Genetic Background and Underlying Mechanism in the Development of Postmenopausal Hypertension

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。首先，我们试图通过切除Dahl-Iwai盐敏感(DS)大鼠的卵巢来建立雌性盐敏感的绝经后高血压模型。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。收缩压与17β-雌二醇水平及子宫重量/体重比值呈负相关。第二，通过体内灌流研究卵巢切除对血压-钠排泄的影响。在去卵巢的DS大鼠中，血压-钠尿关系被钝化。第三，我们检测了去卵巢对细胞内钙离子的影响。内部钙容量降低。收缩压与体内钙排泄量呈负相关。第四，为了阐明去卵巢DS大鼠的血小板聚集是如何增强的，我们通过添加蛋白激酶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。去卵巢DS大鼠的血小板聚集性通过激活蛋白激酶C和抑制一氧化氮合成而增强。我们得出结论：去卵巢通过钝化压力-钠尿关系而增强钠诱导的高血压，并通过蛋白激酶C激活和抑制一氧化氮合成而增加血小板聚集性。

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.