Atrial natriuretic peptide

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For other uses, see ANP.
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Atrial natriuretic peptide (ANP) is a peptide hormone which reduces an expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized, and secreted by cardiac muscle cells in the walls of the atria in the heart. These cells contain volume receptors which respond to increased stretching of the atrial wall due to increased atrial blood volume. ANP is one of a family of nine natriuretic peptides: seven are atrial in origin.

ANP acts on the kidney to increase sodium and water excretion (natriuresis) in the following ways: 1) it dilates the glomerular afferent and efferent arterioles, and relaxes the mesangial cells. This increases pressure in the glomerular capillaries, increasing the glomerular filtration rate (GFR), resulting in an increased amount of sodium and water being filtered and excreted. 2) It increases blood flow through the vasa recta, which washes the solutes sodium chloride (NaCl) and urea out of the medullary interstitium – the lower osmolarity here leads to less reabsorption of tubular fluid and increased excretion. 3) It decreases sodium reabsorption in the distal convoluted tubule and cortical collecting duct. 4) It inhibits renin secretion, thereby inhibiting the production of angiotensin and aldosterone. 5) It inhibits the renal sympathetic nervous system. ANP has the opposite effect of aldosterone on the kidney: aldosterone increases renal sodium retention and ANP increases renal sodium loss.[1][2]

Reduction of blood volume by ANP can result in secondary effects such as reduction of extracellular fluid (ECF) volume (edema), improved cardiac ejection fraction with resultant improved organ perfusion, decreased blood pressure, and increased serum potassium. These effects may be blunted or negated by various counter-regulatory mechanisms operating concurrently on each of these secondary effects.

Brain natriuretic peptide (BNP) – a misnomer; it is secreted by cardiac muscle cells in the heart ventricles – is similar to ANP in its effect. It acts via the same receptors as ANP does, but with 10-fold lower affinity than ANP. 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 choices than ANP for diagnostic blood testing.

Discovery

The discovery of ANP was reported in 1981, when rat atrial extracts were found to contain a substance that increased salt and urine output in the kidney.[3] Later, the substance was purified from heart tissue by several groups and named atrial natriuretic factor (ANF) or ANP.[4]

Structure

ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23. ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share a similar amino acid ring structure. ANP is one of a family of nine structurally similar natriuretic hormones: seven are atrial in origen.[5]

Production

Human ANP is encoded by the NPPA gene on the short arm of chromosome 1, which has 3 exons and 2 introns. The gene is expressed primarily in atrial myocytes. Lower levels of NPPA expression are found in other tissues such as the brain, kidney, lung, uterus and placenta.

In atrial myocytes, ANP is made as a precursor form, i.e. prepro-ANP, a polypeptide of 151 amino acids. After the signal peptide is removed in the endoplasmic reticulum, the 126-amino-acid pro-ANP is stored in the intracellular granules. When the cells are stimulated, pro-ANP is released and converted to the 28-amino-acid C-terminal mature ANP on the cell surface by the cardiac transmembrane serine protease corin.[6][7]

ANP is secreted in response to:

Receptors

Three types of atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. They are all cell surface receptors and designated:

  • guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANPA) or NPR1
  • guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANPB) or NPR2
  • natriuretic peptide clearance receptor (NPRC/ANPC) or NPR3

NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds the ligand. The intracellular domain maintains two consensus catalytic domains for guanylyl cyclase activity. Binding of a natriuretic peptide induces a conformational change in the receptor that causes receptor dimerization and activation.

The binding of ANP to its receptor causes the conversion of GTP to cGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) that phosphorylates proteins at specific serine and threonine residues. In the medullary collecting duct, the cGMP generated in response to ANP may act not only through PKG but also via direct modulation of ion channels.[9]

NPR-C functions mainly as a clearance receptor by binding and sequestering ANP from the circulation. All natriuretic peptides are bound by the NPR-C.

Physiological effects

Maintenance of the ECF volume (space), and its subcompartment the vascular space, is crucial for survival. These compartments are maintained within a narrow range, despite wide variations in dietary sodium intake. There are three volume regulating systems: two salt saving systems, the renin angiotensin aldosterone system (RAAS) and the renal sympathetic system (RSS); and the salt excreting natriuretic peptide (NP) hormone system. When the vascular space contracts, the RAAS and RSS are "turned on" ; when the atria expand, NP's are "turned on". Each system also suppresses its counteracting system(s). NP's are made in cardiac, intestinal, renal, and adrenal tissue: ANP in one of a family of cardiac NP's: others at BNP, CNP, and DNP.[10]

ANP binds to a specific set of receptors – ANP receptors. Receptor-agonist binding causes the increase in renal sodium excretion, which results in a decreased ECF and blood volume. Secondary effects may be an improvement in cardiac ejection fraction and reduction of systemic blood pressure.

Renal

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.[14]

Cardiac

  • Inhibits maladaptive cardiac hypertrophy
  • 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

Degradation

Modulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzyme neutral endopeptidase (NEP). Recently, NEP inhibitors have been developed; however they have not yet been licensed. They may be clinically useful in treating congestive heart disease.

Biomarker

Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.[15] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.[16][17][18][19]

Large amounts of ANP secretion has been noted to cause electrolyte disturbances (hyponatremia) and polyuria. These indications can be a marker of a large atrial myxoma.[20]

Therapeutic use and drug development

Recombinant human ANP has been approved in Japan to treat patients with heart failure.[21]

As of 2017 a truncated form of ANP called ularitide was under development in Phase III trials for heart failure.[22]

Other natriuretic peptides

Brain natriuretic peptide (BNP) – a misnomer; it is secreted by ventricular myocytes – is similar to ANP in its effect. It acts via atrial natriuretic peptide receptors but with 10-fold lower affinity than ANP. 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 choices than ANP for diagnostic blood testing.

In addition to the mammalian natriuretic peptides (ANP, BNP, CNP), other natriuretic peptides with similar structure and properties have been isolated elsewhere in the animal kingdom. A salmon natriuretic peptide known as salmon cardiac peptide has been described,[23] and dendroaspis natriuretic peptide (DNP) has been found in the venom of the green mamba, as well as an NP in a species of African snake.[24]

Beside these four, five additional natriuretic peptides have been identified: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, urodilatin, and adrenomedullin.[25]

Pharmacological modulation

Neutral endopeptidase (NEP) also known as neprilysin is the enzyme that metabolizes natriuretic peptides. Several inhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure. Most of them are dual inhibitors (NEP and ACE). In 2014, PARADIGM-HF study was published in NEJM. This study considered as a landmark study in treatment of heart failure. The study was double blinded; compared LCZ696 versus enalapril in patients with heart failure. The study showed lower all cause mortality, cardiovascular mortality and hospitalization in LCZ696 arm.[26] Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.[27]

Synonyms

ANP is also called atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), cardionatrine, cardiodilatin (CDD), and atriopeptin.

Outside reading

References

  1. ↑ Goetz KL (Jan 1988). "Physiology and pathophysiology of atrial peptides" (PDF). The American Journal of Physiology. 254 (1 Pt 1): E1–15. PMID 2962513.
  2. ↑ Hoehn K, Marieb EN (2013). "16". Human anatomy & physiology (9th ed.). Boston: Pearson. p. 629. ISBN 978-0-321-74326-8. question number 14
  3. ↑ de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (Jan 1981). "A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats". Life Sciences. 28 (1): 89–94. doi:10.1016/0024-3205(81)90370-2. PMID 7219045.
  4. ↑ de Bold AJ (Nov 1985). "Atrial natriuretic factor: a hormone produced by the heart". Science. 230 (4727): 767–70. Bibcode:1985Sci...230..767D. doi:10.1126/science.2932797. PMID 2932797.
  5. ↑ Vesely Chapter 39, Antinatriureic peptides, in Seldin and Giebisch’s The Kidney, Fifth Edition. Page 1242. DOI:http://dx.doi.org/10.1016/B978-0-12-381462-3.00037-9. 2013 Elsevier Inc. (c) All rights reserved
  6. ↑ Yan W, Sheng N, Seto M, Morser J, Wu Q (May 1999). "Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart". The Journal of Biological Chemistry. 274 (21): 14926–35. doi:10.1074/jbc.274.21.14926. PMID 10329693.
  7. ↑ Yan W, Wu F, Morser J, Wu Q (Jul 2000). "Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme". Proceedings of the National Academy of Sciences of the United States of America. 97 (15): 8525–9. Bibcode:2000PNAS...97.8525Y. doi:10.1073/pnas.150149097. PMC 26981. PMID 10880574.
  8. ↑ name="Widmaier" >Widmaier EP, Raff H, Strang KT (2008). Vander's Human Physiology, 11th Ed. McGraw-Hill. pp. 291, 509–10. ISBN 978-0-07-304962-5.
  9. ↑ Mohler ER, Finkbeiner WE (2011). Medical Physiology (Boron) (2 ed.). Philadelphia: Saunders. ISBN 1-4377-1753-5.
  10. ↑ Chapter 37 – Natriuretic Hormones, in Seldin and Giebisch's The Kidney (Fifth Edition), 2013, Page 1241, David L. Vesely
  11. ↑ Kiberd BA, Larson TS, Robertson CR, Jamison RL (Jun 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. PMID 2954471.
  12. ↑ 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. Seldin and Giebisch's the kidney: physiology and pathophysiology. Amsterdam: Elsevier/Academic Press. doi:10.1016/B978-012088488-9.50034-6. ISBN 0-12-088488-7.
  13. ↑ Fernandes-Cerqueira C, Sampaio-Maia B, Quelhas-Santos J, Moreira-Rodrigues M, Simões-Silva L, Blazquez-Medela AM, Martinez-Salgado C, Lopez-Novoa JM, Pestana M (2013). "Concerted action of ANP and dopamine D1-receptor to regulate sodium homeostasis in nephrotic syndrome". BioMed Research International. 2013: 397391. doi:10.1155/2013/397391. PMC 3727124. PMID 23956981.
  14. ↑ 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 (Apr 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.
  15. ↑ Goetze JP, Hansen LH, Terzic D, Zois NE, Albrethsen J, Timm A, Smith J, Soltysinska E, Lippert SK, Hunter I (Mar 2015). "Atrial natriuretic peptides in plasma". Clinica Chimica Acta; International Journal of Clinical Chemistry. 443: 25–8. doi:10.1016/j.cca.2014.08.017. PMID 25158019.
  16. ↑ Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS (Feb 2004). "Plasma natriuretic peptide levels and the risk of cardiovascular events and death". The New England Journal of Medicine. 350 (7): 655–63. doi:10.1056/NEJMoa031994. PMID 14960742.
  17. ↑ Sabatine MS, Morrow DA, de Lemos JA, Omland T, Sloan S, Jarolim P, Solomon SD, Pfeffer MA, Braunwald E (Jan 2012). "Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease". Circulation. 125 (2): 233–40. doi:10.1161/CIRCULATIONAHA.111.063842. PMC 3277287. PMID 22179538.
  18. ↑ Mäkikallio AM, Mäkikallio TH, Korpelainen JT, Vuolteenaho O, Tapanainen JM, Ylitalo K, Sotaniemi KA, Huikuri HV, Myllylä VV (May 2005). "Natriuretic peptides and mortality after stroke". Stroke: A Journal of Cerebral Circulation. 36 (5): 1016–20. doi:10.1161/01.STR.0000162751.54349.ae. PMID 15802631.
  19. ↑ Barbato E, Bartunek J, Marchitti S, Mangiacapra F, Stanzione R, Delrue L, Cotugno M, Di Castro S, De Bruyne B, Wijns W, Volpe M, Rubattu S (Mar 2012). "NT-proANP circulating level is a prognostic marker in stable ischemic heart disease". International Journal of Cardiology. 155 (2): 311–2. doi:10.1016/j.ijcard.2011.11.057. PMID 22177588.
  20. ↑ Ramnarain, D; Mehra, N (2011). "Natriuretic peptide-induced hyponatremia in a patient with left atrial myxoma". Critical Care. 15 (Suppl 1): P368. doi:10.1186/cc9788. PMC 3067042.
  21. ↑ Saito Y (Nov 2010). "Roles of atrial natriuretic peptide and its therapeutic use". Journal of Cardiology. 56 (3): 262–70. doi:10.1016/j.jjcc.2010.08.001. PMID 20884176.
  22. ↑ "Ularitide". AdisInsight. Retrieved 6 August 2017.
  23. ↑ Tervonen V, Arjamaa O, Kokkonen K, Ruskoaho H, Vuolteenaho O (Sep 1998). "A novel cardiac hormone related to A-, B- and C-type natriuretic peptides". Endocrinology. 139 (9): 4021–5. doi:10.1210/en.139.9.4021. PMID 9724061.
  24. ↑ Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M (Jul 1992). "A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps)". The Journal of Biological Chemistry. 267 (20): 13928–32. PMID 1352773.
  25. ↑ Vesely Chapter 39, Antinatriureic peptides, in Seldin and Giebisch’s The Kidney, Fifth Edition. DOI:http://dx.doi.org/10.1016/B978-0-12-381462-3.00037-9. (c)2013 Elsevier Inc.
  26. ↑ McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (Sep 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". The New England Journal of Medicine. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015.
  27. ↑ Venugopal J (2003). "Pharmacological modulation of the natriuretic peptide system". Expert Opinion on Therapeutic Patents. 13 (9): 1389–1409. doi:10.1517/13543776.13.9.1389.

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