The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3rd cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-α (TNF-α) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-α levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-α release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-α production.
Superoxide Is Involved in the Central Nervous System Activation and Sympathoexcitation of Myocardial Infarction–Induced Heart Failure
