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natriuretic peptide precursor A
Identifiers
Symbol	NPPA
Alt. symbols	ANP, PND
Entrez	4878
HUGO	7939
OMIM	108780
PDB	1ANP
RefSeq	NM_006172
UniProt	P01160
Other data
Locus	Chr. 1 p36.21

Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), or atriopeptin, is a powerful vasodilator, and a protein (polypeptide) hormone secreted by heart muscle cells.^[1]^[2] 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 pressure. ANP acts to reduce the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure.^[1]

[edit] 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 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.^[3]

[edit] Production

ANP is produced, stored and released by cardiac myocytes of the atria of the heart. 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 ventricle in response to stress induced by increased afterload (eg. increased ventricular pressure from aortic stenosis) or injury (eg. myocardial infarction).

ANP is secreted in response to:

Atrial distention, stretching of the vessel walls^[1]
Sympathetic stimulation of β-adrenoceptors
Raised sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion^[1]
Angiotensin-II
Endothelin, a potent vasoconstrictor

The atria become distended by high extracellular fluid and blood volume, and atrial fibrillation. Notably, 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 ^[4] .

[edit] Receptors

Three cell surface receptors have been identified on which natriuretic peptides act. They are designated:

guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANP_A) or NPR1
guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANP_B) or NPR2
natriuretic peptide clearance receptor (NPRC/ANP_C) or NPR3

GC-A and GC-B are cell surface, single membrane-spanning receptors with intrinsic guanylate cyclase activity. The vast majority of natriuretic peptide-dependent effects are mediated by elevations of intracellular cGMP concentrations. 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.^[5]

[edit] Physiological effects

ANP binds to a specific set of receptors - ANP 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.

[edit] 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.^[6] The lower osmolarity of the medullary interstitum leads to less reabsorption of tubular fluid and increased excretion.

Decreases sodium reabsorption in the distal convoluted tubule 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 system.

Reduces aldosterone secretion by the adrenal cortex.

[edit] 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

[edit] Cardiac

Inhibits maladaptive cardiac hypertrophy
Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly ^[7]
Re-expression of NPRA rescues the phenotype.

It may be associated with isolated atrial amyloidosis.^[8]

[edit] 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

[edit] 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.

[edit] 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,^[9] while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.^[10]

[edit] Diagnostic Use

Used in conjunction with other clinical information, measurement of B-type natriuretic peptide (BNP) can help determine whether a patient's dyspnea is caused by congestive heart failure in which BNP levels are elevated. This laboratory test has become a valuable and quick method for diagnostic work-up of patients presenting to the emergency department (ED) with acute dyspnea.

[edit] Pharmacological modulation

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.^[11]

[edit] See also

[edit] References

^ ^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.
^ Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". Handb Exp Pharmacol 191 (191): 341–66. doi:10.1007/978-3-540-68964-5_15. PMID 19089336.
^ de Bold A (1985). "Atrial natriuretic factor: a hormone produced by the heart". Science 230 (4727): 767–70. doi:10.1126/science.2932797. PMID 2932797.
^ Kokkonen, Ulla-Maija (2002). Plasma Atrial Natriuretic peptides in the horse and goat with special reference to exercising horses. http://ethesis.helsinki.fi/julkaisut/ela/perus/vk/kokkonen/plasmaat.pdf.
^ Mäkikallio, Kaarin (2002). "ANP". Placental insufficiency and fetal heart: Doppler ultrasonographic and biochemical markers of fetal cardiac dysfunction. Oulu: Oulun yliopisto. ISBN 9514267370. OCLC 58358685. http://herkules.oulu.fi/isbn9514267370/html/x656.html.
^ 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. http://ajprenal.physiology.org/cgi/content/abstract/252/6/F1112.
^ 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 Allergic and Clinical Immunology 119 (1): S127. doi:10.1016/j.jaci.2006.11.482.
^ Röcken C, Peters B, Juenemann G, et al (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. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12379579.
^ 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. http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=9724061.
^ 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1352773.
^ 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. http://www.expertopin.com/doi/abs/10.1517/13543776.13.9.1389.

[edit] External links

MeSH Atrial+Natriuretic+Factor

[Widmaier-0] 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.

[pmid19089336-1] Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM (2009). "Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications". Handb Exp Pharmacol 191 (191): 341–66. doi:10.1007/978-3-540-68964-5_15. PMID 19089336.

[2] Bold A (1985). "Atrial natriuretic factor: a hormone produced by the heart". Science 230 (4727): 767–70. doi:10.1126/science.2932797. PMID 2932797.

[3] Kokkonen, Ulla-Maija (2002). Plasma Atrial Natriuretic peptides in the horse and goat with special reference to exercising horses. http://ethesis.helsinki.fi/julkaisut/ela/perus/vk/kokkonen/plasmaat.pdf.

[4] Mäkikallio, Kaarin (2002). "ANP". Placental insufficiency and fetal heart: Doppler ultrasonographic and biochemical markers of fetal cardiac dysfunction. Oulu: Oulun yliopisto. ISBN 9514267370. OCLC 58358685. http://herkules.oulu.fi/isbn9514267370/html/x656.html.

[pmid2954471-5] 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. http://ajprenal.physiology.org/cgi/content/abstract/252/6/F1112.

[6] 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 Allergic and Clinical Immunology 119 (1): S127. doi:10.1016/j.jaci.2006.11.482.

[pmid12379579-7] Röcken C, Peters B, Juenemann G, et al (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. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12379579.

[8] 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. http://endo.endojournals.org/cgi/pmidlookup?view=long&pmid=9724061.

[9] 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1352773.

[10] 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. http://www.expertopin.com/doi/abs/10.1517/13543776.13.9.1389.

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