Blockade of mineralocorticoid receptors improves salt-induced left-ventricular systolic dysfunction through attenuation of enhanced sympathetic drive in mice with pressure overload
Blockade of mineralocorticoid receptors improves salt-induced left-ventricular systolic dysfunction through attenuation of enhanced sympathetic drive in mice with pressure overload
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DOI：
10.1097/hjh.0b013e328338bb37
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发表时间：
2010-07-01
影响因子：
4.9
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Ito, Koji;Hirooka, Yoshitaka;Sunagawa, Kenji
目标 在压力超负荷模型中，交感神经活动因盐摄入量而增强。盐皮质激素受体和上皮钠通道（ENaC）被认为有助于钠的加工，但其潜在机制尚不清楚。在这里，我们研究了压力超负荷模型中大脑盐皮质激素受体-ENaC 通路对盐诱导交感神经激活的贡献。方法和结果进行主动脉结扎术以产生小鼠压力超负荷模型。主动脉结扎术 (AB-4) 4 周后，左心室 (LV) 壁厚度增加，但缩短百分比 (%FS) 没有变化。 AB-4 中的交感神经活动因 5 天高盐饮食而增加，但 Sham-4 中则不然。 AB-4 中的脑盐皮质激素受体、α ENaC 和血管紧张素 II 1 型受体 (AT1R) 表达水平高于 Sham-4。脑室内（ICV）输注依普利农（一种盐皮质激素受体阻滞剂）可阻断交感神经活性和这些蛋白质表达的增加。在另一个方案中，AB-4 小鼠再喂食高盐饮食 (AB-H) 4 周。 4 周时，与 Sham 组相比，AB-H 组的 %FS 降低，交感神经活动增加。 AB-H 组大脑中盐皮质激素受体和 AT1R 的表达高于 Sham 组。 AB-H 中 ICV 输注依普利酮可减弱盐诱导的交感神经兴奋并降低 %FS。 ICV 输注依普利农也降低了大脑 AT1R 的表达。 结论 这些发现表明，通过盐皮质激素受体激活大脑 α ENaC 和 AT1R 有助于获得 Na 敏感性以诱导交感神经兴奋。因此，在压力超负荷模型中，高盐摄入会加速交感神经激活和左心室收缩功能障碍。 J Hypertens 28：1449-1458 (C) 2010 Wolters Kluwer Health |利平科特·威廉姆斯和威尔金斯。
Objectives In a pressure overload model, sympathetic activity is augmented in response to salt intake. Mineralocorticoid receptors and epithelial Na channels (ENaCs) are thought to contribute to Na-processing, but the underlying mechanism is unknown. Here, we investigated the contribution of the brain mineralocorticoid receptor-ENaC pathway to salt-induced sympathetic activation in a pressure overload model.Methods and results Aortic banding was performed to produce a mouse pressure overload model. Four weeks after aortic banding (AB-4), left-ventricular (LV) wall thickness was increased without a change in percentage fractional shortening (%FS). Sympathetic activity increased in response to a 5-day high-salt diet in AB-4, but not in Sham-4. Brain mineralocorticoid receptor, alpha ENaC, and angiotensin II type 1 receptor (AT1R) expression levels were greater in AB-4 than in Sham-4. The increase in sympathetic activity and in the expression of these proteins was blocked by intracerebroventricular (ICV) infusion of eplerenone, a mineralocorticoid receptor blocker. In another protocol, AB-4 mice were fed a high-salt diet (AB-H) for 4 additional weeks. At 4 weeks, %FS was decreased and sympathetic activity was increased in AB-H compared with Sham. Expression of mineralocorticoid receptors and AT1R in the brain was higher in AB-H than in Sham. ICV infusion of eplerenone in AB-H attenuated salt-induced sympathoexcitation and the decreased %FS. ICV infusion of eplerenone also decreased brain AT1R expression.Conclusions These findings indicate that activation of brain alpha ENaC and AT1R through mineralocorticoid receptors contributes to the acquisition of Na sensitivity to induce sympathoexcitation. Therefore, high salt intake accelerates sympathetic activation and LV systolic dysfunction in a pressure overload model. J Hypertens 28: 1449-1458 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.