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(Circulation Research. 2006;99:758.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Novel Effect of Mineralocorticoid Receptor Antagonism to Reduce Proinflammatory Cytokines and Hypothalamic Activation in Rats With Ischemia-Induced Heart Failure

Yu-Ming Kang, Zhi-Hua Zhang, Ralph F. Johnson, Yang Yu, Terry Beltz, Alan Kim Johnson, Robert M. Weiss, Robert B. Felder

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

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

Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)- in heart failure (HF) rats. TNF- and other proinflammatory cytokines activate neurons in the paraventricular nucleus (PVN) of hypothalamus, including corticotropin-releasing hormone (CRH) neurons, by inducing cyclooxygenase (COX)-2 activity and synthesis of prostaglandin E₂ by perivascular cells of the cerebral vasculature. We tested the hypothesis that systemic treatment with a MR antagonist would reduce hypothalamic COX-2 expression and PVN neuronal activation in HF rats. Rats underwent coronary ligation to induce HF, confirmed by echocardiography, or sham surgery, followed by 6 weeks treatment with eplerenone (30 mg/kg per day, orally) or vehicle (drinking water). Eplerenone-treated HF rats had lower plasma TNF-, interleukin (IL)-1ß and IL-6, less COX-2 staining of small blood vessels penetrating PVN, fewer PVN neurons expressing Fra-like activity (indicating chronic neuronal activation), and fewer PVN neurons staining for TNF-, IL-1ß, and CRH than vehicle-treated HF rats. COX-2 and CRH protein expression in hypothalamus were 1.7- and 1.9-fold higher, respectively, in HF+vehicle versus sham+vehicle rats; these increases were attenuated (26% and 25%, respectively) in HF+eplerenone rats. Eplerenone-treated HF rats had less prostaglandin E₂ in cerebrospinal fluid, lower plasma norepinephrine levels, lower left ventricular end-diastolic pressure, and lower right ventricle/body weight and lung/body weight ratios, but no improvement in left ventricular function. Treatment of HF rats with anticytokine agents, etanercept or pentoxifylline, produced very similar results. This study reveals a previously unrecognized effect of MR antagonism to minimize cytokine-induced central neural excitation in rats with HF.

Key Words: congestive heart failure • aldosterone • cytokines • cyclooxygenase-2 • nervous system

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