RESUMO
Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na+ channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats. Male Wistar rats received aldosterone (1mg kg-1day-1)+1% NaCl for 3weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5mg kg-1day-1). Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PRO80. Expression of fibrotic, inflammatory and oxidative mediators were increased by aldosterone-salt administration and blunted by PRO80. Antioxidant capacity was improved by PRO80. The up-regulated aldosterone mediator SGK1, ENaC and p-Nedd4-2/total Nedd4-2 ratio were blocked by PRO80. PRO80 blunted aldosterone-mineralocorticoid-mediated up-regulation of ENaC provides new mechanistic insight of the beneficial effect of proanthocyanidins preventing the cardiac alterations induced by aldosterone excess.
Assuntos
Suplementos Nutricionais , Complexos Endossomais de Distribuição Requeridos para Transporte/antagonistas & inibidores , Canais Epiteliais de Sódio/metabolismo , Ventrículos do Coração/metabolismo , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proantocianidinas/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Disfunção Ventricular Esquerda/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Biomarcadores/metabolismo , Cardiomegalia/etiologia , Cardiomegalia/prevenção & controle , Cardiotônicos/uso terapêutico , Complexos Endossomais de Distribuição Requeridos para Transporte/agonistas , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Agonistas do Canal de Sódio Epitelial/antagonistas & inibidores , Agonistas do Canal de Sódio Epitelial/metabolismo , Bloqueadores do Canal de Sódio Epitelial/uso terapêutico , Canais Epiteliais de Sódio/química , Fibrose , Ventrículos do Coração/imunologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão/etiologia , Hipertensão/prevenção & controle , Proteínas Imediatamente Precoces/agonistas , Proteínas Imediatamente Precoces/metabolismo , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ubiquitina-Proteína Ligases Nedd4 , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos Wistar , Ubiquitina-Proteína Ligases/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND AND PURPOSE: Pharmacological enhancement of vectorial Na⺠transport may be useful to increase alveolar fluid clearance. Herein, we investigated the influence of the benzimidazolones 1-ethyl-1,3-dihydro-2-benzimidazolone (1-EBIO), 5,6-dichloro-1-EBIO (DC-EBIO) and chlorzoxazone on vectorial epithelial Na⺠transport. EXPERIMENTAL APPROACH: Effects on vectorial Na⺠transport and amiloride-sensitive apical membrane Na⺠permeability were determined by measuring short-circuit currents (I(SC)) in rat fetal distal lung epithelial (FDLE) monolayers. Furthermore, amiloride-sensitive membrane conductance and the open probability of epithelial Na⺠channels (ENaC) were determined by patch clamp experiments using A549 cells. KEY RESULTS: I(SC) was increased by approximately 50% after addition of 1-EBIO, DC-EBIO and chlorzoxazone. With permeabilized basolateral membranes in the presence of a 145:5 apical to basolateral Na⺠gradient, the benzimidazolones markedly increased amiloride-sensitive I(SC). 5-(N-Ethyl-N-isopropyl)amiloride-induced inhibition of I(SC) was not affected. The benzamil-sensitive I(SC) was increased in benzimidazolone-stimulated monolayers. Pretreating the apical membrane with amiloride, which inhibits ENaC, completely prevented the stimulating effects of benzimidazolones on I(SC). Furthermore, 1-EBIO (1 mM) and DC-EBIO (0.1 mM) significantly increased (threefold) the open probability of ENaC without influencing current amplitude. Whole cell measurements showed that DC-EBIO (0.1 mM) induced an amiloride-sensitive increase in membrane conductance. CONCLUSION AND IMPLICATIONS: Benzimidazolones have a stimulating effect on vectorial Na⺠transport. The antagonist sensitivity of this effect suggests the benzimidazolones elicit this action by activating the highly selective ENaC currents. Thus, the results demonstrate a possible new strategy for directly enhancing epithelial Na⺠transport.