Active form

Fig. 1. The formation of BNP (active form) from preproBNP.

is present in all natriuretic peptides (20,21). Eleven amino acids in the ring are homologous among all members of the natriuretic peptide family. BNP DNA has a 3'-untrans-lated region that is rich in an adenosine-thiamine sequence. This sequence destabilizes the mRNA molecule and causes it to have a short half-life (22,23). This TATTAT sequence is absent in ANP DNA.

BNP expression in myocytes is induced with rapid kinetics of the primary response gene (24). The rapid induction of transcription can be achieved by molecules that increase the half-life of mRNA. One of these molecules is an a-adrenergic receptor agonist that stabilizes BNP mRNA and induces its expression (24). In addition, BNP mRNA is inducible via ventricular wall tension or stretch (25-27). As a result, changes in BNP expression may represent myocardial ischemia, necrosis, damage, and local mechanical stress on ventricular myocytes, even when the global hemodynamic parameters remain unchanged (17).

Mechanism of Action

The natriuretic peptides incite their action through binding to high-affinity receptors mainly on endothelial cells, vascular smooth muscle cells, and other target cells. Three distinct natriuretic peptide receptors (NPRs) have been identified in mammalian tissues: NPR-A, -B, and -C (28). NPR-A and -B are structurally similar, with a 44% homology in the ligand-binding domain (29,30). A single membrane-spanning portion bridges the intracellular and extracellular segments of these receptors. Both types of receptors utilize a cGMP signaling cascade (28). NPR-B is mostly found in the brain, whereas NPR-A is more commonly located in large blood vessels (28). Both receptor types are also found in the adrenal glands and kidneys. NPR-A binds preferentially to ANP, but also binds to BNP. On the other hand, CNP is the natural ligand for B receptors (28).

BNP is removed from plasma through two distinct mechanisms: endocytosis and enzymatic degradation by endopeptidases (31). NPR-C binds to all members of natriuretic peptide family with equal affinity. When a ligand-receptor complex forms, the complex undergoes receptor-mediated endocytosis. The C-type receptors are recycled to the cellular membrane, and the various natriuretic peptides are degraded to building blocks.

Fig. 2. Age- and gender-related changes in BNP concentrations. (Data adapted from Wierzorek et al. Am Heart J 2002;144(5):834-839.) White bars: all subjects, dotted bars: males, black bars: females.

Fig. 2. Age- and gender-related changes in BNP concentrations. (Data adapted from Wierzorek et al. Am Heart J 2002;144(5):834-839.) White bars: all subjects, dotted bars: males, black bars: females.

The second mechanism to remove natriuretic peptides from plasma involves zinc-containing endopeptidases. These enzymes are present in renal tubules and vascular endothelial cells. They chew and degrade natriuretic peptides among other proteins.

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