Selective estrogen receptor modulators, nitric oxide and vascular reactivity

The risk of cardiovascular diseases increases sharply after menopause. In this natural state of estrogen deficiency, hormone replacement therapy (HRT) may potentially delay the onset of cardiovascular disorders in postmenopausal women. Despite the epidemiological evidence showing that postmenopausal estrogen therapy is cardioprotective, estrogens are thought to induce breast and uterine cancer, as well as resumption of menses, mastodynia, and weight gain. Recent clinical trials found no overall therapeutic benefits of HRT since HRT actually increases the cardiovascular risks in some patients. In search for more selective estrogen substitutes, selective estrogen receptor modulators (SERMs) have been developed. SERMs act as estrogen receptor antagonists in the breast and uterus, devoid of harmful effects of estrogens, but preserve the beneficial effects of estrogen on bone, lipids, and cardiovascular system. Raloxifene, the 2nd-generation SERM, has been approved for the treatment of postmenopausal osteoporosis. The potential vascular beneficial effects of SERMs may lead to novel therapeutic strategies for the treatment of hypertension, stroke and atherosclerosis. However, the cellular and molecular mechanisms by which SERMs exert their vascular actions are incompletely understood although the vascular effects of estrogen have been extensively characterized. This study was therefore employed a combination of techniques to examine the above mechanisms. They include electrophysiology (standard two-electrode oocyte clamp), isometric force measurement, radioimmunoassay, measurement of nitrite content, Western blotting, and immunohistochemistry.; In conclusion, the present studies have provided the following lines of novel findings regarding the effects of sex steroid hormones and SERMs on the rat arteries. (i) 17beta-Estradiol non-genomically stimulates BKCa channels without effecting on KV1.5 channels; progesterone inhibits activities of both BKCa and KV1.5 channels. (ii) Raloxifene relaxed isolated rat aortas in large part via stimulation of inducible NO production, which is independent of the presence of the endothelium. This relaxant effect appears to be mediated through estrogen receptors involving genomic mechanisms. (iii) Raloxifene reverses free radicals-induced endothelial dysfunction likely by enhanced bioavailability of NO resulting from up-regulation of the eNOS protein expression in vitro. (iv) Chronic oral administration of raloxifene to aged Ovx female rats augmented both basal and agonist-stimulated release of endothelial NO in isolated aortic rings. The results of the present investigation further suggest the potential benefit of use of raloxifene in the treatment of endothelial dysfunction-dependent cardiovascular diseases.