title: Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Faculté de Médecine et Pharmacie, INSERM U644, 22 Boulevard Gambetta, 76183 Rouen Cedex, France. paul.mulder@univ-rouen.fr
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Virginie
authors.initials: V
authors.lastname: Mellin
authors.forename: Julie
authors.initials: J
authors.lastname: Favre
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.forename: Christelle
authors.initials: C
authors.lastname: Monteil
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Sylvanie
authors.initials: S
authors.lastname: Renet
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Arco Y
authors.initials: AY
authors.lastname: Jeng
authors.forename: Randy L
authors.initials: RL
authors.lastname: Webb
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000502:physiology; D017316:Fadrozole / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D008026:Ligation; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole