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Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are key regulators in the homeostasis of salt and water balance and in maintaining peripheral vessel tone. In the nearly 30 years since ANP was discovered by de Bold et al , 1 substantial knowledge has been advanced in this field. ANP and BNP expression and secretion increase significantly in response to pathophysiological stressors, such as hypertension, hypoxia, infection, cardiac ischaemia, ventricular hypertrophy, heart failure (HF) and cardiac allograft rejection. Radioimmunoassay and ELISA for natriuretic peptides have been developed and extensively used as biomarkers in a variety of clinical settings, 2 3 particularly in acute myocardial infarction (AMI) and HF diagnosis, risk stratification and treatment response monitoring. Most assays currently used in the clinical setting, however, cannot determine precise molecular forms of the natriuretic peptides. In contrast, chromatography-based methods, such as high-performance liquid chromatography (HPLC) and gel filtration chromatography (GFC) followed by western blotting or mass spectrometry, provide more accurate information about molecular forms of these peptides. In this article, we review the molecular forms of pro-ANP and pro-BNP and their derivatives, analyse available data in the literature and discuss their potential clinical implications.
ANP and BNP synthesis, function and modulation
Synthesis
During embryonic development, ANP and BNP genes are expressed in both the atrium and ventricle. After birth, these peptides are expressed mainly in the atrium, but are downregulated in the ventricle. In cardiomyocytes, ANP is synthesised as an inactive prepropeptide. After removal of the signal peptide, a 126 amino acid precursor, pro-ANP, is derived. Upon secretion from myocytes, pro-ANP is processed by the transmembrane enzyme corin at arginine 98, generating the amino-terminal (NT)-pro-ANP fragment of 98 amino acids and the carboxyl terminal (C-terminal) bioactive ANP of 28 amino acids. 4 5 Pro-ANP, NT-pro-ANP and ANP are all released into the circulation ( figure 1 ). Pro-BNP is synthesised in both the atrium and ventricle and is cleaved at arginine 76 to yield NT-pro-BNP and C-terminal bioactive BNP of 32 amino acids. In in-vitro experiments, both corin and furin cleaved pro-BNP into BNP. 5 6 However, the mechanism for pro-BNP post-translational maturation in vivo has not been established. In circulation, a small portion of BNP is further processed to BNP79-108 by dipeptidyl peptidase...