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Atrial natriuretic peptide

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Title: Atrial natriuretic peptide  
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Subject: Pacemaker syndrome, Renal physiology, Vasopressin, Adolfo J. de Bold, Natriuretic peptide
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Atrial natriuretic peptide

Natriuretic peptide A
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; ANF; ANP; ATFB6; ATRST2; CDD; CDD-ANF; CDP; PND
External IDs ChEMBL: GeneCards:
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), Cardionatrine, Cardiodilatine (CDD) or atriopeptin, is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells.[1][2][3] It is involved in the homeostatic control of body water, sodium, potassium and fat (adipose tissue). It is released by muscle cells in the upper chambers (atria) of the heart (atrial myocytes) in response to high blood volume. ANP acts to reduce the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure.[1] ANP has exactly the opposite function of the aldosterone secreted by the zona glomerulosa in regard to its effect on sodium in the kidney – that is, aldosterone stimulates sodium retention and ANP generates sodium loss.[4][5]

Contents

  • Discovery 1
  • Structure 2
  • Production 3
  • Receptors 4
  • Physiological effects 5
    • Renal 5.1
    • Adrenal 5.2
    • Vascular 5.3
    • Cardiac 5.4
    • Adipose tissue 5.5
  • Degradation 6
  • Biomarker 7
  • Therapeutic use 8
  • Other natriuretic factors 9
  • Pharmacological modulation 10
  • See also 11
  • References 12
  • External links 13

Discovery

ANP was discovered in the early 1980s. de Bold and colleagues in Kingston, Ontario, Canada found that rat atrial extracts contained a substance that increased salt and urine output in the kidney.[6] Later, the substance was purified from the heart by several groups and named ANF or ANP.[7]

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.

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 cardiac myocytes. Lower levels of NPPA expression are found in other tissues such as the brain, kidney, lung, uterus and placenta.

In cardiac 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.[8][9]

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.[11]

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.

ANP and brain natriuretic peptide bind and activate GC-A, whereas CNP binds and activates GC-B.[12]

Physiological effects

ANP binds to a specific set of receptorsANP receptors. Receptor-agonist binding causes a reduction in blood volume and, therefore, a reduction in cardiac output and systemic blood pressure. Lipolysis is increased and renal sodium reabsorption is decreased. The overall effect of ANP on the body is to counter increases in blood pressure and volume caused by the renin-angiotensin system.

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 excretion of sodium and water.
  • Increases blood flow through the vasa recta, which will wash the solutes (NaCl and urea) out of the medullary interstitium.[13] 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)[14] 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.[15]

Cardiac

  • Inhibits maladaptive cardiac hypertrophy
  • Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly[16]
  • Re-expression of NPRA rescues the phenotype.

It may be associated with isolated atrial amyloidosis.[17]

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

Regulation 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 the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.[18] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.[19][20][21][22]

Therapeutic use

Recombinant human ANP has been approved in Japan to treat patients with heart failure.[23]

Other natriuretic factors

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. Tervonen (1998) described a salmon natriuretic peptide known as salmon cardiac peptide,[24] while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.[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. 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 currently being developed by pharmaceutical companies.[27]

See also

References

  1. ^ a b c d Widmaier EP, Raff H, Strang KT (2008). Vander's Human Physiology, 11th Ed. McGraw-Hill. pp. 291, 509–10.  
  2. ^ Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". Handbook of Experimental Pharmacology. Handbook of Experimental Pharmacology 191 (191): 341–66.  
  3. ^ Addicks K, Forssmann WG, Henkel H, Holthausen U, Menz V, Rippegather G, Ziskoven D (1989). "Calcium-calmodulin antagonists Influences the release of cardiodilatin/ANP from atrial cardiocytes". In Wambach G, Kaufmann W. Endocrinology of the heart. Berlin: Springer-Verlag.  
  4. ^ Goetz KL (Jan 1988). "Physiology and pathophysiology of atrial peptides" (PDF). The American Journal of Physiology 254 (1 Pt 1): E1–15.  
  5. ^ Hoehn K, Marieb EN (2013). "16". Human anatomy & physiology (9th ed.). Boston: Pearson. p. 629.  
  6. ^ 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.  
  7. ^ de Bold AJ (Nov 1985). "Atrial natriuretic factor: a hormone produced by the heart". Science 230 (4727): 767–70.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ Kokkonen UM, Pösö AR, Hyyppä S, Huttunen P, Leppäluoto J (Apr 2002). "Exercise-induced changes in atrial peptides in relation to neuroendocrine responses and fluid balance in the horse". Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine 49 (3): 144–50.  
  11. ^ Mohler ER, Finkbeiner WE (2011). Medical Physiology (Boron) (2 ed.). Philadelphia: Saunders.  
  12. ^ Mäkikallio K (2002). "ANP". Placental insufficiency and fetal heart: Doppler ultrasonographic and biochemical markers of fetal cardiac dysfunction. Oulu: Oulun yliopisto.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ Kong X, Wang X, Hellermann G, Lockey RF, Mohapatra S (2007). "Mice Deficient in Atrial Natriuretic Peptide Receptor A (NPRA) Exhibit Decreased Lung Inflammation: Implication of NPRA Signaling in Asthma Pathogenesis". The Journal of Allergy and Clinical Immunology 119 (1): S127.  
  17. ^ Röcken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C, Roessner A, Goette A (Oct 2002). "Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation". Circulation 106 (16): 2091–7.  
  18. ^ 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.  
  19. ^ 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.  
  20. ^ 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.  
  21. ^ 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.  
  22. ^ 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.  
  23. ^ Saito Y (Nov 2010). "Roles of atrial natriuretic peptide and its therapeutic use". Journal of Cardiology 56 (3): 262–70.  
  24. ^ 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.  
  25. ^ 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.  
  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.  
  27. ^ Venugopal J (2003). "Pharmacological modulation of the natriuretic peptide system". Expert Opinion on Therapeutic Patents 13 (9): 1389–1409.  

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