The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides.

Natriuretic peptides and the reninangiotensin-aldosterone system (RAAS) have reciprocal effects at multiple sites and in varied situations. They interact in health and cardiovascular disease to influence renal, endocrine, and haemodynamic function and cardiovascular cell growth. The atrial natriuretic peptide (atrial natriuretic factor, ANF) discovered by De Bold in 19811 was cloned and sequenced by molecular biological techniques in 1984.2 The related peptides, brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), were sequenced in 1988 and 1990, respectively.34 The mature forms of the peptides share a common core structure consisting of a 17-amino acid ring with some conservation of amino acid residues between peptides (fig 1).24 ANF is present at high concentrations in atrial tissue, and in lesser amounts in the central nervous system and plasma. BNP was originally identified in the porcine brain, but subsequent work showed that it is primarily a cardiac hormone. CNP, the most recently discovered member of the natriuretic peptide family, has no carboxy terminal extension (fig 1). It is widespread in vascular endothelium and is the most prevalent of the three peptides within the central nervous system, while little is present in the heart. The natriuretic peptides exert their biological activity through specific cell receptors. Three natriuretic peptide receptors (NPR) have been characterised. NPR-A and NPR-B have guanylate cyclase activity and mediate biological activity through the second messenger cyclic guanosine monophosphate (cGMP). NPR-C is not guanylate cyclase linked, and functions as a "clearance receptor", removing natriuretic peptides from the circulation.5 ANF and BNP stimulate cGMP production through the NPR-A receptor. The NPR-B receptor is selective for CNP.6 The NPR-C (clearance receptor) binds all three of the natriuretic peptides. Natriuretic peptides are also subject to clearance by enzymatic degradation. The neutral endopeptidase EC 3A4'24'11 contributes to ANF clearance (and to a lesser extent BNP clearance) in humans.7 The biochemistry of natriuretic peptides is further detailed in a recent review.8 The focus of the present review is the interaction of the cardiac natriuretic peptides with the RAAS. Studies in humans will be reviewed, with additional information from in vitro or intact animal experiments where appropriate.