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

Abstract

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 AT(2) 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.

• Authors: Paul Mulder, Virginie Mellin, Julie Favre, Magali Vercauteren, Isabelle Remy-Jouet, Christelle Monteil, Vincent Richard, Sylvanie Renet, Jean Paul Henry, Arco Y Jeng, Randy L Webb, Christian Thuillez
• Journal: European heart journal (Eur Heart J) Vol. 29 Issue 17 Pg. 2171-9 (Sep 2008) ISSN: 1522-9645 [Electronic] England
• PMID: 18586661 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Mineralocorticoid Receptor Antagonists
• Spironolactone
• Cytochrome P-450 CYP11B2
• Fadrozole

Topics

• Angiotensin Receptor Antagonists (pharmacology)
• Animals
• Cytochrome P-450 CYP11B2 (antagonists & inhibitors)
• Endothelium, Vascular (physiology)
• Fadrozole (pharmacology)
• Heart Failure (drug therapy, pathology, physiopathology)
• Hemodynamics (physiology)
• Ligation
• Male
• Mineralocorticoid Receptor Antagonists (pharmacology)
• Oxidative Stress (physiology)
• Rats
• Rats, Wistar
• Spironolactone (pharmacology)
• Ventricular Dysfunction, Left (drug therapy, pathology, physiopathology)
• Ventricular Remodeling (physiology)