Chronic effect of co-administration of endopeptidase inhibitor and adrenomedullin (AM) in heart failure (HF) in rats

Abstract Background: We have recently reported that chronic AM administration has beneficial effects in HF. This study sought to examine the effect of combined endopeptidase inhibition and AM in HF in rats, because AM is metabolized partly via neutral endopeptidase pathway. Methods and Results: Dahl salt-sensitive rats (DS) were randomly divided into three groups, omapatrilat group (35 mg/kg/day; n = 16), omapatrilat+ AM (500 ng/h; n = 16) group, and untreated group (n = 16). We assessed HF after 7 weeks treatment. Results: Omapatrilat reduced left ventricular weight (LVW), blood pressure, LVEDP, and right ventricular systolic pressure (RVSP) compared with untreated DS. Plasma atrial natriuretic peptide (ANP), and AM were decreased, but renin and aldosterone did not change. In addition, omaparilat decreased mRNA levels of ANP, AM, TGF and collagen I and III in the left ventricle. Histological examination also decreased perifibrosis score. Although there were no differences in blood pressure between omapatrilat and omapatrilat+AM groups, omapatrilat+AM further decreased LVW, LVEDP, RVSP, and mRNA expression of TGF and collagen I and III. Interestingly, omapatrilat+AM further reduced mRNA levels of ANP and AM, there were no differences in plasma ANP or AM levels between the two groups. Conclusion: These results suggest that cotreatment with AM and omapatrilat may be a new therapeutic strategy to the treatment of HF, partly mediated via the inhibition of metabolism of ANP or AM.