The natriuretic peptide family consists of a number of structurally homologous but genetically distinct polypeptide mediators. The peptides are highly conserved across mammalian and invertebrate species and, in humans, are released from various tissues in response to physiological and pathological stimuli. All the peptides have at their core a 17-amino acid disulfide ring essential for receptor recognition and biological function.
The first description of secretory granules in the cardiac atria was given in 1956, to be followed by the physiological characterisation of an atrial natriuretic factor in the work of de Bold and colleagues in 1981.1 Several further natriuretic peptides have subsequently been identified. These include B type natriuretic peptide (BNP) predominantly from ventricular myocardium (although originally isolated from pig brain)2 and C type natriuretic peptide (CNP) expressed in the nervous system and endothelial cells.3 A homologue of the natriuretic factor, DNP, in the venom of the green mamba Dendroaspis angusticeps, is found in plasma and atrial myocardium of normal humans.4 Urodilatin is a renal derived natriuretic peptide.5 ANP and BNP, the predominant natriuretic peptides in mammalian cardiomyocytes, are stored within secretory granules as pro-peptides, pro-ANP and pro-BNP, that are post-translationally modified by peptide bond cleavage to form the mature circulating peptides and amino (N)-terminal residues.6
Biological activity of the peptides generally resides in the mature carboxy-terminal residues, although pro-ANP and pro-BNP may exhibit some activity. The (N)-terminal residues are generally inactive. Relatively little is known about the processing of BNP in the circulation. The peptides are eventually cleared by the natriuretic peptide-C receptor (NPR-C)—a clearance receptor. Binding of natriuretic peptides to NPR-C leads to internalisation and degradation.7 Neutral endopeptidase 24.11 (NEP) also takes part in the inactivation of natriuretic peptides and there is a minor contribution from renal excretion. Both NPR-C and NEP are widely expressed in the kidneys, lungs, and the vascular wall.
A variety of physiological and pathological stimuli evoke the release of ANP and BNP. Such stimuli include exercise, hypoxia, ischaemia, increased wall stress and dilatation of the cardiac chambers, and sepsis. The classical endocrine actions of ANP and BNP, namely vasodilatation and natriuresis, are mediated by interaction with a natriuretic peptide receptor (NPR)-A which is a particulate guanylyl cyclase (pGC). This cyclase subserves the same biochemical function as soluble guanylyl cyclase (sGC)—the principal intracellular receptor for NO—namely, the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP). NPR-A is widely expressed in cardiovascular tissues, and its activation by ANP and BNP leads to elevation of intracellular cGMP and activation of the cGMP dependent protein kinase (PKG-I).7 CNP engages another receptor subtype, NPR-B, also a pGC receptor, while DNP acts via NPR-A, mediating a predominant vasorelaxing action.8