Hou Xiaohong, Theriault Steven F, Dostanic-Larson Iva, Moseley Amy E, Lingrel Jerry B, Wu Hengwei, Dean Stephanie, Van Huysse James W
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7.
Am J Physiol Regul Integr Comp Physiol. 2009 May;296(5):R1427-38. doi: 10.1152/ajpregu.00809.2007. Epub 2009 Feb 25.
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.
脑室内（ICV）注入氯化钠可模拟高盐饮食对盐敏感性高血压的影响，提高脑脊液中的钠浓度（CSF [Na]），随后增加脑内内源性哇巴因样物质（OLS）的浓度。反过来，OLS会抑制脑Na(+)-K(+)-ATP酶，导致脑肾素-血管紧张素系统（RAS）活性和血压升高。介导对升高的CSF [Na]产生升压反应的Na(+)-K(+)-ATP酶α（催化）同工型尚不清楚，但可能涉及一种或多种与哇巴因具有高亲和力的同工型（例如，Na(+)-K(+)-ATP酶α(2)-和/或α(3)-亚基）。我们假设OLS诱导的α(2)-亚基抑制介导了这种反应。因此，通过杂合基因敲除（α(2) +/-）使α(2)表达长期降低，应会增强对升高的CSF [Na]的升压反应。脑室内（ICV）注入含0.225 M氯化钠的人工脑脊液可使野生型（+/+）和α(2) +/-小鼠的平均动脉压（MAP）升高，但α(2) +/-小鼠升高的幅度更大。同样，α(2) +/-小鼠对ICV哇巴因的升压反应增强，表明其对脑Na(+)-K(+)-ATP酶抑制本身的敏感性增强。与α(2)+/+小鼠相比，α(2) +/-小鼠对ICV血管紧张素I而非血管紧张素II的升压反应也增强，这表明脑RAS活性增强，可能是由脑内血管紧张素转换酶（ACE）增加介导的。在终板血管器中ACE配体结合增强支持了后一种假设。这些研究表明，通过杂合敲除使Na(+)-K(+)-ATP酶α(2)-同工型表达长期下调，会增加对升高的CSF [Na]的升压反应并激活脑RAS。由于这些变化与内源性脑OLS产生的变化相似，在CSF [Na]升高时，如在盐依赖性高血压中，脑α(2)-同工型可能是脑OLS的作用靶点。
