Estrogens are known to contribute to endothelial function and sympathetic activity, both of which are strongly associated with the pathogenesis of ischemic heart disease. In addition, estrogens improve impaired lipid profile, a risk factor of endothelial dysfunction. In this study, we investigated the effects of OS-0544, a structurally new selective estrogen receptor modulator (SERM), on endothelial function, sympathetic activity, and plasma cholesterol level in ovariectomized (OVX) rats. Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (or OS-0689, the (R)-enantiomer of OS-0544), or 17beta-estradiol (E2) for 4 weeks, starting the next days after ovariectomy or for 1 week, starting 6 weeks after ovariectomy. Ovariectomy significantly increased vasopressin-induced mean blood pressure (AVP-MBP) (57+/-3.3 mm Hg vs. 46+/-3.5 mm Hg, P<0.05) and decreased acetylcholine (Ach)-induced maximum vasorelaxation response (69+/-5.6% vs. 81+/-4.0%, P<0.05). OS-0544 significantly inhibited AVP-MBP elevation (46+/-3.5 mm Hg vs. 57+/-3.3 mm Hg, P<0.05) and decreased Ach-induced maximum vasorelaxation response (90+/-3.3% vs. 69+/-5.6%, P<0.05) in OVX rats. In addition, OS-0689 as well as E2 significantly reduced (up to 67%) the increase in sympathetic activity in OVX rats. Moreover, like E2, OS-0544 significantly decreased plasma cholesterol level in OVX rats. These results demonstrate that OS-0544 has vascular protective effect on vascular function after ovariectomy. It is therefore believed that OS-0544 has vascular protective effect in postmenopausal woman.
2005-08-16·Maturitas3区 · 医学
Effect of OS-0689, a novel SERM, on periarterial nerve function in tail arteries of ovariectomized rats
We have previously shown that OS-0689 attenuates the rise in tail skin temperature of ovariectomized rats, which is believed to be relevant to human symptoms of hot flush. In this study, we elucidate the mechanism underlying the ameliorating effects of OS-0689 on elevated tail skin temperature.
Female Sprague-Dawley rats were ovariectomized and orally treated with OS-0544 (1 mg/kg), OS-0689 (3 mg/kg; (+)-enantiomer of OS-0544) or 17beta-estradiol (3 mg/kg; E2) for 1 week. At 1, 3 or 6 weeks after ovariectomy, the vasoconstrictions and vasorelaxations induced by periarterial nerve stimulation (PNS), l-noradrenaline (NA), and rat calcitonin gene-related peptide (CGRP) in isolated tail arteries were compared between OVX and sham-operated rats.
Three weeks after ovariectomy, vasoconstrictions in response to PNS and NA in the arteries of OVX rats were markedly less than those in the arteries of sham-operated rats. However, at 1 and 6 weeks after ovariectomy the stimuli-induced vasoconstrictions in the arteries of OVX rats were greater than those of sham-operated rats. Moreover, NA reactivity was not attenuated in the mesenteric arteries at 3 weeks after ovariectomy. OS-0544, OS-0689 and E2 prevented the decrease in vasoconstrictions in the tail arteries. Vasorelaxations in response to PNS and rat CGRP were significantly greater in the arteries of OVX rats than in those of the sham-operated rats. OS-0689 inhibited the increase in vasorelaxation induced by both stimuli, whereas E2 had no effects.
Ovariectomy not only decreases adrenergic function but also enhances CGRPergic function in rats' tail arteries. OS-0689 improves both impairments and thereby improves on rat hot flush.