Natriuretic peptides: update on Peptide release, bioactivity, and clinical use.

In the 25 years since de Bold et al demonstrated the existence of an atrial natriuretic factor, investigation of the cardiac natriuretic peptides has produced a maturing knowledge base1,2 identifying the cardiac peptides and addressing stimuli for secretion of atrial (ANP) and B-type (BNP) natriuretic peptides, the processing and release of the mature bioactive carboxy terminal peptides, together with their propeptides and amino terminal fragments, the nature of natriuretic peptide receptors, and the bioactivities of natriuretic peptides (including natriuresis, vasodilatation, suppression of renin–angiotensin–aldosterone and sympathetic nervous activity, and trophic effects inhibiting vascular and cardiac hypertrophy and fibrosis). Less is known of the more recently discovered C-type natriuretic peptide (CNP and its cosecreted amino-terminal peptide, NTproCNP).3,4 Increasingly, measurements of the B-type peptides have found diagnostic and prognostic application in cardiovascular disease.5–7 The genes for ANP and BNP are in tandem on human chromosome 1.8 Upstream regulatory regions identified for the BNP gene include an AP1 binding site, serum response elements, M-CAT and GATA sites.9,10 Translation results in pre-pro BNP from which a 26 amino acid signal peptide is cleaved to produce the 108 amino acid precursor proBNP. This in turn is processed between amino acid residues 76 and 77 resulting in a 32 amino acid biologically active peptide (BNP) from its carboxy terminal plus the remaining amino terminal peptide sequence (NTproBNP 1 to 76). ANP is synthesized as a 126 amino acid precursor and is stored in granules within atrial tissue.11 During or shortly after secretion, the precursor is processed to an active 28 amino acid carboxy terminal peptide (ANP) and amino terminal ANP (proANP 1 to 98). The amino terminal propeptides NTproANP, NTproBNP, and NTproCNP have no known biological actions. The mature bioactive human forms of ANP, BNP, and CNP all contain a 17 member amino acid ring bound by cysteine-to-cysteine disulphide bonds with 11 of the 16 residues being conserved across ANP, BNP, and CNP. The 3 peptides have varying length amino terminal and carboxy terminal amino acid residue “tails” with CNP essentially lacking any carboxy terminal extension beyond the ring structure. The actions of ANP and BNP are mediated predominantly via the GC-A receptor and those of CNP via the GC-B receptor. All 3 peptides are subject to varying degrees of degradation by neutral endopeptidase (EC 3.4.24.11) and via uptake by the C (“clearance”) receptor. ANP and BNP and their receptors are widely distributed in brain, spinal cord, pituitary, kidney, adrenal gland, and vasculature in addition to the heart. Concentrations of immunoreactive ANP and BNP within the heart are up to 3 orders of magnitude higher than elsewhere, and within cardiac atria the concentrations of both peptides are 1 to 2 orders of magnitude higher than in ventricle.12 CNP is also widely distributed mainly in the vasculature with far lower cardiac levels than ANP or BNP. Diastolic stretch activates BNP promotion in human ventricular tissue.13 How myocytes sense strain is uncertain but may involve extra-cellular matrix-integrin cell surface attachments14,15 increasing gene transcription through the binding of transcription factors to upstream GATA elements in the BNP gene. Natriuretic peptide secretion is modulated by endothelin-1 and angiotensin II acting in paracrine-autocrine fashion.16,17 Estrogen levels and cytokine activity (including interleukin [IL]-1 ) can also alter natriuretic peptide secretory responses.10 Levels are also influenced, via uncertain pathways, by gender, age, glucocorticoid and thyroid hormone status, and hypoxemia. Much remains to be discovered concerning factors influencing expression, synthesis, and release of these peptides; and the determinants of receptor-mediated bioactivity. The clinical application of peptide immunoassays requires refinement to account for potentially confounding conditions including impaired renal function and obesity. The remainder of this brief review summarizes relevant reports that have been published in Hypertension over the 2004 to 2006 period.