Chronic effect of combined treatment with omapatrilat and adrenomedullin on the progression of heart failure in rats.
BACKGROUND
We and other investigators have reported that short- and long-term treatment with adrenomedullin has beneficial effects in heart failure. This study examined the effects of long-term treatment with a vasopeptidase inhibitor plus adrenomedullin in a model of heart failure in rats and assessed potential mechanisms of action.


METHODS
Dahl salt-sensitive rats aged 11 weeks were randomly divided into three groups: an omapatrilat group, an omapatrilat plus adrenomedullin group, and an untreated group. The effects of these treatments were evaluated after 7 weeks of treatment.


RESULTS
Omapatrilat monotherapy significantly improved left ventricular weight (LVW), blood pressure (BP), and central hemodynamics as compared with the untreated group. Omapatrilat decreased the gene expression levels of adrenomedullin and atrial natriuretic peptide (ANP) in the left ventricle. In addition, omapatrilat decreased mRNA levels of transforming growth factor-beta (TGF-beta), collagen I, collagen III, plasminogen activator inhibitor-1 (PAI-1), and intercellular adhesion molecule-1 (ICAM-1) in the left ventricle, and omapatrilat decreased perifibrosis score and myocyte area histologically. Omapatrilat plus adrenomedullin further improved LVW, central hemodynamics, and mRNA expression of TGF-beta, collagen I, collagen III, PAI-1, and ICAM-1 without changing BP. Omapatrilat plus adrenomedullin further reduced mRNA levels of ANP and adrenomedullin without altering levels of ANP or adrenomedullin in plasma. Interestingly, omapatrilat slightly decreased mRNA levels of subunits of NADPH oxidase, whereas omapatrilat plus adrenomedullin further decreased these variables.


CONCLUSIONS
Our results suggest that combined treatment with adrenomedullin and omapatrilat may be a new strategy for the management of heart failure, acting partly by inhibition of the extracellular matrix gene, adhesion molecule, antifibrinolysis, and oxidative stress production.
Nishikimi
Toshio
T
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. nishikim@dokkyomed.ac.jp
Mori
Yosuke
Y
Ishimura
Kimihiko
K
Ishikawa
Yayoi
Y
Koshikawa
Shogo
S
Akimoto
Kazumi
K
Minamino
Naoto
N
Kangawa
Kenji
K
Matsuoka
Hiroaki
H
D053607:Adrenomedullin / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000959:Antihypertensive Agents; D017395:Plasminogen Activator Inhibitor 1; D011725:Pyridines; D012333:RNA, Messenger; D013841:Thiazepines; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D053607:Adrenomedullin; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019255:NADPH Oxidases