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(Hypertension. 2006;48:127.)
© 2006 American Heart Association, Inc.

Original Articles

11ß-Hydroxysteroid Dehydrogenase Type 2 Activity in Hypothalamic Paraventricular Nucleus Modulates Sympathetic Excitation

Zhi-Hua Zhang; Yu-Ming Kang; Yang Yu; Shun-Guang Wei; Thomas J. Schmidt; Alan Kim Johnson; Robert B. Felder

From the Departments of Internal Medicine (Z.-H.Z., Y.-M.K., Y.Y., S.-G.W., R.B.F.), Physiology and Biophysics (T.J.S.), and Psychology (A.K.J.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, and Veterans Affairs Medical Center (R.B.F.), Iowa City, Iowa.

Correspondence to Robert B. Felder, MD, University of Iowa College of Medicine, E318-GH, 200 Hawkins Drive, Iowa City, IA 52242. E-mail robert-felder{at}uiowa.edu

Aldosterone stimulates the sympathetic nervous system by binding to a select population of brain mineralocorticoid receptors (MR). These MR have an equal affinity for corticosterone that is present in substantially higher concentrations, but are held in reserve for aldosterone by activity of the enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD-2), which converts corticosterone to an inactive metabolite. Thus, colocalization of MR and 11ß-HSD-2 activity may help identify brain regions that mediate the effects of aldosterone. The present studies tested the hypothesis that 11ß-HSD-2 activity regulates MR-mediated responses in the paraventricular nucleus (PVN) of the hypothalamus, a forebrain region implicated in sympathetic regulation. Real-time–polymerase chain reaction revealed the presence of 11ß-HSD-2 mRNA in PVN. In anesthetized adult male Sprague-Dawley rats, microinjection of the 11ß-HSD-2 inhibitor carbenoxolone (CBX) into PVN increased mean arterial pressure, heart rate, and renal sympathetic nerve activity. Intracerebroventricular injections of CBX excited PVN neurons and increased mean arterial pressure, heart rate, and renal sympathetic nerve activity. The ability of CBX to increase sympathetic activity by inhibiting 11ß-HSD-2, thereby permitting corticosterone to activate MR, was confirmed by the following: Intracerebroventricular glycyrrhizic acid, another 11ß-HSD-2 inhibitor, mimicked the sympathoexcitatory effects of CBX; the sympathoexcitatory effects of CBX were blocked by spironolactone, a MR antagonist. Neither CBX nor glycyrrhizic acid elicited a response in adrenalectomized rats. These findings suggest that MR in PVN contribute to sympathetic regulation and may be activated by aldosterone or corticosterone (or cortisol in humans) depending on the state of 11ß-HSD-2 activity.

Key Words: aldosterone • corticosterone • brain

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