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1.
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
2.
J Hypertens Suppl ; 21(3): S19-23, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12929471

RESUMO

Epidemiological studies in the past decade have stressed the importance of both pulse pressure and mean arterial pressure (MAP) as important risk factors in hypertension-related cardiovascular disease. Pulse pressure and MAP are determined by different segments of the cardiovascular system. Pulse pressure is the pulsatile component of the blood pressure curve. It is determined by left ventricular ejection, the cushioning capacity (compliance) of the large arteries, and the timing and intensity of wave reflections from the microcirculation. MAP is the steady component; it is determined by cardiac output and peripheral (micro)vascular resistance. To a large degree, the structural design of the heart and vascular tree determine the pulse pressure and MAP, in addition to the propagation of the pressure wave through the vasculature. Pressure and flow, in contrast, influence the composition and geometry of the heart and vasculature. Hypertensive disease is associated with important structural alterations of the heart, such as hypertrophy and fibrosis, and of the vasculature, such as large artery stiffening, small artery remodelling and microvascular rarefaction. Recent basic research has revealed some of the molecular pathways involved in the remodelling of the cardiovascular system under the influence of physical forces. For correct understanding of the pathophysiology of hypertensive disease, its risks for target-organ damage and its effective treatment, both the pulsatile and steady components of the blood pressure curve must be considered.


Assuntos
Circulação Coronária/fisiologia , Coração/fisiopatologia , Hipertensão/fisiopatologia , Microcirculação/fisiologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Circulação Coronária/efeitos dos fármacos , Coração/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Microcirculação/efeitos dos fármacos , Fatores de Risco
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