Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

Abstract

Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin-angiotensin-aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.

Figure 1

The three major human endogenous natriuretic peptides, their processing and degradation. (A) ProANP1–126 and signal peptide, cleaved to NT-ProANP1–98 and the active hormone ANP1–28. (B) ProBNP1–108 and signal peptide, cleaved to NT-ProBNP1–76 and the active hormone BNP1–32. (C) ProCNP1–103 and signal peptide, cleaved to NT-ProCNP1–80(50) and the active hormones CNP1–22 and CNP1–53. Red arrows indicate processing site by corin or furin. Blue arrows indicate neutral endopeptidase cleavage sites. Yellow-labelled amino acids indicate glycosylation sites that may prevent processing. Purple-labelled amino acid sequence indicates the signal peptide.

Figure 2

Known actions of the natriuretic peptides through GC-A and GC-B activation. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; DNP, dendroaspis natriuretic peptide; cGMP, cyclic guanosine monophospate; sGC, soluble guanylyl cyclase; GC-A, guanylyl cyclase-A; GC-B, guanylyl cyclase-B; NO, nitric oxide; NPR-C, natriuretic peptide receptor-C; PDE, phosphodiesterase; PKG, protein kinase G; DPP4, dipeptidyl peptidase IV.

Figure 3

Angiotensin receptor blockade with neutral endopeptidase inhibition effects: decreased blood pressure as a result of the direct antihypertrophic, anti-fibrotic, endothelial, and renal-enhancing actions mediated by increased biological activities of the natriuretic peptides and by increased angiotensin type 2 receptor binding (adapted from Ruilope et al., Copyright 2010, with permission from Elsevier).