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European Heart Journal Advance Access published online on June 27, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn277
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone

Paul Mulder1,2,*, Virginie Mellin1,2, Julie Favre1,2, Magali Vercauteren1,2, Isabelle Remy-Jouet1,2, Christelle Monteil1,2, Vincent Richard1,2, Sylvanie Renet1,2, Jean Paul Henry1, Arco Y. Jeng3, Randy L. Webb3 and Christian Thuillez1,2

1 INSERM U644, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France
2 Institut Hospitalo-Universitaire de Recherche Bio-Medicale, UFR de Médecine et de Pharmacie, Rouen, France
3 Novartis Institute for BioMedical Research, East Hanover, New Jersey, NJ, USA

Received 30 August 2007; revised 19 May 2008; accepted 5 June 2008.

* Corresponding author. Tel: +33 2 35 14 83 59, Fax: +33 2 35 14 83 65, Email: paul.mulder{at}univ-rouen.fr

Aims: Inhibition of aldosterone synthase, the key enzyme in aldosterone formation, could be an alternative strategy for mineralocorticoid-receptor antagonists in congestive heart failure (CHF), but its effect in CHF is unknown.

Methods and results: We compared, in rats with CHF, the effects of a 7 day and a 12 week treatment with the aldosterone synthase inhibitor FAD286 (4 mg kg–1 day–1) with those induced by spironolactone (80 mg kg–1 day–1). FAD286/spironolactone increased cardiac output without modifying arterial pressure. Long-term FAD286 and spironolactone reduced left ventricular (LV) end-diastolic pressure, LV relaxation constant, and LV dilatation, and these effects were more marked with FAD286, whereas both drugs reduced LV hypertrophy and collagen accumulation to the same extent. Long-term FAD286/spironolactone prevented CHF-related enhancement in LV ACE and reduction in LV ACE-2, but only FAD286 prevented the reduction in LV AT2 receptors. FAD286, but not long-term spironolactone, reduced the CHF-related enhancements in LV reactive oxygen species, reduced-oxidized glutathione ratio, and aortic nicotinamide adenine dinucleotide phosphate oxidase activity. FAD286 normalized the CHF-induced impairment of endothelium-dependent vasodilatation.

Conclusion: In experimental CHF, FAD286 and spironolactone improve LV haemodynamics, remodelling, and function, but only FAD286 persistently normalizes LV ‘redox status’. These results suggest that aldosterone synthase inhibition is a potential therapeutic strategy for the treatment of CHF.

Key Words: Aldosterone • Heart failure • Spironolactone • Aldosterone synthase inhibition


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