Atrial natriuretic peptide

Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), atrial natriuretic hormone (ANH), Cardionatrine, Cardiodilatine (CDD) or atriopeptin, is a powerful vasodilator, and a protein (is_associated_with::polypeptide) is_associated_with::hormone secreted by heart muscle cells. It is involved in the homeostatic control of body is_associated_with::water, is_associated_with::sodium, is_associated_with::potassium and fat (is_associated_with::adipose tissue). It is released by muscle cells in the upper chambers (atria) of the heart (is_associated_with::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 is_associated_with::aldosterone secreted by the is_associated_with::zona glomerulosa in regard to its effect on sodium in the kidney – that is, aldosterone stimulates sodium retention and ANP generates sodium loss.

Discovery
ANP was discovered in the early 1980s. de Bold and colleagues in Kingston, is_associated_with::Ontario, is_associated_with::Canada found that rat atrial extracts contained a substance that increased salt and urine output in the kidney. Later, the substance was purified from the heart by several groups and named ANF or ANP.

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 is_associated_with::cysteine residues at positions 7 and 23. ANP is closely related to BNP (is_associated_with::brain natriuretic peptide) and CNP (is_associated_with::C-type natriuretic peptide), which all share a similar amino acid ring structure.

Production
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 is_associated_with::cardiac myocytes. Lower levels of NPPA expression are found in other tissues such as the brain, kidney, lung, uterus and placenta.

In is_associated_with::cardiac 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 is_associated_with::corin.

ANP is secreted in response to:
 * Stretching of the atrial wall
 * Reduced Sympathetic stimulation of β-adrenoceptors
 * Raised is_associated_with::sodium concentration (is_associated_with::hypernatremia), though sodium concentration is not the direct stimulus for increased ANP secretion
 * is_associated_with::Angiotensin-II
 * is_associated_with::Endothelin, a potent is_associated_with::vasoconstrictor
 * exercise

Receptors
Three types of is_associated_with::atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. They are all is_associated_with::cell surface receptors and designated:


 * guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANPA) or is_associated_with::NPR1
 * guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANPB) or is_associated_with::NPR2
 * natriuretic peptide clearance receptor (NPRC/ANPC) or is_associated_with::NPR3

NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds the is_associated_with::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.

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.

ANP and is_associated_with::brain natriuretic peptide bind and activate GC-A, whereas CNP binds and activates GC-B.

Physiological effects
ANP binds to a specific set of receptors – is_associated_with::ANP receptors. Receptor-is_associated_with::agonist binding causes a reduction in blood volume and, therefore, a reduction in cardiac output and systemic blood pressure. is_associated_with::Lipolysis is increased and is_associated_with::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 is_associated_with::renin-angiotensin system.

Renal

 * Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the is_associated_with::mesangial cells. This increases pressure in the glomerular capillaries, thus increasing the is_associated_with::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 is_associated_with::distal convoluted tubule (interaction with NCC) and is_associated_with::cortical collecting duct of the is_associated_with::nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC
 * Inhibits is_associated_with::renin secretion, thereby inhibiting the is_associated_with::renin–angiotensin–aldosterone system.

Adrenal

 * Reduces aldosterone secretion by the zona glomerulosa of the is_associated_with::adrenal cortex.

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.

Cardiac

 * 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.

It may be associated with isolated atrial is_associated_with::amyloidosis.

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 is_associated_with::NPR-A
 * Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of a is_associated_with::cGMP-dependent protein kinase-I (cGK-I)
 * Does not modulate cAMP production or PKA activity

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.

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

Therapeutic use
Recombinant human ANP has been approved in Japan to treat patients with heart failure.

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 is_associated_with::salmon natriuretic peptide known as salmon cardiac peptide, while is_associated_with::dendroaspis natriuretic peptide (DNP) can be found in the venom of the green is_associated_with::mamba, a species of African snake.

Pharmacological modulation
Neutral endopeptidase (NEP) also known as is_associated_with::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. 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 is_associated_with::LCZ696 versus is_associated_with::enalapril in patients with heart failure. The study showed lower all cause mortality, cardiovascular mortality and hospitalization in is_associated_with::LCZ696 arm. is_associated_with::Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to is_associated_with::angioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are currently being developed by pharmaceutical companies.