OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF). BACKGROUND: In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified. METHODS: The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months. RESULTS: Compared with the placebo group, plasma levels of BNP (-23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (-19% at 3 months, p = 0.03; -16% at 6 months, p = 0.11) were decreased after sp0ironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001). CONCLUSIONS: Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.