Atrial natriuretic peptide
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| Location (UCSC) | Chr 1: 11.85 – 11.85 Mb | Chr 4: 148.09 – 148.09 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Atrial Natriuretic Peptide (ANP) or atrial natriuretic factor (ANF) is a natriuretic peptide hormone secreted from the cardiac atria that in humans is encoded by the NPPA
Reduction of blood volume by ANP can result in secondary effects such as reduction of extracellular fluid (ECF) volume, 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.
Clinical significance
A member of the natriuretic peptide gene family, NPPA encodes an important cardiac signaling molecule known as atrial natriuretic peptide/factor (ANP).[7] ANP carries out endocrine functions of the heart. It acts as a diuretic by inhibiting sodium reabsorption in the kidneys. ANP also acts in the heart to prevent cardiac hypertrophy and to regulate vascular remodeling and energy metabolism.[8] NPPA expression is varied throughout mammalian development into adulthood. Fetal expression of NPPA is associated with the formation of chamber myocardium, muscle cells of the atria and ventricles in the early developing heart.[9] Early expression of this gene has been associated with ventricular hypertrophy in both in vitro and in vivo models.[10] NPPA variants affect plasma ANP concentrations, blood pressure levels, and cardiovascular diseases such as atrial fibrillation (AF).[citation needed] ANP-deficient mice were found to have a large increase in heart and left ventricular weight in response to volume overload, which is normally prevented by proper regulation of blood pressure.[11] Using a knock-in (KI) rat model, researchers found an AF-associated human variant in NPPA caused inflammation, fibroblast activation, atrial fibrosis, and AF in KI rats.[12] These findings suggest NPPA is a critical gene in cardiac development and dysfunction of this gene can lead to heart problems via altered ANP levels.
Discovery
The discovery of a natriuretic factor (one that promotes kidney excretion of salt and water) was first reported by Adolfo José de Bold in 1981 when rat atrial extracts were found to contain a substance that increased salt and urine output in the kidney.[13] Later, the substance was purified from heart tissue by several groups and named atrial natriuretic factor (ANF) or ANP.[14]
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
Production
ANP is synthesized as an inactive
ANP is secreted in response to:
- Stretching of the atrial wall, via Atrial volume receptors
- Increased β-adrenoceptors
- Increased sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion[20]
- vasoconstrictor
Receptors
Three types of
- 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
The binding of ANP to its receptor causes the conversion of
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.[citation needed]
Physiological effects
Maintenance of the ECF volume (space), and its subcompartment the vascular space, is crucial for survival.[
ANP binds to a specific set of
Renal
ANP acts on the kidney to increase sodium and water excretion (natriuresis) in the following ways:[22][23]
- The medullary collecting duct is the main site of ANP regulation of sodium excretion.[24] ANP effects sodium channels at both the apical and basolateral sides.[24] ANP inhibits ENaC on the apical side and the Sodium Potassium ATPase pump on the basolateral side in a cGMP PKG dependent manner resulting in less sodium re-absorption and more sodium excretion.[25]
- ANP increases glomerular filtration rate and glomerular permeability.[24] ANP directly dilates the afferent arteriole and counteracts the norepinephrine induced vasoconstriction of the afferent arteriole.[25] Some studies suggest that ANP also constricts the efferent arteriole, but this is not a unanimous finding.[25] ANP inhibits the effect of Angiotensin II on the mesangial cells, thereby relaxing them.[25] ANP increases the radius and number of glomerular pores, thereby increasing glomerular permeability and resulting in greater filter load of sodium and water.[24]
- Increases blood flow through the vasa recta, which will wash the solutes (sodium chloride (NaCl), and urea) out of the medullary interstitium. The lower osmolarity of the medullary interstitium leads to less reabsorption of tubular fluid and increased excretion.
- Decreases sodium reabsorption at least in the .
- It inhibits renin secretion, thereby inhibiting the production of angiotensin and aldosterone.
- It inhibits the renal sympathetic nervous system.
ANP has the opposite effect of angiotensin II on the kidney: angiotensin II increases renal sodium retention and ANP increases renal sodium loss.
Adrenal
- Reduces aldosterone secretion by the zona glomerulosa of the adrenal cortex.[citation needed]
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.[26]
Cardiac
- ANP inhibits cardiac hypertrophy in heart failure as well as fibrosis.[27] Fibrosis is inhibited by preventing fibroblasts from entering heart tissue and replicating, as well as decreasing inflammation.[27] ANP prevents hypertrophy by inhibiting calcium influx that is caused by norepinephrine.[27]
- Re-expression of NPRA rescues the phenotype.[citation needed]
Adipose tissue
- Increases the release of free fatty acidsfrom 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.
Immune System
ANP is produced locally by several immune cells. ANP is shown to regulate several functions of innate and adaptive immune system as well as shown to have cytoprotective effects.[28]
- ANP modulates innate immunity by raising defence against extracellular microbes and inhibiting the release of pro-inflammatory markers and expression of adhesion molecules.[28]
- There is evidence of cytoprotective effects of ANP in myocardial, vascular smooth, endothelial, hepatocytes and tumour cells.[28]
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, such as Sacubitril and Sacubitril/valsartan. They may be clinically useful in treating patients in heart failure with reduced ejection fraction .
Biomarker
Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.[29] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.[30][31][32][33] A specific ANP precursor called mid-regional pro-atrial natriuretic peptide (MRproANP) is a highly sensitive biomarker in heart failure.[34] MRproANP levels below 120 pmol/L can be used to effectively rule out acute heart failure.[34]
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.[35]
Therapeutic use and drug development
Opinions regarding the use of ANP for the treatment of
Other natriuretic peptides
In addition to the mammalian natriuretic peptides (ANP,
Beside these four, five additional natriuretic peptides have been identified: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide, urodilatin, and adrenomedullin.[15]
Pharmacological modulation
Neutral endopeptidase (NEP) also known as
Synonyms
ANP is also called atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), cardionatrine, cardiodilatin (CDD), and atriopeptin.
Notes
Wikidata Q28082833 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000175206 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041616 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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question number 14
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External links
- Atrial+Natriuretic+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human NPPA genome location and NPPA gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P01160 (Natriuretic peptides A) at the PDBe-KB.