Atrial natriuretic peptide
|Natriuretic peptide A|
|Symbols||; ANF; ANP; ATFB6; CDD-ANF; PND|
|External IDs||ChEMBL: GeneCards:|
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. 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. 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.
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.
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. 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:
- Atrial distention, stretching of the vessel walls
- Sympathetic stimulation of β-adrenoceptors
- Raised sodium concentration (hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion
- Endothelin, a potent vasoconstrictor
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.
- 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. 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.
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.
- 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. 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) and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC
- Reduces aldosterone secretion by the adrenal cortex.
- 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+.
Relaxes vascular smooth muscle in arterioles and venules by:
- Membrane Receptor-mediated elevation of vascular smooth muscle cGMP
- Inhibition of the effects of catecholamines
- Inhibits maladaptive cardiac hypertrophy
- Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly
- Re-expression of NPRA rescues the phenotype.
- 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
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
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, while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba, a species of African snake.
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.
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