Atrial natriuretic peptide
Encyclopedia
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. 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.
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
after they made the seminal observation that injection of atrial (but not ventricular) tissue extracts into rats caused copious natriuresis.
, exercise or caloric restriction. The hormone is constitutively expressed in the ventricle 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:
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 horse
s.
s have been identified on which natriuretic peptides act. They are all cell surface receptors and are designated:
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.
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
.
It may be associated with isolated atrial amyloidosis
.
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.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
secreted by heart muscle cells. It is involved in the homeostatic
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
control of body water
Water
Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
, sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
, potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
and fat (adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
). It is released by muscle cells in the upper chambers (atria
Atrium (anatomy)
In anatomy, the atrium , sometimes called auricle , refers to a chamber or space. For example, the term is used for a portion of the lateral ventricle in the brain and the blood collection chamber of the heart...
) 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.
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 cysteineCysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues at positions 7 and 23. ANP is closely related to BNP (brain natriuretic peptide
Brain natriuretic peptide
Brain natriuretic peptide , now known as B-type natriuretic peptide or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells...
) 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
Ontario
Ontario is a province of Canada, located in east-central Canada. It is Canada's most populous province and second largest in total area. It is home to the nation's most populous city, Toronto, and the nation's capital, Ottawa....
, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
after they made the seminal observation that injection of atrial (but not ventricular) tissue extracts into rats caused copious natriuresis.
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 hypervolemiaHypervolemia
Hypervolemia, or fluid overload, is the medical condition where there is too much fluid in the blood.The opposite condition is hypovolemia, which is too little fluid volume in the blood.-Causes:Excessive sodium or fluid intake:* IV therapy...
, exercise or caloric restriction. The hormone is constitutively expressed in the ventricle 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
- SympatheticSympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
stimulation of β-adrenoceptors - Raised sodiumSodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
concentration (hypernatremiaHypernatremiaHypernatremia or hypernatraemia is an electrolyte disturbance that is defined by an elevated sodium level in the blood. Hypernatremia is generally not caused by an excess of sodium, but rather by a relative deficit of free water in the body...
), though sodium concentration is not the direct stimulus for increased ANP secretion - AngiotensinAngiotensinAngiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...
-II - EndothelinEndothelinEndothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure and heart disease....
, a potent vasoconstrictor
The atria become distended by high extracellular fluid and blood volume, and atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
. 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 horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
s.
Receptors
Three types of atrial natriuretic peptide receptorAtrial natriuretic peptide receptor
A atrial natriuretic peptide receptor is a receptor for atrial natriuretic peptide.- Mechanism :NPRA and NPRB are linked to guanylyl cyclases, while NPRAC is G-protein-linked and is a "clearance receptor" that acts to internalise and destroy the ligand....
s have been identified on which natriuretic peptides act. They are all cell surface receptors and are designated:
- guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANPA) or NPR1NPR1Natriuretic peptide receptor A/guanylate cyclase A , also known as NPR1, is an atrial natriuretic peptide receptor...
- guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANPB) or NPR2NPR2Natriuretic peptide receptor B/guanylate cyclase B , also known as NPR2, is an atrial natriuretic peptide receptor. In humans it is encoded by the NPR2 gene.-External links:...
- natriuretic peptide clearance receptor (NPRC/ANPC) or NPR3NPR3Natriuretic peptide receptor C/guanylate cyclase C , also known as NPR3, is an atrial natriuretic peptide receptor...
NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds the ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
. 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
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...
to cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) that phosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
proteins at specific serine and threonine residues. In the medullary collecting duct
Collecting duct system
The collecting duct system of the kidney consists of a series of tubules and ducts that connect the nephrons to the ureter. It participates in electrolyte and fluid balance through reabsorption and excretion, processes regulated by the hormones aldosterone and antidiuretic hormone.There are several...
, 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
Brain natriuretic peptide
Brain natriuretic peptide , now known as B-type natriuretic peptide or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells...
bind and activate GC-A, whereas CNP binds and activates GC-B.
Physiological effects
ANP binds to a specific set of receptors - ANP receptors. Receptor-agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
binding causes a reduction in blood volume and therefore a reduction in cardiac output and systemic blood pressure. Lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
is increased and renal sodium reabsorption
Renal sodium reabsorption
Renal reabsorption of sodium is a part of renal physiology. It uses Na-H antiport, Na-glucose symport, sodium ion channels . It is stimulated by angiotensin II and aldosterone, and inhibited by atrial natriuretic peptide....
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
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
.
Renal
- Dilates the afferent glomerular arteriole, constricts the efferent glomerular arteriole, and relaxes the mesangial cellMesangial cellMesangial cells are specialized cells around blood vessels in the kidneys, at the mesangium. They are specialized smooth muscle cells that function to regulate blood flow through the capillaries, usually divided into two types, each having a very distinct function and location:* Extraglomerular...
s. This increases pressure in the glomerularGlomerulusA glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...
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 interstitum leads to less reabsorption of tubular fluid and increased excretion.
- Decreases sodium reabsorption in the proximal convoluted tubule and cortical collecting duct of the nephronNephronThe renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
via guanosine 3',5'-cyclic monophosphate (cGMPCyclic guanosine monophosphateCyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
) dependent phosphorylation of ENaCEpithelial sodium channelThe epithelial sodium channel is a membrane-bound ion-channel that is permeable for Li+-ions, protons and especially Na+-ions. It is a constitutively active ion-channel...
- Inhibits reninReninRenin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
secretion, thereby inhibiting the renin-angiotensin system.
- Reduces aldosterone secretion by the 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
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 amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
.
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 kinaseCGMP-dependent protein kinasecGMP-dependent protein kinase or Protein Kinase G is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell...
-I (cGK-I) - Does not modulate cAMPCyclic adenosine monophosphateCyclic adenosine monophosphate is a second messenger important in many biological processes...
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.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 salmonSalmon
Salmon is the common name for several species of fish in the family Salmonidae. Several other fish in the same family are called trout; the difference is often said to be that salmon migrate and trout are resident, but this distinction does not strictly hold true...
natriuretic peptide known as salmon cardiac peptide, while dendroaspis natriuretic peptide (DNP) can be found in the venom of the green mamba
Mamba
Mambas, of the genus Dendroaspis , are a group of highly venomous, fast-moving land-dwelling snakes of Africa. They belong to the family of Elapidae which includes cobras, coral snakes, taipans, brown snakes, tiger snakes, death adders, kraits and, debatably, sea snakes...
, a species of African snake.
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.See also
- Brain natriuretic peptideBrain natriuretic peptideBrain natriuretic peptide , now known as B-type natriuretic peptide or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells...
- C-type natriuretic peptide
- Atrial volume receptorsAtrial volume receptorsAtrial volume receptors are low pressure baroreceptors that are found in the atria of heart.When these receptors detect pressure drop in the atria, which is indicative for a decrease in blood volume, signal is transmitted from the atrial volume receptors to the hypothalamus of brain. The...