Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibition - Mechanistic evidence to support RALES

Background-A marked reduction of overall mortality in patients with severe congestive heart failure (CHF) has been demonstrated by addition of the min eralocorticoid receptor antagonist spironolactone to ACE inhibition. The ai m of the present study was to examine a hypothesized interaction of spirono lactone and ACE inhibitors in renal electrolyte and volume regulation. Methods and Results-Wistar rats with extensive myocardial infarction or sha m operation were treated with either placebo, the ACE inhibitor trandolapri l, low-dose spironolactone, or a combination of the 2. Twelve weeks after i nfarction, rats were housed in metabolic cages. Urinary volume and sodium e xcretion were significantly increased in CHF rats on a combined treatment w ith spironolactone and trandolapril (21.2+/-2.6 mL/d, 2489+/-320 mmol/d, me an+/-SD; P<0.05 versus other experimental groups) versus placebo-treated ra ts (16.7+/-5.6 mL/d, 1431+/-458 mmol/d), whereas these parameters were not affected in rats on either spironolactone (16.1+/-6.6 mL/d, 1153+/-273 mmol /d) or trandolapril alone (15.9+/-4.2 mL/d, 1392+/-294 mmol/d). The effects on natriuresis coincided with a significant reduction of left ventricular end-diastolic pressure (LVEDP) in rats on trandolapril and spironolactone ( 10.8+/-8.2 mm Hg; P<0.05 versus CHF placebo: 23.3+/-7.2 mm Hg; sham-operate d rats: 5.1+/-0.9 mm Hg), whereas LVEDP remained elevated in rats treated w ith either compound alone. Conclusions-In the present study, we found an unexpected interaction of low -dose spironolactone and the ACE inhibitor trandolapril in experimental CHF leading to marked effects on renal electrolyte and volume regulation that were not apparent by treatment with either drug alone. These findings may e xplain the beneficial effects of spironolactone in CHF patients.