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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous ₂ Na⁺-K⁺-ATPase knockout mice

¹Hypertension Unit, University of Ottawa Heart Institute, Ottawa; ²Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine and ³Department of Cellular and Molecular Medicine, University of Ottawa; and ⁴Departments of Medicine and Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

Submitted 6 November 2007 ; accepted in final form 12 February 2009

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 (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 ₂- and/or ₃-subunits). We hypothesize that OLS-induced inhibition of the ₂-subunit mediates this response. Therefore, a chronic reduction in ₂ expression via a heterozygous gene knockout (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 ₂ +/– mice, but to a greater extent in ₂ +/–. Likewise, the pressor response to ICV ouabain was enhanced in 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 ₂ +/– vs. 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 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 ₂-isoform may be a target for the brain OLS during increases in CSF [Na], such as in salt-dependent hypertension.

₂-isoform; gene knockout; sodium chloride; brain ouabain-like substance; brain renin-angiotensin system; intracerebroventricular infusion