Chronic effects of toremifene on the vasculature of menopause-induced rats

During menopause, women have a higher propensity for developing cardiovascular diseases. Recent studies have shown that treatment with selective estrogen receptor modulators (SERMs) improves cardiovascular status in menopausal women. The mechanisms involved, however, have not been elucidated. The present study evaluates the effect of toremifene (10 mg/kg/day), a new member of SERM family, on the vasculature of ovariectomized (Ovx) Sprague-Dawley rats that have been treated with the drug for a 4-week period. Age-matched sham, Ovx-untreated, and Ovx 17beta-estradiol-treated rats were used as controls. Aortic rings from treated and untreated animals were used to determine vascular responses to norepinephrine, acetylcholine, and sodium nitroprusside. Systolic blood pressure (SBP), plasmatic nitric oxide (NO) concentration, estrogen levels, aortic wall thickness, and cholesterol profiles were also determined. Toremifene displaces the concentration-response curve (CRC) for the acetylcholine-induced relaxation to the left and increases the Emax by 34% (from 59.2 +/- 4.2% in Ovx-untreated to 90.2 +/- 3.1% in Ovx-treated rats, n = 9, P < .05). Toremifene increases the Emax (by 22%) without modifying the EC5o for the NE-induced contraction. In addition, toremifene amplifies the relaxing responses to sodium nitroprusside compared to Ovx-untreated group (P < .05). SBP was significantly reduced in the Ovx toremifene-treated group when compared to the Ovx-untreated group (124 +/- 3.5 mm Hg for Ovx toremifene-treated vs. 161 +/- 4.3 mm Hg for Ovx-untreated, n = 10, P < .05). Rats treated chronically with toremifene also exhibited a significantly higher plasmatic NO levels, and a decrease in basal resting tension and aortic wall thickness. The drug, however, did not affect the plasmatic high-density lipoprotein (HDL)/total cholesterol ratio. These results suggest that chronic administration of toremifene improves cardiovascular performance in menopause-induced rats by reversing endothelial dysfunction and decreasing vascular resting tone. Thus, use of toremifene may help to diminish total peripheral resistance and improve cardiovascular status in Ovx rats.