Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2147-53. doi: 10.1152/ajpheart.01216.2010. Epub 2011 Aug 19.
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 α(2)-isoform (α2(S/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 α2(S/S) versus knockout/knockin mice with a ouabain-resistant endogenous α(2)-subunit (α2(R/R)). In α2(R/R), there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The α2(R/R) genotype 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 α(2)-isoform of the Na,K-ATPase.
脑脊髓液（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展至关重要。这一概念与以下事实一致：通过向大鼠脑室内（icv）输注富含 NaCl 的人工 CSF（aCSF-HiNaCl）来慢性增加 CSF[NaCl]，会通过与盐敏感品系中饮食钠相同的机制（即脑内醛固酮-哇巴因途径）引起高血压。我们首先在此证明，icv aCSF-HiNaCl 连续 10 天也会引起野生型（WT）小鼠的高血压。然后，我们使用 WT 和基因靶向小鼠来探索这些机制。在具有哇巴因敏感的 Na,K-ATPaseα（2）同工型（α2（S/S））的 WT 小鼠中，在开始 aCSF-HiNaCl（0.6 nmol Na/min）的 2 天内，平均动脉压升高约 25mmHg，并在整个研究过程中保持升高。哇巴因（171 pmol/天 icv）使血压升高到相似程度。与 icv 相比，以相同速率皮下给予 aCSF-HiNaCl 或哇巴因对血压没有影响。通过 icv 给予抗哇巴因抗体可消除 icv aCSF-HiNaCl 引起的升压反应，但皮下给予则没有，表明它是由脑内内源性哇巴因样物质介导的。我们比较了 icv aCSF-HiNaCl 或 icv 哇巴因对 WT 与具有哇巴因抗性内源性α（2）亚基（α2（R/R））的α2（S/S）敲除/敲入小鼠血压的影响。在α2（R/R）中，与 WT 小鼠相比，icv aCSF-HiNaCl 没有引起升压反应。α2（R/R）基因型也没有对 icv 哇巴因产生升压反应。这些数据表明，慢性↑CSF[NaCl]可引起小鼠高血压，血压反应由脑内的哇巴因样物质介导，特别是通过其与 Na,K-ATPaseα（2）同工型结合介导。
