Published Online
on January 28, 2008

A more recent version of this article appeared on March 1, 2008

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Submitted on August 13, 2007
Revised on September 3, 2007

Does Aldosterone Upregulate the Brain Renin-Angiotensin System in Rats With Heart Failure?

Yang Yu; Shun-Guang Wei; Zhi-Hua Zhang; Elise Gomez-Sanchez; Robert M. Weiss; and Robert B. Felder^*

From the Department of Internal Medicine (Y.Y., S-G.W., Z-H.Z., R.M.W., R.B.F.), University of Iowa, Iowa City; Research Service (R.M.W., R.B.F.), Veterans’ Affairs Medical Center, Iowa City; Department of Medicine (E.G-S.), University of Mississippi, Jackson; and the Research Service (E.G-S.), G.V. (Sonny) Montgomery Veterans’ Affairs Medical Center, Jackson, Miss.

^* To whom correspondence should be addressed. E-mail: robert-felder{at}uiowa.edu.

Abstract—The brain renin-angiotensin system (RAS) contributes to increased sympathetic drive in heart failure (HF). The factors upregulating the brain RAS in HF remain unknown. We hypothesized that aldosterone (ALDO), a downstream product of the systemic RAS that crosses the blood-brain barrier, signals the brain to increase RAS activity in HF. We examined the relationship between circulating and brain ALDO in normal intact rats, in adrenalectomized rats receiving subcutaneous infusions of ALDO, and in rats with ischemia-induced HF and sham-operated controls. Brain ALDO levels were proportional to plasma ALDO levels across the spectrum of rats studied. Compared with sham-operated controls rats, HF rats had higher plasma and hypothalamic tissue levels of ALDO. HF rats also had higher expression of mRNA and protein for angiotensin-converting enzyme and angiotensin type 1 receptors in the hypothalamus, increased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and superoxide generation in the paraventricular nucleus of the hypothalamus, increased excitation of paraventricular nucleus neurons, and increased plasma norepinephrine. HF rats treated for 4 weeks with intracerebroventricular RU28318 (1 µg/h), a selective mineralocorticoid receptor antagonist, had less hypothalamic angiotensin-converting enzyme and angiotensin type 1 receptor mRNA and protein, less reduced nicotinamide-adenine dinucleotide phosphate–induced superoxide in the paraventricular nucleus, fewer excited paraventricular nucleus neurons, and lower plasma norepinephrine. RU28318 had no effect on plasma ALDO or on angiotensin-converting enzyme or angiotensin type 1 receptor expression in brain cortex. The data demonstrate that ALDO of adrenal origin enters the hypothalamus in direct proportion to plasma levels and suggest that ALDO contributes to the upregulation of hypothalamic RAS activity and sympathetic drive in heart failure.

Key words: hypothalamus • sympathetic nerve activity • superoxide • angiotensin-converting enzyme • angiotensin type 1 receptor

Related Article:

New Twist to the Role of the Renin-Angiotensin System in Heart Failure: Aldosterone Upregulates Renin-Angiotensin System Components in the Brain

Ernesto L. Schiffrin
Hypertension 2008 51: 622-623. [Full Text] [PDF]

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