Like ANP, BNP is synthesized primarily in the heart. Also like ANP, the release of BNP appears to be volume related; indeed, the two peptides may be co-secreted. BNP exhibits natriuretic, diuretic, and hypotensive activities similar to those of ANP but circulates at a lower concentration.
CNP is located predominantly in the central nervous system but is also present in other tissues including the vascular endothelium, kidneys, and intestine. It has not been found in significant concentrations in the circulation. CNP has less natriuretic and diuretic activity than ANP and BNP but is a potent vasodilator and may play a role in the regulation of peripheral resistance.
Urodilatin is synthesized in the distal tubules of the kidneys by alternative processing of the ANP precursor. It elicits potent natriuresis and diuresis, and thus functions as a paracrine regulator of sodium and water excretion. It also relaxes vascular smooth muscle.
The biologic actions of the natriuretic peptides are mediated through association with specific high-affinity receptors located on the surface of the target cells (Figure 17–5). Three receptor subtypes termed NPR-A (ANP-A), NPR-B (ANP-B), and NPR-C (ANP-C) have been identified. The NPR-A and NPR-B receptors contain guanylyl cyclase at their intracellular domains. The primary ligands of the NPR-A receptor are ANP and BNP. The NPR-B receptor is similar in structure to the ANP-A receptor, but its primary ligand appears to be CNP. The NPR-C receptor may be coupled to adenylyl cyclase or phospholipase C; it binds all three natriuretic peptides and functions as a clearance receptor.
The natriuretic peptides have a short half-life in the circulation. They are metabolized in the kidneys, liver, and lungs by the neutral endopeptidase NEP 24.11 (neprilysin). Inhibition of this endopeptidase results in increases in circulating levels of the natriuretic peptides, natriuresis, and diuresis. The peptides are also removed from the circulation by binding to ANP-C receptors in the vascular endothelium. This receptor binds the natriuretic peptides with equal affinity. The receptor and bound peptide are internalized, the peptide is degraded enzymatically, and the receptor is returned to the cell surface. Patients with heart failure have high plasma levels of ANP and BNP; the latter has emerged as a diagnostic and prognostic marker in this condition.
Signaling? Peptide degradation EndocytosisReceptor IDE recycling NEPNPR-A GC-ANPR-A GC-ANPR-B GC-BNPR-B GC-B ANP=CNP>BNP Ring cleavage Tail cleavage GTP cGMP GTP cGMP cGMP GTP IntracellularNPR-CNPR-C
FIGURE 17–5 Natriuretic hormone receptors, intracellular signaling, and degradation processes. GC-A, guanylate cyclase type A; GC-B, guanylate cyclase type B; IDE, insulin degrading enzyme; NEP, neprilysin. (Adapted from Volpe M et al: The natriuretic peptides system in the pathophysiology of heart failure: From molecular basis to treatment. Clin Sci (Lond) 2016;130:57.)