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


OBJECTIVE
This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ishimura
Kimihiko
K
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Nishikimi
Toshio
T
Akimoto
Kazumi
K
Ono
Hidehiko
H
Kangawa
Kenji
K
Matsuoka
Hiroaki
H
D053607:Adrenomedullin; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage; D024042:Collagen Type I / Q000187:drug effects; D024061:Collagen Type III / Q000187:drug effects; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage*; D011480:Protease Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D011994:Recombinant Proteins / Q000008:administration & dosage; D013841:Thiazepines / Q000008:administration & dosage*; D016212:Transforming Growth Factor beta / Q000235:genetics
D000959:Antihypertensive Agents; D024042:Collagen Type I; D024061:Collagen Type III; D010455:Peptides; D011480:Protease Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D053607:Adrenomedullin; C106266:omapatrilat