Nesiritide acetate

Properties

The Mr of mature human BNP is 3466 and the pI is ca. 10. Both pro- and mature BNP are freely soluble in water, acid, and 67% acetone, but insoluble in 99% acetone. BNP solution in water at >10^-4M is stable for more than a year at -20°C.

Gene, mRNA, and precursor

The BNP (NPPB) and atrial natriuretic peptide (ANP) genes (NPPA) are thought to be generated by the tandem duplication of the CNP3 gene (NPPC). The human NPPA and NPPB are located on chromosome 1 (1p36.22). The mouse BNP and ANP genes (Nppb and Nppa) are on chromosome 4. NPPB is composed of three exons. Human BNP mRNA is 708 bp (405 bp coding sequence). One of the characteristics of BNP mRNA is a repetitive AUUUA motif in the 30 -untranslated region. The motif is considered to destabilize mRNA, and does not exist in ANP mRNA, suggesting that NPPB is regulated differently from NPPA. Human proBNP is O-glycosylated posttranslationally. O-Glycosylated proBNP is further processed by specific convertases (probably furin and corin) to give rise to the bioactive, mature form of BNP and inactive N-terminal (NT)-proBNP. It is suggested that the cleavage of proBNP is regulated by O-glycosylation at threonine-71.

Synthesis and release

BNP in the cardiac ventricle is secreted via a constitutive pathway as opposed to ANP secretion that occurs via a regulatory pathway (except BNP in the atrium, where BNP is stored and secreted with ANP). BNP production is regulated transcriptionally and various regulatory elements are located in the 50 -flanking region of NPPB, including GATA, M-CAT, and AP-1/CRE-like elements; NRSE; shear stress-responsive elements; thyroid hormone-responsive elements; and the nuclear factor of the activated T-cell (NFAT) binding site. Putative transcription factors are GATA4, YY1, and KLF13.5 BNP expression in cardiomyocytes is enhanced by mechanical stretch, TGF-β, and ET-1.

Receptors

BNP shares two receptors with ANP and VNP (cardiac NP found in ray-finned fish). The A-type NP receptor (NPR-A or GC-A) is a functional receptor, and has a guanylyl cyclase domain that produces cGMP. The order of potency for cGMP production via NPR-A is ANP≥BNP≥CNP in humans. Another receptor is the C-type NP receptor (NPR-C). The NPR-C lacks a cytoplasmic guanylyl cyclase domain, and acts as a clearance receptor. Affinities of NPR-C to NPs are ANP>CNP>BNP in humans. The longer half-life of plasma BNP is attributable mainly to the lower susceptibility to NPR-C. In mammals, NPR-A is highly expressed in the adrenal, brain, kidney, adipose, aortic, and lung tissues, whereas NPR-C is found ubiquitously in most tissues. For more details on NPR-A and NPR-C, the signaling transduction pathway, and the agonists/ antagonists, Atrial natriuretic peptide

Biological functions

The biological actions of BNP are overlapped with those of ANP because they share the same functional receptor, NPR-A . Briefly, BNP induces natriuresis and diuresis by increasing the glomerular filtration rate and decreasing water and sodium reabsorption by the kidney. In addition, BNP decreases aldosterone secretion from the adrenal and vasopressin secretion from the posterior pituitary, which also accelerates natriuresis and diuresis. BNP also decreases systemic vascular resistance by its direct vasorelaxant action. Thus, the net effect of BNP is to decrease blood volume (preload) and systemic blood pressure (afterload), thereby protecting cardiac function. In eels, again similarly to ANP actions, BNP decreases water intake, plasma sodium concentration, and aortic pressure, but the effect is weaker than that of ANP and VNP in the case of eels that have VNP.

Clinical implications

The elevation of plasma BNP concentration is seen in patients with congestive heart failure (CHF), myocardial infarction, hypertension, left ventricular hypertrophy, and chronic renal failure. Although the plasma ANP level is also elevated by such pathological conditions, the increment of the BNP level is quicker and greater than that of ANP. In CHF, for instance, the plasma BNP and ANP concentrations increase 200–300-fold and 10–30-fold, respectively, compared with those in normal humans. The greater increase in BNP level is probably due to its longer half-life in plasma. Thus, the plasma BNP level is used as a reliable biomarker of both ischemic and CHF. NT-proBNP cleaved with the BNP precursor has a longer half-life (about 120min), and thus is used as a more reliable marker for the diagnosis of heart failure. Recent studies showed that a high level of O-glycosylated proBNP circulates in patients with severe heart failure.

Description

B-type natriuretic peptide is the only cardiac natriuretic peptide common to all vertebrate species thus far examined. The plasma BNP level is used as a robust and reliable biomarker for the diagnosis and prognosis of heart failure. BNP was isolated in 1988 from porcine brain extracts and was thus named the brain natriuretic peptide. Soon thereafter, BNP was found to be expressed abundantly in the cardiac ventricle and scarcely in the brains of humans and rats. Currently, BNP has been recognized as a principal cardiac hormone and referred to as the B-type natriuretic peptide.

Uses

hemostatic, antimicrobial

Clinical Use

The severity of CHF assessed by the New York Heart Association (NYHA) functional classification is correlated positively with the elevation of plasma BNP and NT-proBNP levels. Therefore, these peptides are used for the diagnosis and management of patients with CHF. The use of a recombinant BNP, nesiritide, for treatment has been approved by the US Food and Drug Administration. It has beneficial effects in patients with acute, decompensated heart failure; however, it is reported to increase the risk of renal dysfunction and mortality. Further evaluation is required for the clinical use of nesiritide.

Structure and conformation

Human proBNP consists of 108 aa residues with bioactive mature BNP (47 aa residues) at the C-terminus. Like other natriuretic peptides (NPs), BNP has an intramolecular ring consisting of 17 aa residues and N- and C-terminal extensions of varying length. All vertebrate species (tetrapods and fish) except for chondrichthyes and cyclostomes possess BNP.2 Thus, the BNP gene (nppb) is considered to have occurred before the divergence of ray-finned fish and lobefinned fish. The sequence identity of mature BNP is quite variable in mammals (<50% identity between human and mouse BNP), whereas the identity is relatively high among nonmammalian vertebrates.

References

1. Ziskoven D, Forssmann WG, Holthausen U, Menz G, Addicks K, Rippegater G: Calcium Calmodulinantagonists Influences the release of Cardiodilatin/ANP from Atrial Cardiocytes. Handbook Endocrinology of the Heart, edited by Kaufmann W, Wambach G, 01/1989; Springer Verlag Berlin Heidelberg New York;2. Maisel A, Krishnaswamy P, Nowak R, McCord J, Hollander J, Duc P, Omland T, Storrow A, Abraham W, Wu A, Clopton P, Steg P, Westheim A, Knudsen C, Perez A, Kazanegra R, Herrmann H, McCullough P (2002). "Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure". N Engl J Med 347 (3): 161–7.3. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. TheNew Englandjournal of medicine 2011;365:32-43.