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Genetic Background and Underlying Mechanism in the Development of Postmenopausal Hypertension

绝经后高血压发生的遗传背景和潜在机制

基本信息

批准号：
07457126
负责人：
SARUTA Takao
金额：
$ 3.33万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Several epidemiological studies have shown that the incidence of cardiovascular disease rapidly increases after menopause. Hypertension is one of the main risk factors for cardiovascular disease, and there are gender differences in its prevalence. However, underlying mechanisms of sexual differences remain unclear. One of the most important clinical characteristics of postmenopausal hypertension is salt sensitivity.First, we attempted to establish a female salt-sensitive postmenopausal hypertensive model by ovariectomizing Dahl-Iwai salt-sensitive (DS) rats. Ovariectomy aggravated hypertension and platelet aggregation in DS rats. Estrogen supplement improved hypertension and platelet dysfunction. Systolic blood pressure was inversely correlated with 17beta-estradiol level and with uterus weight to body weight ratio.Second, we investigated the effect of ovariectomy on pressure-natriuresis by in vivo perfusion studies. The pressure-natriuresis relationship was blunted in ovariectomized DS rats.Third, we examined the effect of ovariectomy on intracellular Ca^<2+>. The internal Ca^<2+> discharge capacity was reduced. Systolic blood pressure was inversely correlated with the internal Ca^<2+> discharge capacity.Fourth, to clarify how platelet aggregation was enhanced in ovariectomized DS rats, we assessed the changes in platelet aggregation by adding a protein kinase C activator or an inhibitor of nitric oxide synthase. Platelet aggregation was proved to be augmented in ovariectomized DS rats by activating protein kinase C and by suppressing nitric oxide synthesis.We concluded that ovariectomy enhanced sodium-induced hypertension by blunting the pressure-natriuresis relationship, associated with the decreased internal Ca^<2+> discharge capacity and increased platelet aggregation through protein kinase C activation and the suppression of nitric oxide synthesis in DS rats.

一些流行病学研究表明，绝经后心血管疾病的发病率迅速增加。高血压是心血管疾病的主要危险因素之一，其患病率存在性别差异。然而，性别差异的潜在机制仍不清楚。盐敏感性是绝经后高血压最重要的临床特征之一，本研究首先通过切除卵巢的Dahl-Iwai盐敏感（DS）大鼠建立了一种雌性盐敏感性绝经后高血压模型。卵巢切除加重了DS大鼠的高血压和血小板聚集。补充雌激素可改善高血压和血小板功能障碍。收缩期血压与17 β-雌二醇水平和子宫重量与体重的比值呈负相关。第二，我们通过体内灌注研究探讨了卵巢切除术对压力-尿钠排泄的影响。在去卵巢的DS大鼠中，压力-尿钠排泄的关系减弱。第三，我们检测了去卵巢对细胞内Ca^<2+>的影响。内部Ca^<2+>放电容量降低。收缩压与体内Ca^<2+>释放量呈负相关。第四，为了阐明去卵巢DS大鼠血小板聚集是如何增强的，我们通过加入蛋白激酶C激活剂或一氧化氮合酶抑制剂来评估血小板聚集的变化。在去卵巢的DS大鼠中，通过激活蛋白激酶C和抑制一氧化氮的合成，血小板聚集被证实增加，我们得出结论，去卵巢通过钝化压力-钠尿关系，与减少的内部Ca^<2+>放电能力和通过激活蛋白激酶C和抑制一氧化氮的合成增加DS大鼠血小板聚集有关，从而增强钠诱导的高血压。