Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α2-isoform

Van Huysse JW, Dostanic I, Lingrel JB, Hou X, Wu H. Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na, K-ATPase alpha(2)-isoform. Am J Physiol Heart Circ Physiol 301: H2147-H2153, 2011. First published August 19, 2011; doi:10.1152/ajpheart.01216.2010.-A chronic increase in the concentration of sodium chloride in the cerebrospinal fluid (CSF) (up arrow 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 alpha(2)-isoform (alpha 2(S/S)), mean arterial pressure rose by similar to 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 alpha 2(S/S) versus knockout/knockin mice with a ouabain-resistant endogenous alpha(2)-subunit (alpha 2(R/R)). In alpha 2(R/R), there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The alpha 2(R/R) genotype also lacked a pressor response to icv ouabain. These data demonstrate that chronic up arrow 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 alpha(2)-isoform of the Na,K-ATPase.