Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction.
OBJECTIVE
To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF).


BACKGROUND
Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects.


METHODS
Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks.


RESULTS
Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups.


CONCLUSIONS
In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.
Schäfer
Andreas
A
Medizinische Klinik der Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany.
Fraccarollo
Daniela
D
Hildemann
Steven K
SK
Tas
Piet
P
Ertl
Georg
G
Bauersachs
Johann
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D000077545:Eplerenone; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D066298:In Vitro Techniques; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy; D009599:Nitroprusside; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D014665:Vasodilator Agents
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; D014665:Vasodilator Agents; D009599:Nitroprusside; C052035:trandolapril; D013148:Spironolactone; D000077545:Eplerenone