Hormonal Mechanisms of Postmenopausal Hypertension

妇女绝经后心血管疾病通常会增加。心血管疾病的主要危险因素之一是高血压，妇女在绝经后，血压逐渐升高。然而，绝经后血压升高的机制尚未阐明。肾素-血管紧张素系统（RAS）的激活、内皮素的增加和氧化应激是绝经后（PM）妇女的特征。雄激素也可能增加。进展 由于缺乏合适的动物模型，对PM高血压机制的阐明受到阻碍。在最近的研究中，我们的特点是老年女性自发性高血压大鼠（SHR）作为PM高血压的模型，因为他们表现出许多在PM女性中发现的体液特征。雌性SHR在10-12月龄停止周期性运动，血清雌二醇水平降低。到18个月时，与绝经前SHR相比，血压升高20-25 mm Hg。正如在PM女性中发现的，PM SHR表现出血浆肾素活性增加和肾血管收缩。在初步研究中， 降低PM大鼠的血压，暗示RAS在大鼠PM高血压中的作用。我们也有初步的数据表明，内皮素受体（ETA）拮抗剂减弱高血压，支持内皮素在高血压中的致病作用，如PM女性所示。氧化应激存在于PM SHR和PM女性中，并且慢性抗氧化剂治疗导致血压降低。已发现血清睾酮在某些绝经后妇女中升高， 雄激素连续测量超过10年。在PM SHR中，血清睾酮增加，并且在初步研究中，雄激素受体拮抗剂氟替卡松降低血压。因此，老年女性SHR密切类似于绝经后妇女的许多心血管特征，是研究PM高血压的合适模型。 基于我们的初步研究，总体工作假设是，PM大鼠血压升高是由血压-尿钠排泄关系向右偏移引起的，血压-尿钠排泄关系由肾素-血管紧张素系统激活介导，随后内皮素和氧化应激增加。我们还提出雄激素的增加通过激活肾RAS和内皮素系统并促进氧化应激而导致高血压。将采用生物化学、分子学和生理学技术的整合，在绝经前（4和8个月）或绝经后（18个月）的清醒、长期使用仪器的雌性SHR和Sprague道利大鼠以及年龄匹配的雄性SHR（18个月）中检验这些假设。具体而言，在目标1中，将检验RAS激活在介导PM SHR血压升高中起核心作用的假设。将在目标2中检验内皮素导致PM SHR血压升高以及血管紧张素II介导内皮素升高的假设。目的3：验证氧化应激在PM高血压中起重要作用，RAS和内皮素介导氧化应激的假说。最后，在目标4中，将确定雄激素在PM高血压中的作用。待检验的假设是雄激素通过激活RAS、刺激内皮素合成和氧化应激在PM高血压中发挥作用。

Women typically have increased cardiovascular disease following menopause. One of the major risk factors for cardiovascular disease is hypertension, and after menopause, blood pressure increases progressively in women. However, the mechanism(s) responsible for the post-menopausal increase in blood pressure are yet to be elucidated. Activation of the renin-angiotensin system (RAS), increases in endothelin, and oxidative stress are hallmarks that characterize postmenopausal (PM) women. Androgens may also be increased. Progress in elucidating the mechanisms responsible for PM hypertension has been hampered by the lack of a suitable animal model. In recent studies we have characterized the aging female spontaneously hypertensive rat (SHR) as a model of PM hypertension, since they exhibit many of the humoral characteristics found in PM women. Female SHR stop cycling at 10-12 mos of age and serum estradiol levels are decreased. By 18 mos of age, blood pressure is increased by 20-25 mm Hg, compared to pre-menopausal SHR. Just as found in PM women, PM SHR exhibit increased plasma renin activity and renal vasoconstriction. In preliminary studies losartan reduced the blood pressure in PM rats, implicating a role for the RAS in PM hypertension in the rat. We also have preliminary data indicating that endothelin receptor (ETA) antagonism attenuates the higher blood pressure which supports a causative role for endothelin in the hypertension, as suggested in PM women. Oxidative stress is present in PM SHR as in PM women, and chronic antioxidant treatment results in a reduction in blood pressure. Serum testosterone has been found to be increased in some postmenopausal women in whom androgens were measured serially over 10 years. In PM SHR, serum testosterone is increased, and in preliminary studies flutamide, an androgen receptor antagonist, reduces blood pressure. Thus the aging female SHR closely resembles many of the cardiovascular characteristics in postmenopausal women and is an appropriate model in which to study PM hypertension. Based on our preliminary studies the overall working hypothesis is that the increase in blood pressure in PM rats is caused by a shift to the right in the pressure-natriuresis relationship mediated by activation of the renin-angiotensin system with subsequent increases in endothelin and oxidative stress. We also propose that an increase in androgens contributes to the hypertension by activating, the renal RAS and endothelin system and promoting oxidative stress. These hypotheses will be tested in conscious, chronically instrumented female SHR and Sprague Dawley rats, that are pre-menopausal (4 and 8 mos) or postmenopausal (18 mos) and in age-matched male SHR (18 mos), by employing an integration of biochemical, molecular and physiological techniques. Specifically, in Aim 1, the hypothesis that activation of the RAS plays a central role in mediating the increase in blood pressure in PM SHR will be tested. The hypotheses that endothelin contributes to the increased blood pressure in PM SHR and that angiotensin II mediates the increase in endothelin will be tested in Aim 2. In Aim 3, the hypotheses that oxidative stress plays an important role in PM hypertension, and the RAS and endothelin mediate the oxidative stress will be tested. Finally, in Aim 4 the role that androgens play in PM hypertension will be determined. The hypotheses to be tested are that androgens play a role in PM hypertension by activating the RAS, stimulating endothelin synthesis and oxidative stress.