Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous α2 Na+-K+-ATPase knockout mice
Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous α2 Na+-K+-ATPase knockout mice
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DOI：
10.1152/ajpregu.00809.2007
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发表时间：
2009-05-01
影响因子：
2.8
通讯作者：
Van Huysse, James W.
中科院分区：
文献类型：
--
作者：
Hou, Xiaohong;Theriault, Steven F.;Van Huysse, James W.
首页--期刊主要分类--期刊细介绍--期刊题录与文摘--期刊详细文摘内容杂合子α(2)Na+-K+-ATPase基因敲除小鼠对升高的脑脊液钠浓度和对中枢Ang I的升压反应增强。Am J Physiol Regul Integr Comp Physiol 296：R1427-R1438,2009.2009年2月25日首次出版；doi：10.1152/ajpregu.00809.2007。-脑室(Icv)注入氯化钠模拟高盐饮食对盐敏感型高血压的影响，提高脑脊液(CSF[Na])中的钠浓度，随后增加大脑中内源性哇巴因类物质(OLS)的浓度。OLS反过来抑制大脑的Na+-K+-ATPase，导致大脑肾素-血管紧张素系统(RAS)活性和血压增加。介导脑脊液[Na]升高的升压反应的Na+-K+-ATPaseα(催化)-异构体(S)尚不清楚，但可能涉及一个或多个与哇巴因高亲和力结合的异构体(例如，Na+-K+-ATPaseα(2)-和/或α(3)-亚基)。我们假设OLS诱导的对α(2)亚单位的抑制介导了这一反应。因此，通过杂合基因敲除(α(2)+/-)导致的α(2)表达的慢性降低应该会增强对升高的脑脊液[Na]的升压反应。侧脑室注入含有0.225 M氯化钠的人工脑脊液使野生型(+/+)和α(2)+/-小鼠的平均动脉压(MAP)均升高，但在α(2)+/-小鼠中升高的幅度更大。同样，脑室注射哇巴因的升压反应在阿尔法(2)+/-小鼠中增强，显示出对脑内Na+-K+-ATPase抑制本身的敏感性增强。与α(2)+/+小鼠相比，脑室注射Ang I而不是Ang II的升压反应也增强，提示脑RAS活性增强可能是通过增加脑血管紧张素转换酶(ACE)来实现的。终板血管器的ACE配体结合增强支持了后一种假设。这些研究表明，杂合基因敲除导致Na+-K+-ATPaseα(2)亚型表达的慢性下调增加了对脑脊液[Na]升高的升压反应，并激活了脑RAS。由于这些变化类似于内源性大脑OLS所产生的变化，因此在脑脊液[Na]升高期间，例如在盐依赖型高血压中，大脑α(2)-亚型可能是大脑OLS的靶标。
Hou X, Theriault SF, Dostanic-Larson I, Moseley AE, Lingrel JB, Wu H, Dean S, Van Huysse JW. Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous alpha(2) Na+-K+-ATPase knockout mice. Am J Physiol Regul Integr Comp Physiol 296: R1427-R1438, 2009. First published February 25, 2009; doi:10.1152/ajpregu.00809.2007. - Intracerebroventricular (ICV) infusion of NaCl mimics the effects of a high-salt diet in salt-sensitive hypertension, raising the sodium concentration in the cerebrospinal fluid (CSF[Na]) and subsequently increasing the concentration of an endogenous ouabain-like substance (OLS) in the brain. The OLS, in turn, inhibits the brain Na+-K+-ATPase, causing increases in the activity of the brain renin-angiotensin system (RAS) and blood pressure. The Na+-K+-ATPase alpha (catalytic)- isoform(s) that mediates the pressor response to increased CSF [ Na] is unknown, but it is likely that one or more isoforms that bind ouabain with high affinity are involved (e.g., the Na+-K+-ATPase alpha(2)-and/ or alpha(3)-subunits). We hypothesize that OLS-induced inhibition of the alpha(2)-subunit mediates this response. Therefore, a chronic reduction in alpha(2) expression via a heterozygous gene knockout (alpha(2) +/-) should enhance the pressor response to increased CSF [Na]. Intracerebroventricular (ICV) infusion of artificial CSF containing 0.225 M NaCl increased mean arterial pressure ( MAP) in both wild-type (+/+) and alpha(2) +/- mice, but to a greater extent in alpha(2) +/-. Likewise, the pressor response to ICV ouabain was enhanced in alpha(2) +/- mice, demonstrating enhanced sensitivity to brain Na+-K+-ATPase inhibition per se. The pressor response to ICV ANG I but not ANG II was also enhanced in alpha(2) +/- vs. alpha(2) +/+ mice, suggesting an enhanced brain RAS activity that may be mediated by increased brain angiotensin converting enzyme (ACE). The latter hypothesis is supported by enhanced ACE ligand binding in the organum vasculosum laminae terminalis. These studies demonstrate that chronic downregulation of Na+-K+-ATPase alpha(2)-isoform expression by heterozygous knockout increases the pressor response to increased CSF [Na] and activates the brain RAS. Since these changes mimic those produced by the endogenous brain OLS, the brain alpha(2)-isoform may be a target for the brain OLS during increases in CSF [Na], such as in salt-dependent hypertension.