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Fadrozole Reverses Cardiac Fibrosis in Spontaneously Hypertensive Heart Failure Rats: Discordant Enantioselectivity Versus Reduction of Plasma Aldosterone

Department of Pharmacology and Toxicology (M.M-H., J.M.A,E., I.P.E.B., G.M.S.C., H.v.E., E.R., H.C.J.O., J.F.M.S., J.J.R.H.), Cardiovascular Research Institute, University of Maastricht, 6200 MD Maastricht, The Netherlands; Biomodeling and Bioinformatics (L.R., K.P., P.A.J.H.), Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands; NV Organon (R.P., M.E.d.G.), R&D Laboratories, 5340 BH Oss, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. J. Rob Hermans, Department of Pharmacology and Toxicology, Cardiovascular Research Institute, Universiteit Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands. E-mail: r.hermans{at}farmaco.unimaas.nl.

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.