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1.
Eur J Heart Fail ; 10(12): 1166-71, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19000945

RESUMO

BACKGROUND: Aldosterone plays a detrimental role in the pathology of chronic heart failure. An important mechanism resides in its ability to evoke extensive fibrosis in the heart. However, the locations of the aldosterone interaction sites responsible for triggering cardiac fibrosis are puzzling. Extra-cardiac aldosterone actions are known to contribute to cardiac fibrosis but whether local cardiac aldosterone actions are involved is unclear. AIMS: This study aimed to investigate whether local aldosterone actions contribute to cardiac fibrosis in vivo. METHODS: Saline treated male Wistar rats were intravenously (systemically) or intrapericardially (locally) infused for 8 weeks with 75 or 750 ng/h aldosterone to monitor end point left ventricular epicardial collagen levels (histology). RESULTS: Perivascular fibrosis was observed only at high dose aldosterone infusions and was not different for the administration routes. Regarding interstitial fibrosis however, clear differences between the administration routes were seen. Intrapericardial aldosterone infusions increased interstitial collagen levels 1.72x (P<0.05) at low dose, but -surprisingly- had no significant effect at high dose. In contrast, intravenous aldosterone had no significant effect at low dose but increased interstitial collagen 1.72x (P<0.05) at high dose. CONCLUSION: Our data suggest that local cardiac aldosterone actions contribute to the development of left ventricular interstitial fibrosis.


Assuntos
Aldosterona/efeitos adversos , Fibrose/induzido quimicamente , Ventrículos do Coração/efeitos dos fármacos , Pericárdio/efeitos dos fármacos , Disfunção Ventricular Esquerda/induzido quimicamente , Aldosterona/administração & dosagem , Animais , Modelos Animais de Doenças , Fibrose/fisiopatologia , Ventrículos do Coração/patologia , Infusões Intravenosas , Infusões Parenterais , Masculino , Ratos , Ratos Wistar , Fatores de Risco , Disfunção Ventricular Esquerda/fisiopatologia
2.
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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