Delayed metabolism of human brain natriuretic peptide reflects resistance to neutral endopeptidase

Metabolism of natriuretic peptides is regulated by two degradative pathways : uptake by the clearance receptor (natriuretic peptide receptor C - NPR-C) and hydrolysis by neutral endopeptidase (NEP). Affinity studies favour a d ominant role of NPR-C in hormone degradation in several species but do not account for the efficacy of NEP inhibitors in vivo, nor the uniquely prolon ged half life (t (1/2)) of human brain natriuretic peptide (hBNP). Postulat ing that (1) delayed metabolism of hBNP reflects resistance to NEP and (2) interactions between NPR-C and NEP increase enzyme activity, we have used p urified ovine and human NEP, plus ovine lung plasma membranes to study the relative importance of receptor and enzyme pathways. We have also related t he findings to hormone metabolism in vivo. Binding affinities of atrial nat riuretic peptide (ANP), hBNP and ovine BNP (oBNP) to oNPR-C were similar (K -d=8-16 pM). In contrast, unlike ANP and oBNP, hBNP was not significantly d egraded by purified oNEP or plasma membranes. Despite similar land high) af finity of oNPR-C for oBNP and hBNP, the t (1/2) of hBNP (12(.)7min) was mor e than fourfold that of oBNP (2(.)6 min). Although we found no evidence for receptor-enzyme interaction, our results show that the delayed metabolism of hBNP reflects resistance to NEP. These findings have important implicati ons for future treatment strategies in human disease.