Brain natriuretic peptide 32 (BNP)

August 29, 2022

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Brain natriuretic peptide 32 (BNP), also known as B-type natriuretic peptide, is a hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume. BNP is one of two natriuretic peptides
- ^{“UniProt”. www.uniprot.org. Retrieved 11 August 2022.}

The 32-amino acid polypeptide BNP is secreted attached to a 76–amino acid N-terminal fragment in the prohormone called NT-proBNP (BNPT), which is biologically inactive. Once released, BNP binds to and activates the atrial natriuretic factor receptor NPRA, and to a lesser extent NPRB, in a fashion similar to atrial natriuretic peptide (ANP) but with 10-fold lower affinity. The biological half-life of BNP, however, is twice as long as that of ANP, and that of NT-proBNP is even longer, making these peptides better targets than ANP for diagnostic blood testing.

The physiologic actions of BNP are similar to those of ANP and include decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis. The net effect of these peptides is a decrease in blood pressure due to the decrease in systemic vascular resistance and, thus, afterload. Additionally, the actions of both BNP and ANP result in a decrease in cardiac output due to an overall decrease in central venous pressure and preload as a result of the reduction in blood volume that follows natriuresis and diuresis.
- ^{“CV Pharmacology – Natriuretic Peptides”. cvpharmacology.com. Archived from the original on 21 October 2017. Retrieved 29 April 2018.}

Biosynthesis

BNP is synthesized as a 134-amino acid preprohormone (preproBNP), encoded by the human gene NPPB. Removal of the 25-residue N-terminal signal peptide generates the prohormone, proBNP, which is stored intracellularly as an O-linked glycoprotein; proBNP is subsequently cleaved between arginine-102 and serine-103 by a specific convertase (probably furin or corin) into NT-proBNP and the biologically active 32-amino acid polypeptide BNP-32, which are secreted into the blood in equimolar amounts.
- ^{Schellenberger U, O’Rear J, Guzzetta A, Jue RA, Protter AA, Pollitt NS (July 2006). “The precursor to B-type natriuretic peptide is an O-linked glycoprotein”. Archives of Biochemistry and Biophysics. 451 (2): 160–6. doi:10.1016/j.abb.2006.03.028. PMID 16750161.}
Cleavage at other sites produces shorter BNP peptides with unknown biological activity.
- ^{Niederkofler EE, Kiernan UA, O’Rear J, Menon S, Saghir S, Protter AA, Nelson RW, Schellenberger U (November 2008). “Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure”. Circulation: Heart Failure. 1 (4): 258–64. doi:10.1161/CIRCHEARTFAILURE.108.790774. PMID 19808300.}
Processing of proBNP may be regulated by O-glycosylation of residues near the cleavage sites.
- ^{Semenov AG, Postnikov AB, Tamm NN, Seferian KR, Karpova NS, Bloshchitsyna MN, Koshkina EV, Krasnoselsky MI, Serebryanaya DV, Katrukha AG (March 2009). “Processing of pro-brain natriuretic peptide is suppressed by O-glycosylation in the region close to the cleavage site”. Clinical Chemistry. 55 (3): 489–98. doi:10.1373/clinchem.2008.113373. PMID 19168558.}

Physiologic effects

Since the actions of BNP are mediated via the ANP receptors, the physiologic effects of BNP are identical to those of ANP, those will be reviewed here.^{[citation needed]}

Receptor-agonist binding causes a reduction in renal sodium reabsorption, which results in a decreased blood volume. Secondary effects may be an improvement in cardiac ejection fraction and reduction of systemic blood pressure. Lipolysis is also increased.^{[citation needed]}

Renal

Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the glomerular filtration rate (GFR), resulting in greater filter load of sodium and water.
Increases blood flow through the vasa recta, which will wash the solutes (NaCl and urea) out of the medullary interstitium.
- ^{Kiberd BA, Larson TS, Robertson CR, Jamison RL (June 1987). “Effect of atrial natriuretic peptide on vasa recta blood flow in the rat”. The American Journal of Physiology. 252 (6 Pt 2): F1112-7. doi:10.1152/ajprenal.1987.252.6.F1112. PMID2954471}
The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
Decreases sodium reabsorption in the distal convoluted tubule (interaction with NCC)
- ^{Reeves WB, Andreoli TE (2008). “Chapter 31 – Sodium Chloride Transport in the Loop of Henle, Distal Convoluted Tubule, and Collecting Duct”. In Giebisch GH, Alpern RA, Herbert SC, Seldin DW (eds.). Seldin and Giebisch’s the kidney: physiology and pathophysiology. Amsterdam: Elsevier/Academic Press. pp. 849–887. doi:10.1016/B978-012088488-9.50034-6. ISBN 978-0-12-088488-9}
and cortical collecting duct of the nephron via guanosine 3′,5′-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC.
Inhibits renin secretion, thereby inhibiting the renin–angiotensin–aldosterone system.

Adrenal

Reduces aldosterone secretion by the zona glomerulosa of the adrenal cortex.

Vascular

Relaxes vascular smooth muscle in arterioles and venules by:

Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
Inhibition of the effects of catecholamines

Promotes uterine spiral artery remodeling, which is important for preventing pregnancy-induced hypertension.
- ^{Cui Y, Wang W, Dong N, Lou J, Srinivasan DK, Cheng W, Huang X, Liu M, Fang C, Peng J, Chen S, Wu S, Liu Z, Dong L, Zhou Y, Wu Q (March 2012). “Role of corin in trophoblast invasion and uterine spiral artery remodelling in pregnancy”. Nature. 484 (7393): 246–50. Bibcode:2012Natur.484..246C. doi:10.1038/nature10897. PMC 3578422. PMID 22437503.}

Cardiac

Inhibits maladaptive cardiac hypertrophy
Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly
- ^{Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M (April 2000). “Cardiac fibrosis in mice lacking brain natriuretic peptide”. Proceedings of the National Academy of Sciences of the United States of America. 97 (8): 4239–44. Bibcode:2000PNAS…97.4239T. doi:10.1073/pnas.070371497. PMC 18212. PMID 10737768.}
Re-expression of NPRA rescues the phenotype.

Adipose tissue

Increases the release of free fatty acids from adipose tissue. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A
Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a cGMP-dependent protein kinase-I (cGK-I)
Does not modulate cAMP production or PKA activity

Measurement

BNP and NT-proBNP are measured by immunoassay.
- ^{Clerico A, Zaninotto M, Prontera C, Giovannini S, Ndreu R, Franzini M, Zucchelli GC, Plebani M (December 2012). “State of the art of BNP and NT-proBNP immunoassays: the CardioOrmoCheck study”. Clinica Chimica Acta; International Journal of Clinical Chemistry. 414: 112–9. doi:10.1016/j.cca.2012.07.017. hdl:11382/365432. PMID 22910582.}

Interpretation of BNP

The main clinical utility of either BNP or NT-proBNP is that a normal level helps to rule out chronic heart failure in the emergency setting. An elevated BNP or NT-proBNP should never be used exclusively to “rule in” acute or chronic heart failure in the emergency setting due to lack of specificity^{[dubious – discuss]}. (dubious? you know right there this is something to look at another day)
- ^{Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA (July 2002). “Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure”. The New England Journal of Medicine. 347 (3): 161–7. doi:10.1056/NEJMoa020233. PMID 12124404.}
Either BNP or NT-proBNP can also be used for screening and prognosis of heart failure.
- ^{Bhalla V, Willis S, Maisel AS (2004). “B-type natriuretic peptide: the level and the drug–partners in the diagnosis of congestive heart failure”. Congestive Heart Failure. 10 (1 Suppl 1): 3–27. doi:10.1111/j.1527-5299.2004.03310.x. PMID 14872150.}
BNP and NT-proBNP are also typically increased in patients with left ventricular dysfunction, with or without symptoms (BNP accurately reflects current ventricular status, as its half-life is 20 minutes, as opposed to 1–2 hours for NT-proBNP).
- ^{Atisha D, Bhalla MA, Morrison LK, Felicio L, Clopton P, Gardetto N, Kazanegra R, Chiu A, Maisel AS (September 2004). “A prospective study in search of an optimal B-natriuretic peptide level to screen patients for cardiac dysfunction”. American Heart Journal. 148 (3): 518–23. doi:10.1016/j.ahj.2004.03.014. PMID 15389242.}

A preoperative BNP can be predictive of a risk of an acute cardiac event during vascular surgery. A cutoff of 100 pg/ml has a sensitivity of approximately 100%, a negative predictive value of approximately 100%, a specificity of 90%, and a positive predictive value of 78% according to data from the United Kingdom.
- ^{Berry C, Kingsmore D, Gibson S, Hole D, Morton JJ, Byrne D, Dargie HJ (March 2006). “Predictive value of plasma brain natriuretic peptide for cardiac outcome after vascular surgery”. Heart. 92 (3): 401–2. doi:10.1136/hrt.2005.060988. PMC 1860808. PMID 16501204.}

BNP is cleared by binding to natriuretic peptide receptors (NPRs) and neutral endopeptidase (NEP). Less than 5% of BNP is cleared renally. NT-proBNP is the inactive molecule resulting from cleavage of the prohormone Pro-BNP and is reliant solely on the kidney for excretion. The achilles heel of the NT-proBNP molecule is the overlap in kidney disease in the heart failure patient population.
- ^{Austin WJ, Bhalla V, Hernandez-Arce I, Isakson SR, Beede J, Clopton P, Maisel AS, Fitzgerald RL (October 2006). “Correlation and prognostic utility of B-type natriuretic peptide and its amino-terminal fragment in patients with chronic kidney disease”. American Journal of Clinical Pathology. 126 (4): 506–12. doi:10.1309/M7AAXA0J1THMNCDF. PMID 16938661.}
- ^{Daniels LB, Clopton P, Bhalla V, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA, Maisel AS (May 2006). “How obesity affects the cut-points for B-type natriuretic peptide in the diagnosis of acute heart failure. Results from the Breathing Not Properly Multinational Study”. American Heart Journal. 151 (5): 999–1005. doi:10.1016/j.ahj.2005.10.011. PMID 16644321.}

Some laboratories report in units ng per Litre (ng/L), which is equivalent to pg/mL

There is a diagnostic ‘gray area’, often defined as between 100 and 500 pg/mL, for which the test is considered inconclusive, but, in general, levels above 500 pg/ml are considered to be an indicator of heart failure. This so-called gray zone has been addressed in several studies, and using clinical history or other available simple tools can help make the diagnosis.
- ^{Strunk A, Bhalla V, Clopton P, Nowak RM, McCord J, Hollander JE, Duc P, Storrow AB, Abraham WT, Wu AH, Steg G, Perez A, Kazanegra R, Herrmann HC, Aumont MC, McCullough PA, Maisel A (January 2006). “Impact of the history of congestive heart failure on the utility of B-type natriuretic peptide in the emergency diagnosis of heart failure: results from the Breathing Not Properly Multinational Study”. The American Journal of Medicine. 119 (1): 69.e1–11. doi:10.1016/j.amjmed.2005.04.029. PMID 16431187.}
- ^{Brenden CK, Hollander JE, Guss D, McCullough PA, Nowak R, Green G, Saltzberg M, Ellison SR, Bhalla MA, Bhalla V, Clopton P, Jesse R, Maisel AS (May 2006). “Gray zone BNP levels in heart failure patients in the emergency department: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study”. American Heart Journal. 151 (5): 1006–11. doi:10.1016/j.ahj.2005.10.017. PMID 16644322.}

BNP may be a reliable predictor of cardiovascular mortality in diabetics.
- ^{Bhalla MA, Chiang A, Epshteyn VA, Kazanegra R, Bhalla V, Clopton P, Krishnaswamy P, Morrison LK, Chiu A, Gardetto N, Mudaliar S, Edelman SV, Henry RR, Maisel AS (September 2004). “Prognostic role of B-type natriuretic peptide levels in patients with type 2 diabetes mellitus”. Journal of the American College of Cardiology. 44 (5): 1047–52. doi:10.1016/j.jacc.2004.05.071. PMID 15337217.}

BNP was found to have an important role in prognostication of heart surgery patients
- ^{Hutfless R, Kazanegra R, Madani M, Bhalla MA, Tulua-Tata A, Chen A, Clopton P, James C, Chiu A, Maisel AS (May 2004). “Utility of B-type natriuretic peptide in predicting postoperative complications and outcomes in patients undergoing heart surgery”. Journal of the American College of Cardiology. 43 (10): 1873–9. doi:10.1016/j.jacc.2003.12.048. PMID 15145114.}
and in the emergency department.
- ^{Maisel A, Hollander JE, Guss D, McCullough P, Nowak R, Green G, Saltzberg M, Ellison SR, Bhalla MA, Bhalla V, Clopton P, Jesse R (September 2004). “Primary results of the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT). A multicenter study of B-type natriuretic peptide levels, emergency department decision making, and outcomes in patients presenting with shortness of breath”. Journal of the American College of Cardiology. 44 (6): 1328–33. doi:10.1016/j.jacc.2004.06.015. PMID 15364340.}
Bhalla et al. showed that combining BNP with other tools like ICG can improve early diagnosis of heart failure and advance prevention strategies.
- ^{Bhalla V, Isakson S, Bhalla MA, Lin JP, Clopton P, Gardetto N, Maisel AS (February 2005). “Diagnostic ability of B-type natriuretic peptide and impedance cardiography: testing to identify left ventricular dysfunction in hypertensive patients”. American Journal of Hypertension. 18 (2 Pt 2): 73S–81S. doi:10.1016/j.amjhyper.2004.11.044. PMID 15752936.}
- ^{Castellanos LR, Bhalla V, Isakson S, Daniels LB, Bhalla MA, Lin JP, Clopton P, Gardetto N, Hoshino M, Chiu A, Fitzgerald R, Maisel AS (February 2009). “B-type natriuretic peptide and impedance cardiography at the time of routine echocardiography predict subsequent heart failure events”. Journal of Cardiac Failure. 15 (1): 41–7. doi:10.1016/j.cardfail.2008.09.003. PMID 19181293.}
Utility of BNP has also been explored in various settings like preeclampsia, ICU and shock and ESRD.
- ^{Resnik JL, Hong C, Resnik R, Kazanegra R, Beede J, Bhalla V, Maisel A (August 2005). “Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women”. American Journal of Obstetrics and Gynecology. 193 (2): 450–4. doi:10.1016/j.ajog.2004.12.006. PMID16098869}
- ^{Bhalla V, Bhalla MA, Maisel AS (August 2004). “Evolution of B-type natriuretic peptide in evaluation of intensive care unit shock”. Critical Care Medicine. 32 (8): 1787–9. doi:10.1097/01.CCM.0000135748.75590.54. PMID 15286561.}
- ^{Sheen V, Bhalla V, Tulua-Tata A, Bhalla MA, Weiss D, Chiu A, Abdeen O, Mullaney S, Maisel A (February 2007). “The use of B-type natriuretic peptide to assess volume status in patients with end-stage renal disease”. American Heart Journal. 153 (2): 244.e1–5. doi:10.1016/j.ahj.2006.10.041. PMID 17239684.}

The effect or race and gender on value of BNP and its utility in that context has been studied extensively.
- ^{Maisel AS, Clopton P, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Steg G, Westheim A, Knudsen CW, Perez A, Kazanegra R, Bhalla V, Herrmann HC, Aumont MC, McCullough PA (June 2004). “Impact of age, race, and sex on the ability of B-type natriuretic peptide to aid in the emergency diagnosis of heart failure: results from the Breathing Not Properly (BNP) multinational study”. American Heart Journal. 147 (6): 1078–84. doi:10.1016/j.ahj.2004.01.013. PMID 15199359.}
- ^{Daniels LB, Bhalla V, Clopton P, Hollander JE, Guss D, McCullough PA, Nowak R, Green G, Saltzberg M, Ellison SR, Bhalla MA, Jesse R, Maisel A (May 2006). “B-type natriuretic peptide (BNP) levels and ethnic disparities in perceived severity of heart failure: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study of BNP levels and emergency department decision making in patients presenting with shortness of breath”. Journal of Cardiac Failure. 12 (4): 281–5. doi:10.1016/j.cardfail.2006.01.008. PMID 16679261.}

	NYHA I	NYHA II	NYHA III	NYHA IV
5th Percentile	33	103	126	148
Mean	1015	1666	3029	3465
95th Percentile	3410	6567	10,449	12,188

The BNP test is used as an aid in the diagnosis and assessment of severity of heart failure. A recent meta-analysis concerning effects of BNP testing on clinical outcomes of patients presenting to the emergency department with acute dyspnea revealed that BNP testing led to a decrease in admission rates and decrease in mean length of stay, although neither was statistically significant. Effects on all cause hospital mortality was inconclusive.
- ^{Lam LL, Cameron PA, Schneider HG, Abramson MJ, Müller C, Krum H (December 2010). “Meta-analysis: effect of B-type natriuretic peptide testing on clinical outcomes in patients with acute dyspnea in the emergency setting”. Annals of Internal Medicine. 153 (11): 728–35. doi:10.7326/0003-4819-153-11-201012070-00006. PMID 21135296. S2CID 27272593.}
The BNP test is also used for the risk stratification of patients with acute coronary syndromes.
- ^{Bibbins-Domingo K, Gupta R, Na B, Wu AH, Schiller NB, Whooley MA (January 2007). “N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease”. JAMA. 297 (2): 169–76. doi:10.1001/jama.297.2.169. PMC 2848442. PMID 17213400.}
- ^{Fitzgerald RL, Cremo R, Gardetto N, Chiu A, Clopton P, Bhalla V, Maisel AS (September 2005). “Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure”. American Heart Journal. 150 (3): 471–7. doi:10.1016/j.ahj.2004.11.021. PMID 16169326.}

When interpreting an elevated BNP level, values may be elevated due to factors other than heart failure. Lower levels are often seen in obese patients.
- ^{Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS (February 2004). “Impact of obesity on plasma natriuretic peptide levels”. Circulation. 109 (5): 594–600. CiteSeerX 10.1.1.541.9955. doi:10.1161/01.CIR.0000112582.16683.EA. PMID 14769680. S2CID 13454777.}
Higher levels are seen in those with renal disease, in the absence of heart failure.

Therapeutic application

Recombinant BNP, nesiritide, has been suggested as a treatment for decompensated heart failure. However, a clinical trial failed to show a benefit of nesiritide in patients with acute decompensated heart failure.
- ^{O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. (July 2011). “Effect of nesiritide in patients with acute decompensated heart failure” (PDF). The New England Journal of Medicine. 365 (1): 32–43. doi:10.1056/NEJMoa1100171. hdl:11379/60663. PMID 21732835.}
Blockade of neprilysin, a protease known to degrade members of the natriuretic peptide family, has also been suggested as a possible treatment for heart failure. Dual administration of neprilysin inhibitors and angiotensin receptor blockers has been shown to be advantageous to ACE inhibitors, the current first-line therapy, in multiple settings.
- ^{McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (September 2014). “Angiotensin-neprilysin inhibition versus enalapril in heart failure”. The New England Journal of Medicine. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. hdl:10993/27659. PMID 25176015.}
- ^{Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E (February 2019). “Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure”. The New England Journal of Medicine. 380 (6): 539–548. doi:10.1056/NEJMoa1812851. PMID 30415601}

External links

Brain+Natriuretic+Peptide at the US National Library of Medicine Medical Subject Headings (MeSH)
BNP and NT-proBNP at Lab Tests Online
Human NPPB genome location and NPPB gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P16860 (Natriuretic peptides B) at the PDBe-KB.

Hormones

Protein: nerve tissue protein

attribution: copied from Brain natriuretic peptide version as of 13:57, 4 December 2019

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From Wikipedia where this page was last updated August 12, 2022