Electron micrograph of ventricular (left) and atrialmyocyte (right) showing location of ANP storage granules in a mouse model. Captured by Dr. Stephen C. Pang fromQueen's University.
Atrial natriuretic peptide (natriuretic polypeptide (ANP)[5] oratrial natriuretic factor (ANF)[6] is a natriuretic peptide hormone secreted from thecardiac atria that in humans is encoded by theNPPAgene.[7] Natriuretic peptides (ANP,BNP, andCNP) are a family of hormone/paracrine factors that are structurally related.[8] The main function of ANP is causing a reduction in expandedextracellular fluid (ECF) volume by increasingrenalsodium excretion. ANP is synthesized and secreted bycardiac muscle cells in the walls of theatria in theheart. These cells containvolume receptors which respond to increased stretching of the atrial wall due to increased atrialblood volume.
Reduction of blood volume by ANP can result in secondary effects such as reduction ofextracellular fluid (ECF) volume, improved cardiacejection fraction with resultant improved organ perfusion, decreasedblood pressure, and increased serumpotassium. These effects may be blunted or negated by various counter-regulatory mechanisms operating concurrently on each of these secondary effects.
Brain natriuretic peptide (BNP) – a misnomer; it is secreted by cardiac muscle cells in theheart ventricles – is similar to ANP in its effect. It acts via the same receptors as ANP does, but with 10-fold lower affinity than ANP. Thebiological half-life of BNP, however, is twice as long as that of ANP, and that ofNT-proBNP is even longer, making these peptides better choices than ANP for diagnostic blood testing.
A member of the natriuretic peptide gene family,NPPA encodes an important cardiac signaling molecule known as atrial natriuretic peptide/factor (ANP).[9] 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.[10]NPPA expression is varied throughout mammalian development into adulthood. Fetal expression ofNPPA is associated with the formation of chamber myocardium, muscle cells of the atria and ventricles in the early developing heart.[11] Early expression of this gene has been associated with ventricular hypertrophy in bothin vitro andin vivo models.[12]NPPA variants affect plasma ANP concentrations, blood pressure levels, and cardiovascular diseases such as atrial fibrillation (AF).[13] 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.[14] Using a knock-in (KI) rat model, researchers found an AF-associated human variant inNPPA caused inflammation, fibroblast activation, atrial fibrosis, and AF in KI rats.[15] 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.
The discovery of a natriuretic factor (one that promotes kidney excretion of salt and water) was first reported byAdolfo José de Bold in 1981 when rat atrial extracts were found to contain a substance that increased salt and urine output in the kidney.[16] Later, the substance was purified from heart tissue by several groups and named atrial natriuretic factor (ANF) or ANP.[17]
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 twocysteine residues at positions 7 and 23. ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share a similar amino acid ring structure. ANP is one of a family of nine structurally similar natriuretic hormones: seven are atrial in origin.[18]
ANP is synthesized as an inactivepreprohormone, encoded by the human NPPA gene located on theshort arm ofchromosome 1.[8] The NPPA gene is expressed primarily in atrialmyocytes and consists of 2introns and threeexons, withtranslation of this gene yielding a high molecular mass 151 amino acidpolypeptide known as preproANP.[19] The preprohormone is activated viapost-translational modification that involves cleavage of the 25 amino acidsignal sequence to produce proANP, a 126 amino acid peptide that is the major form of ANP stored in intracellular granules of theatria.[19] Following stimulation of atrial cells, proANP is released and rapidly converted to the 28-amino-acid C-terminal mature ANP on the cell surface by the cardiac transmembrane serineprotease corin.[20][21] Recently, it was discovered that ANP also can beO-glycosylated.[22]
NPR-A and NPR-B have a single membrane-spanning segment with an extracellular domain that binds theligand.[citation needed] 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 receptordimerization and activation.[citation needed]
The binding of ANP to its receptor causes the conversion ofGTP tocGMP and raises intracellular cGMP. As a consequence, cGMP activates a cGMP-dependent kinase (PKG or cGK) thatphosphorylates proteins at specific serine and threonine residues. In themedullary collecting duct, the cGMP generated in response to ANP may act not only through PKG but also via direct modulation of ion channels.[24]
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]
Maintenance of the ECF volume (space), and its subcompartment the vascular space, is crucial for survival.[citation needed] These compartments are maintained within a narrow range, despite wide variations in dietary sodium intake. There are three volume regulating systems: two salt saving systems, therenin angiotensin aldosterone system (RAAS) and the renalsympathetic system (RSS); and the salt excretingnatriuretic peptide (NP) hormone system. When the vascular space contracts, the RAAS and RSS are "turned on"; when the atria expand, NPs are "turned on". Each system also suppresses its counteracting system(s). NPs are made in cardiac, intestinal, renal, and adrenal tissue: ANP in one of a family of cardiac NPs: others areBNP,CNP, andDNP.[18]
ANP binds to a specific set ofreceptors –ANP receptors. Receptor-agonist binding causes the increase in renal sodium excretion, which results in a decreased ECF and blood volume. Secondary effects may be an improvement in cardiac ejection fraction and reduction of systemic blood pressure.[citation needed]
ANP acts on thekidney to increase sodium and water excretion (natriuresis) in the following ways:[25][26]
The medullarycollecting duct is the main site of ANP regulation of sodium excretion.[27] ANP effects sodium channels at both the apical and basolateral sides.[27] ANP inhibitsENaC on the apical side and thesodium potassium ATPase pump on the basolateral side in acGMP PKG dependent manner resulting in less sodium re-absorption and more sodium excretion.[28]
ANP increasesglomerular filtration rate and glomerular permeability.[27] ANP directly dilates the afferent arteriole and counteracts thenorepinephrine inducedvasoconstriction of the afferent arteriole.[28] Some studies suggest that ANP also constricts the efferent arteriole, but this is not a unanimous finding.[28] ANP inhibits the effect ofAngiotensin II on the mesangial cells, thereby relaxing them.[28] ANP increases the radius and number of glomerular pores, thereby increasing glomerular permeability and resulting in greater filter load of sodium and water.[27]
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.
ANP inhibits cardiac hypertrophy in heart failure as well as fibrosis.[30] Fibrosis is inhibited by preventing fibroblasts from entering heart tissue and replicating, as well as decreasing inflammation.[30] ANP prevents hypertrophy by inhibiting calcium influx that is caused by norepinephrine.[30]
Re-expression of NPRA rescues the phenotype.[citation needed]
Increases the release offree 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 receptorsNPR-A
Increases intracellular cGMP levels that induce the phosphorylation of a hormone-sensitive lipase and perilipin A via the activation of acGMP-dependent protein kinase-I (cGK-I)
ANP modulatesinnate immunity by raising defence against extracellular microbes and inhibiting the release of pro-inflammatory markers and expression of adhesion molecules.[31]
There is evidence of cytoprotective effects of ANP in myocardial, vascular smooth, endothelial, hepatocytes and tumour cells.[31]
Modulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzymeneutral endopeptidase (NEP). Recently, NEP inhibitors have been developed, such asSacubitril andSacubitril/valsartan. They may be clinically useful in treating patients in heart failure with reduced ejection fraction .
Fragments derived from the ANP precursor, including the signal peptide, N-terminal pro-ANP and ANP, have been detected in human blood.[32] ANP and related peptides are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure.[33][34][35][36] A specific ANP precursor called mid-regional pro-atrial natriuretic peptide (MRproANP) is a highly sensitivebiomarker in heart failure.[37] MRproANP levels below 120 pmol/L can be used to effectively rule out acute heart failure.[37]
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.[38]
Opinions regarding the use of ANP for the treatment ofacute heart failure andkidney disease are varied.[39] While this molecule has been shown to successfully restore somehemodynamic parameters following heart failure, and yield clinical improvement for kidney injury, whether it ultimately reduces mortality and its long-term effects are unknown.[40] Therefore, more studies need to be conducted to better understand the therapeutic effects of ANP.[40] Newly synthesizedhomologues of ANP molecule are being assessed for the treatment of acute heart failure.[41] Preliminary research on one of such molecules, ularitide, has shown that this drug is safe, well tolerated, and effective in the treatment of acute heart failure.[41]
Brain natriuretic peptide (BNP) – a misnomer; it is secreted by ventricular myocytes – is similar to ANP in its effect. It acts viaatrial natriuretic peptide receptors but with 10-fold lower affinity than ANP. Thebiological half-life of BNP, however, is twice as long as that of ANP, and that ofNT-proBNP is even longer, making these peptides better choices than ANP for diagnostic blood testing.
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. Asalmon natriuretic peptide known as salmon cardiac peptide has been described,[42] anddendroaspis natriuretic peptide (DNP) has been found in the venom of the greenmamba, as well as an NP in a species of African snake.[43]
Beside these four, five additional natriuretic peptides have been identified: long-acting natriuretic peptide (LANP), vessel dilator, kaliuretic peptide,urodilatin, andadrenomedullin.[18]
Neutral endopeptidase (NEP) also known asneprilysin is the enzyme that metabolizes natriuretic peptides. Severalinhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure. Most of them are dual inhibitors (NEP andACE). 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; comparedLCZ696 versusenalapril in patients with heart failure. The study showed lower all cause mortality, cardiovascular mortality and hospitalization inLCZ696 arm.[44]Omapatrilat (dual inhibitor of NEP andangiotensin-converting enzyme) developed by BMS did not receive FDA approval due toangioedema safety concerns. Other dual inhibitors of NEP with ACE/angiotensin receptor are (in 2003) being developed by pharmaceutical companies.[45]
Renin-angiotensin system: When the blood flow through the juxtaglomerular apparatus decreases, blood pressure is considered low, and the adrenal cortex secretes aldosterone to increase sodium reabsorption in the collecting duct, thereby increasing blood pressure.
Bainbridge reflex: In response to stretching of the right atrium wall, heart rate increases, lowering venous blood pressure.
Baroreflex: When the stretch receptors in the aortic arch and carotid sinus increase, the blood pressure is considered to be elevated and the heart rate decreases to lower blood pressure.
Antidiuretic hormone: The hypothalamus detects the extracellular fluid hyperosmolality and the posterior pituitary gland secretes antidiuretic hormone to increase water reabsorption in the collecting duct.
^Vandenberg M (September 2004). "Depletion of atrial natriuretic peptide during longstanding atrial fibrillation".Europace.6 (5):433–437.doi:10.1016/j.eupc.2004.04.006.
^de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (January 1981). "A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats".Life Sciences.28 (1):89–94.doi:10.1016/0024-3205(81)90370-2.PMID7219045.S2CID10331174.
^Mohler ER, Finkbeiner WE (2011).Medical Physiology (Boron) (2 ed.). Philadelphia: Saunders.ISBN978-1-4377-1753-2.
^Hoehn K, Marieb EN (2013). "16".Human anatomy & physiology (9th ed.). Boston: Pearson. p. 629.ISBN978-0-321-74326-8.question number 14
^Goetz KL (January 1988). "Physiology and pathophysiology of atrial peptides".The American Journal of Physiology.254 (1 Pt 1): E1–15.doi:10.1152/ajpendo.1988.254.1.E1.PMID2962513.
^abKobayashi D, Yamaguchi N, Takahashi O, Deshpande GA, Fukui T (January 2012). "Human atrial natriuretic peptide treatment for acute heart failure: a systematic review of efficacy and mortality".The Canadian Journal of Cardiology.28 (1):102–9.doi:10.1016/j.cjca.2011.04.011.PMID21908161.
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