| First Author | Van Huysse JW | Year | 2011 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 301 |
| Issue | 5 | Pages | H2147-53 |
| PubMed ID | 21856907 | Mgi Jnum | J:178352 |
| Mgi Id | MGI:5298175 | Doi | 10.1152/ajpheart.01216.2010 |
| Citation | Van Huysse JW, et al. (2011) Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase alpha2-isoform. Am J Physiol Heart Circ Physiol 301(5):H2147-53 |
| abstractText | A chronic increase in the concentration of sodium chloride in the cerebrospinal fluid (CSF) ( upward arrowCSF [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 (alpha2(S/S)), mean arterial pressure rose by approximately 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 alpha2(S/S) versus knockout/knockin mice with a ouabain-resistant endogenous alpha(2)-subunit (alpha2(R/R)). In alpha2(R/R), there was no pressor response to icv aCSF-HiNaCl in contrast to WT mice. The alpha2(R/R) genotype also lacked a pressor response to icv ouabain. These data demonstrate that chronic upward arrowCSF [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. |
