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 infarc tion (MI) which preserves responsiveness to exogenously administered n atriuretic peptide, and investigated the potentiating action of neutra l endopeptidase (NEP) inhibition on the renal response to endogenous n atriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenou s plasma concentration of or-rat atrial natriuretic peptide (alpha-rAN P) 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 inhib itor, induced larger increases in circulating alpha-rANP levels and na triuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/min/kg) was equal to that of exogen ously administered alpha-rANP (100 pmol/min/kg) in MI rats, whereas pl asma alpha-rANP concentration under NEP inhibition was much lower than that after administration of alpha-rANP. The endogenous alpha-rANP le vels in AVF rats were as high as those in MI rats. However, the natriu retic effect of phosphoramidon was less in AVF rats than in MI rats, w hich was consistent with the decreased natriuretic activity observed w ith administration of exogenous to alpha-rANP in the AVF rat. These re sults indicate that the natriuretic effect of NEP inhibition is depend ent on elevated endogenous alpha-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circula ting alpha-rANP levels. Endogenous natriuretic peptide-mediated natriu resis under NEP inhibition also appears to correlate with the responsi veness to the exogenously administered peptide.