Hypertension from chronic central sodium in mice is mediated by a brain ouabain‐like substance (OLS) and by the ouabain‐binding site on the Na, K‐ATPase alpha‐2 isoform

An increase in the concentration of sodium in the CSF (↑ CSF [Na]) appears to be critically important for the development of salt‐dependent hypertension. We used both wild‐type (WT) and knockout/knockin mice with a ouabain‐resistant but otherwise functional endogenous α2 Na, K‐ATPase subunit (α2 R/R ) to explore the mechanisms of hypertension caused by chronic ↑ CSF [Na]. CSF [Na] was elevated by the intracerebroventri‐cular (i.c.v.) infusion of Na‐rich artificial CSF (aCSF‐HiNa) for 10 days (Days 1–10).Genotype‐Treatment Baseline MAP ΔMAP‐Day 10WT‐aCSF, n=8 111 ± 3 1 ± 5 WT‐aCSF‐HiNa, n=5 110 ± 6 23 ± 2 * WT‐aCSF‐HiNa +Ab, n=9 119 ± 4 −7 ± 2 α2 R/R ‐aCSF‐HiNa, n=10 122 ± 6 −4 ± 3* P<0.05 vs. other 3 groups. ΔMAP = change in BP (mm Hg) from baseline. Ab = anti‐ouabain antibody.Similar changes occurred in nighttime MAP. Ouabain given i.c.v. increased BP to a similar extent as aCSF‐HiNa. The same doses of ouabain, aCSF‐HiNa or Ab given s.c. instead of i.c.v. had no effect on BP. The α2 R/R genotype also lacked a pressor response to i.c.v. ouabain. Hypothalamic levels of endogenous OLS: α2 R/R > WT. We conclude that chronically ↑ CSF [Na] causes hypertension in mice and that the blood pressure response is mediated by the endogenous OLS in the brain, specifically by its binding to the α2 isoform of the Na, K‐ATPase. Supported by the Heart & Stroke Foundation of Ontario and NIH