Renoprotective effect of long-term combined treatment with adrenomedullin and omapatrilat in hypertensive rats

Abstract

Previous studies demonstrated that adrenomedullin (AM) is metabolized by neutral endopeptidases and that the renal effect of AM is augmented by the inhibition of neutral endopeptidases. We have recently shown that the long-term administration of AM has renoprotective effects. This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved. We studied the following four groups: control Dahl salt-resistant (DR) rats, untreated Dahl salt-sensitive (DS) rats, omapatrilat (35 mg/kg per day)-treated DS rats; and human AM (500 ng/h) plus omapatrilat-treated DS rats. After 7 weeks' treatment, blood pressure, renal function, neurohumoral factors, gene expression levels, and histological findings were examined. DS rats were characterized by increased blood pressure, decreased renal function, abnormal histological findings, and increased gene expression of collagen I and III, transforming growth factor beta (TGF-beta), and NADPH oxidase subunits (p40phox, p47phox, and gp91phox) in the renal cortex compared with DR rats. Compared with DS rats, omapatrilat significantly decreased systolic blood pressure (-26 mmHg), improved renal function, histological findings, and messenger RNA expression levels of collagen I, collagen III, and TGF-beta. Combined treatment with omapatrilat and AM further improved renal function, histological findings, and mRNA expression levels of collagen I, collagen III, and TGF-beta, without a further reduction in blood pressure. Only combined treatment decreased mRNA levels of p40phox, p47phox, and gp91phox. There were no differences in plasma AM or atrial natriuretic peptide levels among three DS groups. Our results suggest that combined treatment with omapatrilat and AM provides additional renoprotective effects independent of blood pressure-lowering activity partly via inhibition of gene expressions of oxidative stress and extracellular matrix.