Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure.
Blocking brain mineralocorticoid receptors (MRs) reduces the high circulating levels of tumor necrosis factor (TNF)-alpha in heart failure (HF) rats. TNF-alpha 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-alpha, interleukin (IL)-1beta 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-alpha, IL-1beta, 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.
Kang
Yu-Ming
YM
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Zhang
Zhi-Hua
ZH
Johnson
Ralph F
RF
Yu
Yang
Y
Beltz
Terry
T
Johnson
Alan Kim
AK
Weiss
Robert M
RM
Felder
Robert B
RB
D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004357:Drug Synergism; D004452:Echocardiography; D000077545:Eplerenone; D000068800:Etanercept; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology*; D007031:Hypothalamus / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D017202:Myocardial Ischemia / Q000150:complications*; D037342:Pertussis Toxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
D016207:Cytokines; D007074:Immunoglobulin G; D018836:Inflammation Mediators; D000451:Mineralocorticoid Receptor Antagonists; D018124:Receptors, Tumor Necrosis Factor; D013148:Spironolactone; D000077545:Eplerenone; D037342:Pertussis Toxin; D000068800:Etanercept