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Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.

Abstract
Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg.d) or high (1.2 mg/kg.d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas at the high dose, R-fadrozole effectively reversed preexistent left ventricular interstitial fibrosis by 50% (vs. 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart.
AuthorsMonica Minnaard-Huiban, Judith M A Emmen, Luc Roumen, Ilona P E Beugels, Géraldine M S Cohuet, Helma van Essen, Eveline Ruijters, Koen Pieterse, Peter A J Hilbers, Harry C J Ottenheijm, Ralf Plate, Marcel E de Gooyer, Jos F M Smits, J J Rob Hermans
JournalEndocrinology (Endocrinology) Vol. 149 Issue 1 Pg. 28-31 (Jan 2008) ISSN: 0013-7227 [Print] United States
PMID17884944 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III
  • Mineralocorticoid Receptor Antagonists
  • Aldosterone
  • Canrenoic Acid
  • Fadrozole
Topics
  • Aldosterone (blood, urine)
  • Animals
  • Canrenoic Acid (pharmacology)
  • Collagen Type I (genetics, metabolism)
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III (genetics, metabolism)
  • Drug Evaluation, Preclinical
  • Fadrozole (chemistry, therapeutic use)
  • Fibrosis
  • Gene Expression Regulation (drug effects)
  • Heart (drug effects)
  • Heart Failure (prevention & control, urine)
  • Male
  • Mineralocorticoid Receptor Antagonists (pharmacology)
  • Myocardium (metabolism, pathology)
  • Rats
  • Rats, Inbred SHR
  • Stereoisomerism
  • Structure-Activity Relationship
  • Treatment Outcome

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