title: Hypertension from chronic central sodium chloride in mice is mediated by the ouabain-binding site on the Na,K-ATPase α₂-isoform.
abstract: 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.
authors.affiliation: Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. jvanhuysse@ottawaheart.ca
authors.forename: James W
authors.initials: JW
authors.lastname: Van Huysse
authors.forename: Iva
authors.initials: I
authors.lastname: Dostanic
authors.forename: Jerry B
authors.initials: JB
authors.lastname: Lingrel
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Hou
authors.forename: Hengwei
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure; D018660:Blood Pressure Monitoring, Ambulatory; D001921:Brain / Q000201:enzymology*; D002298:Cardenolides / Q000378:metabolism*; D004195:Disease Models, Animal; D006339:Heart Rate; D006973:Hypertension / Q000134:cerebrospinal fluid / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D057967:Infusions, Intraventricular; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010042:Ouabain / Q000008:administration & dosage; D012503:Saponins / Q000378:metabolism*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000134:cerebrospinal fluid*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry; D013997:Time Factors
chemical_list: D002298:Cardenolides; D012503:Saponins; C034504:digoxin-like factors; D012965:Sodium Chloride; D010042:Ouabain; C401838:Atp1a2 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase