Atrial natriuretic peptide

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For other uses, see ANP.
Natriuretic peptide A
ANP-structure.jpg
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NPPA ; ANF; ANP; ATFB6; CDD-ANF; PND
External IDs OMIM108780 MGI97367 HomoloGene4498 ChEMBL: 1293193 GeneCards: NPPA Gene
Orthologs
Species Human Mouse
Entrez 4878 230899
Ensembl ENSG00000175206 ENSMUSG00000041616
UniProt P01160 P05125
RefSeq (mRNA) NM_006172 NM_008725
RefSeq (protein) NP_006163 NP_032751
Location (UCSC) Chr 1:
11.91 – 11.91 Mb
Chr 4:
148 – 148 Mb
PubMed search [1] [2]

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 regards to its effect on sodium in the kidney - that is, aldosterone stimulates sodium retention and ANP generates sodium loss.[4][5]

Structure[edit]

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 the same amino acid ring. ANP was discovered in 1981 by a team in Kingston, Ontario, Canada, led by Adolfo J. de Bold after they made the seminal observation that injection of atrial (but not ventricular) tissue extracts into rats caused copious natriuresis.[6]

Production[edit]

The ANP gene has 3 exons and 2 introns; it codes 151-amino acid preproANP. Cleaving the 25-amino acid N-terminal results in pro-ANP. Corin, a membrane serine protease, cleaves the final ANP, the 28-amino acid C-terminal.

ANP is produced, stored, and released mainly by cardiac myocytes of the atria of the heart. Synthesis of ANP also takes place in the ventricles, brain, suprarenal glands, and renal glands. It is released in response to atrial stretch and a variety of other signals induced by hypervolemia, exercise, or caloric restriction.[1] The hormone is constitutively expressed in the ventricles in response to stress induced by increased afterload (e.g. increased ventricular pressure from aortic stenosis) or injury (e.g. myocardial infarction).

ANP is secreted in response to:

The atria become distended by high extracellular fluid and blood volume, and atrial fibrillation. It should be noted that ANP secretion increases in response to immersion of the body in water, which causes atrial stretch due to an altered distribution of intravascular fluid. ANP secretion in response to exercise has also been demonstrated in horses.[7]

ANP is also produced by the placenta in pregnant women. The exact function of this remains unclear. [8]

Receptors[edit]

Three types of atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. They are all cell surface receptors and are 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. Thus, 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. Atrial natriuretic peptide and brain natriuretic peptide bind and activate GC-A, whereas CNP binds and activates GC-B.[10]

Physiological effects[edit]

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[edit]

  • 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.[11] The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
  • Atrial natriuretic peptide (ANP) increases Na+ excretion by decreasing the amount of Na+ reabsorbed from the inner medullary collecting duct via a decrease in the permeability of the apical membrane of the collecting duct epithelial cells. Less Na+ is able to enter the epithelial cells and, therefore, less Na+ is reabsorbed. ANP also increases Na+ excretion by increasing the filtered load of Na+.

Vascular[edit]

Relaxes vascular smooth muscle in arterioles and venules by:

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

Cardiac[edit]

  • Inhibits maladaptive cardiac hypertrophy
  • Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly[13]
  • Re-expression of NPRA rescues the phenotype.

It may be associated with isolated atrial amyloidosis.[14]

Adipose tissue[edit]

  • 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[edit]

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.

Other natriuretic factors[edit]

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,[15] while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.[16]

Pharmacological modulation[edit]

Neutral endopeptidase (NEP) 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. 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.[17]

See also[edit]

References[edit]

  1. ^ a b c d e Widmaier, Eric P.; Hershel Raff; Kevin T. Strang (2008). Vander's Human Physiology, 11th Ed. McGraw-Hill. pp. 291, 509–10. ISBN 978-0-07-304962-5. 
  2. ^ Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 191 (191): 341–66. doi:10.1007/978-3-540-68964-5_15. ISBN 978-3-540-68960-7. PMID 19089336. 
  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. ISBN 0-387-51409-0. 
  4. ^ Goetz KL (1988). "Physiology and pathophysiology of atrial peptides". Am. J. Physiol. 254 (1 Pt 1): E1–15. PMID 2962513. 
  5. ^ Hoehn K, Marieb EN (2013). "16". Human anatomy & physiology (9th ed.). Boston: Pearson. p. 629. ISBN 978-0-321-74326-8. "question number 14" 
  6. ^ de Bold AJ (1985). "Atrial natriuretic factor: a hormone produced by the heart". Science 230 (4727): 767–70. doi:10.1126/science.2932797. PMID 2932797. 
  7. ^ Kokkonen, Ulla-Maija (2002). Plasma Atrial Natriuretic peptides in the horse and goat with special reference to exercising horses. 
  8. ^ http://www.biolreprod.org/content/54/4/834.full.pdf
  9. ^ Mohler ER, Finkbeiner WE (2011). Medical Physiology (Boron) (2 ed.). Philadelphia: Saunders. ISBN 1-4377-1753-5. 
  10. ^ Mäkikallio, Kaarin (2002). "ANP". Placental insufficiency and fetal heart: Doppler ultrasonographic and biochemical markers of fetal cardiac dysfunction. Oulu: Oulun yliopisto. ISBN 951-42-6737-0. OCLC 58358685. 
  11. ^ Kiberd BA, Larson TS, Robertson CR, Jamison RL (June 1987). "Effect of atrial natriuretic peptide on vasa recta blood flow in the rat". Am. J. Physiol. 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. ^ 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 As`thma Pathogenesis". The Journal of Allergy and Clinical Immunology 119 (1): S127. doi:10.1016/j.jaci.2006.11.482. 
  14. ^ Röcken C, Peters B, Juenemann G, Saeger W, Klein HU, Huth C, Roessner A, Goette A (October 2002). "Atrial amyloidosis: an arrhythmogenic substrate for persistent atrial fibrillation". Circulation 106 (16): 2091–7. doi:10.1161/01.CIR.0000034511.06350.DF. PMID 12379579. 
  15. ^ Tervonen V, Arjamaa O, Kokkonen K, Ruskoaho H, Vuolteenaho O (September 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. 
  16. ^ Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M (July 1992). "A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps)". J Biol Chem. 267 (20): 13928–32. PMID 1352773. 
  17. ^ Venugopal J (2003). "Pharmacological modulation of the natriuretic peptide system". Expert Opinion on Therapeutic Patents 13 (9): 1389. doi:10.1517/13543776.13.9.1389. 

External links[edit]