benefits in the postmenopausal period.

Endothelial relaxation mechanisms and oxidative stress are restored by atorvastatin therapy in ovariectomized rats.

The studies on hormone replacement therapy (HRT) in females with estrogen deficiency are not conclusive. Thus, non-estrogen therapies, such as atorvastatin (ATO), could be new strategies to substitute or complement HRT. This study evaluated the effects of ATO on mesenteric vascular bed (MVB) function from ovariectomized (OVX) female rats. Female rats were divided into control SHAM, OVX, and OVX treated with 17ß-estradiol (EST) or ATO groups. The MVB reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine staining, and the expression of target proteins by western blot. The reduction in acetylcholine-induced relaxation in OVX rats was restored by ATO or EST treatment. The endothelium-dependent nitric oxide (NO) component was reduced in OVX rats, whereas the endothelium-derived hyperpolarizing factor (EDHF) component or prostanoids were not altered in the MVBs. Endothelial dysfunction in OVX rats was associated with oxidative stress, an up-regulation of iNOS and NADPH oxidase expression and a down-regulation of eNOS expression. Treatment with ATO or EST improved the NO component of the relaxation and normalized oxidative stress and the expression of those signaling pathways enzymes. Thus, the protective effect of ATO on endothelial dysfunction caused by estrogen deficiency highlights a significant therapeutic benefit for statins independent of its effects on cholesterol, thus providing evidence that non-estrogen therapy could be used for cardiovascular benefit in an estrogen-deficient state, such as menopause.