Enhanced pressor response to increased CSF sodium concentration and to central ANG I in heterozygous [[alpha].sub.2] [Na.sup.+]-[K.sup.+]-ATPase knockout mice

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.sup.+]-[K.sup.+]-ATPase, causing increases in the activity of the brain renin-angiotensin system (RAS) and blood pressure. The [Na.sup.+]-[K.sup.+]-ATPase [alpha] (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.sup.+]-[K.sup.+]-ATPase [[alpha].sub.2]- and/or [[alpha].sub.3]-subunits). We hypothesize that OLS-induced inhibition of the [[alpha].sub.2]-subunit mediates this response. Therefore, a chronic reduction in [[alpha].sub.2] expression via a heterozygous gene knockout ([[alpha].sub.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 [[alpha].sub.2] +/- mice, hut to a greater extent in [[alpha].sub.2] +/-. Likewise, the pressor response to ICV ouabain was enhanced in [[alpha].sub.2] +/- mice, demonstrating enhanced sensitivity to brain [Na.sup.+]-[K.sup.+]-ATPase inhibition per se. The pressor response to ICV ANG I but not ANG II was also enhanced in [[alpha].sub.2] +/- vs. [[alpha].sub.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.sup.+]-[K.sup.+]-ATPase [[alpha].sub.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 [[alpha].sub.2]-isoform may be a target for the brain OLS during increases in CSF [Na], such as in salt-dependent hypertension. [[alpha].sub.2]-isoform; gene knockout; sodium chloride; brain ouabain-like substance; brain renin-angiotensin system; intracerebroventricular infusion