Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure

We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of α-rat atrial natriuretic peptide (α-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating α-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/ min/kg) was equal to that of exogenously administered α-rANP (100 pmol/min/kg) in MI rats, whereas plasma α-rANP concentration under NEP inhibition was much lower than that after administration of α-rANP. The endogenous α-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to α-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous α-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating α-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.