Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone.
| Title: | Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone. |
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| Authors: | Minnaard-Huiban M; Department of Pharmacology and Toxicology, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands.; Emmen JM; Roumen L; Beugels IP; Cohuet GM; van Essen H; Ruijters E; Pieterse K; Hilbers PA; Ottenheijm HC; Plate R; de Gooyer ME; Smits JF; Hermans JJ |
| Source: | Endocrinology [Endocrinology] 2008 Jan; Vol. 149 (1), pp. 28-31. Date of Electronic Publication: 2007 Sep 20. |
| Publication Type: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0375040 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0013-7227 (Print) Linking ISSN: 00137227 NLM ISO Abbreviation: Endocrinology Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2017- : New York : Oxford University Press; Original Publication: Los Angeles, Calif. : Association for the Study of Internal Secretions |
| MeSH Terms: | Aldosterone/*blood ; Fadrozole/*chemistry ; Fadrozole/*therapeutic use ; Heart/*drug effects ; Heart Failure/*prevention & control ; Myocardium/*pathology; Aldosterone/urine ; Canrenoic Acid/pharmacology ; Collagen Type I/genetics ; Collagen Type I/metabolism ; Collagen Type III/genetics ; Collagen Type III/metabolism ; Gene Expression Regulation/drug effects ; Heart Failure/urine ; Mineralocorticoid Receptor Antagonists/pharmacology ; Myocardium/metabolism ; Animals ; Collagen Type I, alpha 1 Chain ; Drug Evaluation, Preclinical ; Fibrosis ; Male ; Rats ; Rats, Inbred SHR ; Stereoisomerism ; Structure-Activity Relationship ; Treatment Outcome |
| 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. |
| Substance Nomenclature: | 0 (Collagen Type I); 0 (Collagen Type I, alpha 1 Chain); 0 (Collagen Type III); 0 (Mineralocorticoid Receptor Antagonists); 4964P6T9RB (Aldosterone); 87UG89VA9K (Canrenoic Acid); H3988M64PU (Fadrozole) |
| Entry Date(s): | Date Created: 20070922 Date Completed: 20080226 Latest Revision: 20211203 |
| Update Code: | 20260130 |
| DOI: | 10.1210/en.2007-0584 |
| PMID: | 17884944 |
| Database: | MEDLINE |
Comparative Study; Journal Article; Research Support, Non-U.S. Gov't