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after coronary artery ligation in rats
Departments of 1 Internal Medicine and 3 Psychology and 4 Cardiovascular Center, University of Iowa, and 2 Veterans Affairs Medical Center, Iowa City, Iowa 52242
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-
(TNF-) 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- 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- 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- production.
myocardial infarction; tumor necrosis factor; aldosterone; spironolactone
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