Aldosterone synthase inhibition

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Eur Heart J. 2008 Jun 27. [Epub ahead of print]

Aldosterone synthase inhibition improves cardiovascular function and

structure in rats with heart failure: a comparison with spironolactone.

Mulder P, Mellin V, Favre J, Vercauteren M, Remy-Jouet I, Monteil C,

V, Renet S, Henry JP, Jeng AY, Webb RL, Thuillez C.

INSERM U644, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183

Rouen Cedex, France.

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.

PMID: 18586661 [PubMed - as supplied by publisher]