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

Abstract

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 dominant 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 prolonged half life (t ½ ) of human brain natriuretic peptide (hBNP). Postulating that (1) delayed metabolism of hBNP reflects resistance to NEP and (2) interactions between NPR-C and NEP increase enzyme activity, we have used purified ovine and human NEP, plus ovine lung plasma membranes to study the relative importance of receptor and enzyme pathways. We have also related the findings to hormone metabolism in vivo. Binding affinities of atrial natriuretic 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 degraded by purified oNEP or plasma membranes. Despite similar (and high) affinity of oNPR-C for oBNP and hBNP, the t ½ of hBNP (12·7 min) was more than fourfold that of oBNP (2·6 min). Although we found no evidence for receptorenzyme interaction, our results show that the delayed metabolism of hBNP reflects resistance to NEP. These findings have important implications for future treatment strategies in human disease.

Quality Specifications for B-Type Natriuretic Peptide Assays

“…NEPs are abundant in kidney brush border membranes, cardiac myocytes, and endothelial cells and can degrade other circulating peptides, such as kinins, enkephalins, and neurotensins. Although ANP is cleared by NEPs, this pathway does not appear to be as important for BNP (29 ), leading some to suggest that another, as yet unidentified pathway is important (30 ). However, NEPs are up-regulated in patients with renal failure.…”

Elimination of the Cardiac Natriuretic Peptides B-Type Natriuretic Peptide (BNP) and N-Terminal proBNP by Hemodialysis

“…Both BNP and NT-proBNP can be used for the diagnosis of heart failure, but there are important differences between the two tests, particularly regarding influence of age and renal function (1 ). In addition to glomerular filtration, BNP is eliminated from plasma mainly through natriuretic peptide receptors and degraded by neutral endopeptidases (7)(8)(9). In contrast, NT-proBNP possibly is largely eliminated by glomerular filtration only (4 ).…”

Human Pro–B-Type Natriuretic Peptide Is Processed in the Circulation in a Rat Model

“…The mechanisms that mediate proBNP clearance (removal of unprocessed proBNP from the circulation) are not known. Previous studies have reported that BNP has a short half-life-1.2 min in the case of rat BNP in rats (28 ) and 13-20 min for human BNP in humans (29,30 ). In rats, we estimated the terminal half-life of human BNP as 6.4 (0.5) min.…”