Dietary and cerebrospinal fluid (CSF) Na(+) may act through brain
amiloride-sensitive, Phe-Met-Arg-Phe-NH(2) (
FMRFamide)-gated Na(+) channels (FaNaChs) to cause sympathoexcitation and
hypertension. We hypothesized that FaNaChs cause sympathoexcitation via the activation of brain "
ouabain" and the brain renin-angiotensin system. In conscious Wistar rats, intracerebroventricular (ICV) infusion of Na(+)-rich (0.3 mol/L) artificial CSF (aCSF) and ICV injection of
angiotensin II or
ouabain increase renal sympathetic nerve activity (RSNA), blood pressure (BP), and heart rate (HR). ICV
benzamil, an
amiloride analogue, did not affect baseline values and blocked the responses to ICV infusions of Na(+)-rich aCSF but not ICV
angiotensin II or
ouabain. ICV
FMRFamide also increased RSNA, BP, and HR. Blocking brain "
ouabain" with ICV antibody
Fab fragments abolished the responses to both ICV
FMRFamide and Na(+)-rich aCSF. In conscious spontaneously hypertensive rats (SHR) on a high
salt intake for 6 weeks, prolonged ICV but not
intravenous infusion of
benzamil at 10 to 20 microg/h significantly decreased RSNA, BP, and HR in a dose-related manner. The extent of these responses was significantly smaller in SHR on regular
salt intake. These findings suggest that
benzamil-blockable brain FaNaChs represent the major mechanism through which a small increase in CSF Na(+) by ICV Na(+)-rich aCSF in Wistar rats or high
salt intake in SHR initiates sympathoexcitation and
hypertension. Enhanced Na(+) entry through FaNaChs appears to activate brain "
ouabain" and the brain renin-angiotensin system and, thereby, increases the sympathetic outflow. Brain FaNaChs appear to contribute to the worsening of
hypertension in SHR on a high
salt diet and, to a small extent, to the maintenance of
hypertension in SHR on a regular
salt diet.