Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α₂-isoform.
Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α₂-isoform.
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小鼠慢性中枢氯化钠引起的高血压是由 Na,K-ATP 酶 α-亚型上的哇巴因结合位点介导的。
DOI：
10.1152/ajpheart.01216.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Wu,Hengwei
中科院分区：
文献类型：
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作者：
VanHuysse,JamesW;Dostanic,Iva;Lingrel,JerryB;Hou,Xiaohong;Wu,Hengwei
脑脊液（CSF）中氯化钠浓度的慢性增加（↑CSF [NaCl]）似乎对盐依赖性高血压的发生至关重要。与这一概念一致，在大鼠中通过脑室内（icv）输注富含NaCl的人工CSF（aCSF-HiNaCl）慢性增加CSF [NaCl]通过相同的机制（即，脑中的醛固酮-哇巴因途径），如盐敏感菌株中由膳食钠产生的。我们在此首先证明icv aCSF-HiNaCl 10天也引起野生型（WT）小鼠的高血压。然后，我们使用WT和基因靶向小鼠来探索机制。在具有哇巴因敏感性Na，K-ATP酶α2-亚型（α2S/S）的WT小鼠中，在开始aCSF-HiNaCl（0.6 nmol Na/min）后2天内平均动脉压升高≥ 25 mmHg，并在整个研究期间保持升高。哇巴因（171 pmol/天icv）升高血压的程度相似。以相同速率皮下注射aCSF-HiNaCl或哇巴因而不是脑室内注射对血压没有影响。对icv aCSF-HiNaCl的升压反应被脑室内给予的抗哇巴因抗体而不是皮下给予的抗体消除，表明其由脑中的内源性哇巴因样物质介导。我们比较了icv aCSF-HiNaCl或icv哇巴因对具有哇巴因抗性内源性α2亚基（α 2 R/R）的α2S/S敲除/敲入小鼠血压的影响。在α 2 R/R中，与WT小鼠相比，icv aCSF-HiNaCl没有升压反应。α 2 R/R基因型也缺乏对icv哇巴因的加压反应。这些数据表明，慢性↑CSF [NaCl]导致小鼠高血压，血压反应由脑中的哇巴因样物质介导，特别是通过其与Na，K-ATP酶的α2-亚型结合。
A chronic increase in the concentration of sodium chloride in the cerebrospinal fluid (CSF) (↑CSF [NaCl]) appears to be critically important for the development of salt-dependent hypertension. In agreement with this concept, increasing CSF [NaCl] chronically by intracerebroventricular (icv) infusion of NaCl-rich artificial CSF (aCSF-HiNaCl) in rats produces hypertension by the same mechanisms (i.e., aldosterone-ouabain pathway in the brain) as that produced by dietary sodium in salt-sensitive strains. We first demonstrate here that icv aCSF-HiNaCl for 10 days also causes hypertension in wild-type (WT) mice. We then used both WT and gene-targeted mice to explore the mechanisms. In WT mice with a ouabain-sensitive Na,K-ATPase α2-isoform (α2S/S), mean arterial pressure rose by ∼25 mmHg within 2 days of starting aCSF-HiNaCl (0.6 nmol Na/min) and remained elevated throughout the study. Ouabain (171 pmol/day icv) increased blood pressure to a similar extent. aCSF-HiNaCl or ouabain given at the same rates subcutaneously instead of intracerebroventricularly had no effect on blood pressure. The pressor response to icv aCSF-HiNaCl was abolished by an anti-ouabain antibody given intracerebroventricularly but not subcutaneously, indicating that it is mediated by an endogenous ouabain-like substance in the brain. We compared the effects of icv aCSF-HiNaCl or icv ouabain on blood pressure in α2S/Sversus knockout/knockin mice with a ouabain-resistant endogenous α2-subunit (α2R/R). In α2R/R, there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The α2R/Rgenotype also lacked a pressor response to icv ouabain. These data demonstrate that chronic ↑CSF [NaCl] causes hypertension in mice and that the blood pressure response is mediated by the ouabain-like substance in the brain, specifically by its binding to the α2-isoform of the Na,K-ATPase.