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Atrial natriuretic peptide
From Wikipedia, the free encyclopedia
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natriuretic peptide precursor A
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| Identifiers | |
| Symbol | NPPA |
| Alt. Symbols | ANP, PND |
| Entrez | 4878 |
| HUGO | 7939 |
| OMIM | 108780 |
| RefSeq | NM_006172 |
| UniProt | P01160 |
| Other data | |
| Locus | Chr. 1 p36.21 |
Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), or atriopeptin, is a polypeptide hormone involved in the homeostatic control of body water, sodium, and adiposity. It is released by atrial myocytes, muscle cells in the atria of the heart, in response to high blood pressure. ANP acts to reduce the water, sodium and adipose loads on the circulatory system, thereby reducing blood pressure.
Contents |
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 Ottawa 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.[1]
ANP is produced, stored and released by atrial myocytes, muscle cells in the atria of the heart. It is released in response to a variety of signals induced by hypervolemia, exercise or caloric restriction. The hormone is constitutively expressed in the ventricle in response to stress induced by increased afterload (eg. increased ventricular pressure from aortic stenosis) or injury (eg. myocardial infarction).
ANP is secreted in response to:
- Atrial distention, stretching of the vessel walls
- Sympathetic stimulation of β-adrenoceptors
- Raised sodium concentration (hypernatremia)
- Angiotensin-II
- Endothelin, a potent vasoconstrictor
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 horses.
ANP binds to a specific set of receptors. Receptor-agonist binding causes a reduction in blood volume and therefore a reduction in cardiac output and systemic blood pressure. Lipolysis and renal sodium secretion and excretion are also increased. 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.
- Decreases sodium reabsorption in the distal convoluted tubule and cortical collecting duct of the nephron via guanosine 3',5'-cyclic monophosphate (cGMP) dependent phosphorylation of ENaC
- Inhibits renin secretion, thereby inhibiting the renin-angiotensin system.
- Reduces aldosterone secretion by the adrenal cortex.
- 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
Mediation 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, although they have not yet been licensed. They may be clinically useful in treating congestive heart disease.
In addition to the mammalian natriuretic peptides (ANP, BNP, CNP), two others have been isolated. Tervonen (1998) described a salmon natriuretic peptide, named Salmon cardiac peptide, with similar structure and properties[2]. As well, Dendroaspis Natriuretic Peptide (DNP) was discovered in the venom of the green mamba by Schweitz et al. (1992).
Used in conjunction with other clinical information, measurement of B-type natriuretic peptide (BNP) can help determine whether a patient's dyspnea is caused by congestive heart failure in which BNP levels are elevated. This laboratory test has become a valuable and quick method for diagnostic work-up of patients presenting to the emergency department (ED) with acute dyspnea.
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.[3]
- ^ de Bold A (1985). "Atrial natriuretic factor: a hormone produced by the heart.". Science 230 (4727): 767-70. PMID 2932797.
- ^ Tervonen et al., 1998 Endocrinology 139:4021-4025.
- ^ [1] Joshi Venugopal. (2003) Pharmacological modulation of the natriuretic peptide system. Expert Opinion on Therapeutic Patents 13:9, 1389