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(Hypertension. 2002;39:557.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Brain Amiloride-Sensitive Phe-Met-Arg-Phe-NH₂–Gated Na⁺ Channels and Na⁺-Induced Sympathoexcitation and Hypertension

Bing S. Huang; Frans H.H. Leenen

From the Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Correspondence to Frans H. H. Leenen, MD, PhD, FRCPC, Hypertension Unit, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y4W7, Canada. E-mail fleenen{at}ottawaheart.ca

Dietary and cerebrospinal fluid (CSF) Na⁺ may act through brain amiloride-sensitive, Phe-Met-Arg-Phe-NH₂ (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 µg/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.

Key Words: brain • renin-angiotensin system • sympathetic nervous system • ouabain • sodium

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