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Endocrinology ; 149(1): 28-31, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17884944

RESUMO

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.


Assuntos
Aldosterona/sangue , Fadrozol/química , Fadrozol/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Coração/efeitos dos fármacos , Miocárdio/patologia , Aldosterona/urina , Animais , Ácido Canrenoico/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadeia alfa 1 do Colágeno Tipo I , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Avaliação Pré-Clínica de Medicamentos , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/urina , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos SHR , Estereoisomerismo , Relação Estrutura-Atividade , Resultado do Tratamento
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