**3. B-Type natriuretic peptide (BNP)**

BNP is predominantly produced in the cardiac ventricles. However under pathologic conditions, such as fluid overload, the cardiac atrium can also become a significant source of BNP(Sudoh et al. 1988; McGrath, de Bold, and de Bold 2005). Biosynthesis of BNP begins with a 134 amino acid precursor, preproBNP. Stimuli, such as myocyte stretch, trigger the cleavage of preproBNP forming proBNP, which is subsequently cleaved by a serine protease to the active C-terminal 32 amino acid hormone, BNP, and the inactive N-terminal proBNP (NT-proBNP). BNP binds to 3 known cell membrane receptors, termed natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C). NPR-A and NPR-B are transmembrane receptors that activate particulate guanylate cyclase, which catalyzes the conversion of guanosine triphosphate to cGMP. The third receptor, NPR-C, is involved in clearance via endocytosis. Circulating BNP is also inactivated by cleavage by neutral endopeptidases found in vascular cells and renal tubules (Figure 1) (Yandle 1994; Silver et al. 2004). Animal studies suggest that approximately half of natriuretic peptide clearance is via the NPR-C receptor and half via endopeptidase degradation, but the relative contributions in the human are unclear.

Fig. 1. A schematic of B-type natriuretic peptide (BNP) signaling. BNP binds to 3 natriuretic peptide receptors (NPR), types A, B, and C, on various target cells located in the vasculature, kidney, heart, adrenal glands, and brain. NPR-A and NPR-B are high-affinity receptors with an extracellular binding domain, a single membrane-spanning region, and an intracellular guanylylcyclase domain. Guanylylcyclase catalyzes the conversion of guanosine-5'-triphosphate (GTP) to guanosine-3',5'-cyclic monophosphate (cGMP). BNP is degraded by two mechanisms. Neutral endopeptidases degrade circulating BNP, and binding to NPR-C results in receptor internalization and degradation by endocytosis. NPR-C is then recycled to the cell membrance (not shown).

BNP is predominantly produced in the cardiac ventricles. However under pathologic conditions, such as fluid overload, the cardiac atrium can also become a significant source of BNP(Sudoh et al. 1988; McGrath, de Bold, and de Bold 2005). Biosynthesis of BNP begins with a 134 amino acid precursor, preproBNP. Stimuli, such as myocyte stretch, trigger the cleavage of preproBNP forming proBNP, which is subsequently cleaved by a serine protease to the active C-terminal 32 amino acid hormone, BNP, and the inactive N-terminal proBNP (NT-proBNP). BNP binds to 3 known cell membrane receptors, termed natriuretic peptide receptors (NPR-A, NPR-B, and NPR-C). NPR-A and NPR-B are transmembrane receptors that activate particulate guanylate cyclase, which catalyzes the conversion of guanosine triphosphate to cGMP. The third receptor, NPR-C, is involved in clearance via endocytosis. Circulating BNP is also inactivated by cleavage by neutral endopeptidases found in vascular cells and renal tubules (Figure 1) (Yandle 1994; Silver et al. 2004). Animal studies suggest that approximately half of natriuretic peptide clearance is via the NPR-C receptor and half via endopeptidase degradation, but the relative contributions in the human are unclear.

Fig. 1. A schematic of B-type natriuretic peptide (BNP) signaling. BNP binds to 3 natriuretic

vasculature, kidney, heart, adrenal glands, and brain. NPR-A and NPR-B are high-affinity receptors with an extracellular binding domain, a single membrane-spanning region, and an

guanosine-5'-triphosphate (GTP) to guanosine-3',5'-cyclic monophosphate (cGMP). BNP is degraded by two mechanisms. Neutral endopeptidases degrade circulating BNP, and binding to NPR-C results in receptor internalization and degradation by endocytosis. NPR-

peptide receptors (NPR), types A, B, and C, on various target cells located in the

intracellular guanylylcyclase domain. Guanylylcyclase catalyzes the conversion of

C is then recycled to the cell membrance (not shown).

**3. B-Type natriuretic peptide (BNP)** 

The mechanisms that mediate BNP release and metabolism in health and disease are incompletely understood. In addition, the effect of development on these mechanisms is unknown, but clearly may have great relevance in a pediatric population. Active BNP is stored in the atria in specific storage organelles(McGrath, de Bold, and de Bold 2005). Basal BNP levels result from continuous secretion from the atria. With acute myocardial distention, BNP release increases from this storage pool, in a manner independent of BNP synthesis. However, under acute, sub-acute and chronic conditions of increased cardiac volume or pressure loading, increases in circulating BNP are maintained due to ventricular re-expression of the fetal gene program (Zhang, Carreras, and de Bold 2003; Hama et al. 1995). In addition to volume and pressure loading, acute myocardial ischemia, α agonist stimulation, endothelin-1, and inflammatory mediators, such as tumor necrosis factor-α and interleukin-1β, result in rapid ventricular expression of BNP(Hama et al. 1995). The primary actions of BNP are vascular smooth muscle relaxation and anti-mitogenesis, mediated by cGMP, diuresis, caused by a shift of intravascular volume into the interstitium, and natriuresis, caused by antagonism of renin and aldosterone release(McGrath, de Bold, and de Bold 2005; Sudoh et al. 1988; Yandle 1994).

Of all the natriuretic peptides, BNP has emerged as the most useful biomarker for cardiac disease. Its major advantage over the other natriuretic peptides is the fact that it is produced predominantly in the ventricles, as opposed to the atrium (ANP) or the vascular endothelium (CNP)(Silver et al. 2004; Costello, Goodman, and Green 2006). Both active BNP and the inactive byproduct of its production, NT-proBNP, are used as biomarkers. BNP levels may be better suited to follow dynamic alterations in myocardial performance given the shorter circulating half-life of BNP compared to NT-proBNP (20 minutes vs. 60-120 minutes)(Costello, Goodman, and Green 2006). In addition, the kidneys excrete NT-proBNP, and thus renal function, independent of myocardial function, has a greater influence on NTproBNP levels than BNP levels.

Limited data suggest that BNP levels are high at birth but fall during the first week of life, reaching levels below adult values by 2 weeks of age. Interestingly, although levels in boys tend to decrease with age, girls have an elevation during the second decade of life that is associated with puberty (Koch and Singer 2003; Yoshibayashi et al. 1995; Ationu and Carter 1993).
