Atrial natriuretic peptide

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NPPA
ANP-structure.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NPPA, ANF, ANP, ATFB6, ATRST2, CDD, CDD-ANF, CDP, PND, Atrial natriuretic peptide, natriuretic peptide A
External IDs OMIM: 108780 MGI: 97367 HomoloGene: 4498 GeneCards: NPPA
Gene location (Human)
Chromosome 1 (human)
Chr. Chromosome 1 (human)[1]
Chromosome 1 (human)
Genomic location for NPPA
Genomic location for NPPA
Band 1p36.22 Start 11,845,709 bp[1]
End 11,848,345 bp[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_006172

NM_008725

RefSeq (protein)

NP_006163

NP_032751

Location (UCSC) Chr 1: 11.85 – 11.85 Mb Chr 1: 148 – 148 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Atrial natriuretic peptide (ANP) is a polypeptide hormone which reduces an expanded extracellular fluid (ECF) volume by increasing renal sodium excretion. ANP is synthesized, secreted, and released by heart muscle cells (myocytes) in the atrial wall. 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 hormones: seven are atrial in origen.

ANP acts on the kidney to increase sodium and water excretion in the following ways: 1) it dilates the glomerular afferent arterioles, constricts the 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 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.[5][6]

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 ventricular myocytes – 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[edit]

Discovery of ANP was reported in 1981: de Bold and colleagues found that rat atrial extracts contained a substance that increased salt and urine output in the kidney.[7] Later, the substance was purified from heart tissue by several groups and named ANF or ANP.[8]

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 a similar amino acid ring structure. ANP is one of a family of nine structurally similar natriuretic hormones: seven are atrial in origen.[9]

Production[edit]

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.[10][11]

ANP is secreted in response to:

Receptors[edit]

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.[13]

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[edit]

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[14]

ANP binds to a specific set of receptorsANP 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[edit]

Adrenal[edit]

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

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

Promotes uterine spiral artery remodeling, which is important for preventing pregnancy-induced hypertension.[18]

Cardiac[edit]

  • Inhibits maladaptive cardiac hypertrophy
  • Re-expression of NPRA rescues the phenotype.

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]

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[edit]

Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.[19] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.[20][21][22][23]

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.[24]

Therapeutic use and drug development[edit]

Recombinant human ANP has been approved in Japan to treat patients with heart failure.[25]

As of 2017 a truncated form of ANP called ularitide was under development in Phase III trials for heart failure.[26]

Other natriuretic peptides[edit]

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,[27] 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.[28]

Beside these four, five additional natriuretic peptides have been identified: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, urodilatin, and adrenomedullin.[29]

Pharmacological modulation[edit]

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.[30] 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.[31]

Synonyms[edit]

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

Outside reading[edit]

See also[edit]

References[edit]

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  29. ^ 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.
  30. ^ 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. PMID 25176015. doi:10.1056/NEJMoa1409077. 
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External links[edit]