Atrial Natriuretic Peptides Structure Function Pharmacology Modulation Antagonist and Agonist

A protein (polypeptide) hormone secreted by heart muscle cells. It is a powerful vasodilator. 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 fat loads on the circulatory system, thereby reducing blood pressure. It give opposite function of aldosterone that is conservation of sodium and water.

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Structure Of Atrial Natriuretic Peptides

1. ANP is a 28-amino acid peptide with a 17-amino acid ring in the middle of the molecule.
2. The ring is formed by a disulfide bond between two cysteine residues at positions 7 and 23.
3. ANP is closely related to BNP (brain natriuretic peptide) and CNP (C-type natriuretic peptide), which all share the same amino acid ring.

Structure Of Atrial Natriuretic Peptides

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Production Of Atrial Natriuretic Peptide

1. ANP is produced, stored and released by cardiac myocytes of the atria of the heart.
2. It is released in response to atrial stretch and a variety of other signals induced by hypervolemia, exercise or caloric restriction.
3. 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).
4. 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 28 C-terminal amino acids, yielding the final ANP structure.

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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.

Atrial Distension

• Plasma concentration of ANP increases in response to volume expansion .
• ANP has been found to increase in humans with water immersion, in clinical conditions such as heart failure and renal failure.
• Rate of contraction has been suggested to stimulate ANP secretion .

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Endothelin

• Endothelin-1 is one of the most potent stimuli for ANP secretion.
• Endothelin increases ANP secretion and up-regulates ANP messenger RNA.
• It has been proved that a specific endothelin-1 receptor antagonist attenuates the ANP response to  atrial stretch, thus demonstrating that endothelin plays an essential paracrine role in the stretch-activated ANP secretory process.
• High atrial pressure (8–10 mmHg) produces a marked increase in ANP secretion (30–60 min) compared to the low atrial pressure control period.
• Endothelin further augments this response when added while atrial pressure is elevated (60–90 min).

Receptors Of Atrial Natriuretic Peptide

Three types of atrial natriuretic peptide receptors have been identified on which natriuretic peptides act. 

They are all cell surface receptors and are designated:

1. Guanylyl cyclase-A (GC-A) also known as natriuretic peptide receptor-A (NPRA/ANPA) or NPR1.
2. Guanylyl cyclase-B (GC-B) also known as natriuretic peptide receptor-B (NPRB/ANPB) or NPR2.
3. Natriuretic peptide clearance receptor (NPRC/ANPC) or NPR3.
4. Natriuretic peptide receptors (NPR). 
5. The guanylyl cyclases, NPR-A and NPR-B, contain an extracellular ligand binding domain. NPR-A binds ANP and BNP, whereas NPR-B binds CNP. 
6. NPR-C has the potency to internalise and clear the natriuretic peptides and exerts other biological effects by inhibiting the production of cAMP. 

Receptors Of Atrial Natriuretic Peptide

Pharmacology of Atrial Natriuretic Peptides

1. ANP binds to a specific set of receptors - ANP receptors.
2. Receptor-agonist binding causes a reduction in blood volume and therefore a reduction in cardiac output and systemic blood pressure.
3. Lipolysis is increased and renal sodium reabsorption is decreased.
4. The overall effect of ANP on the body is to counter increases in blood pressure and volume caused by the renin-angiotensin system.

Renal

1. Dilates the afferent glomerular arteriole.
2. Constricts the efferent glomerular arteriole, and
3. Relaxes the mesangial cells.
4. This increases pressure in the glomerular capillaries, thus   increasing the glomerular filtration rate (GFR), resulting in greater excretion of sodium and water.
5. Increases blood flow through the vasa recta which will wash the solutes (NaCl and urea) out of the medullary interstitium.
6. 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.
7. Inhibits renin secretion, thereby inhibiting the renin-angiotensin system.
8. Reduces aldosterone secretion by the adrenal cortex.

Vascular

Relaxes vascular smooth muscle in arterioles and venules by:

1. Membrane Receptor-mediated elevation of vascular smooth muscle cGMP.
2. Inhibition of the effects of catecholamines.

Cardiac

1. Inhibits maladaptive cardiac hypertrophy.
2. Mice lacking cardiac NPRA develop increased cardiac mass and severe fibrosis and die suddenly.
3. Re-expression of NPRA rescues the phenotype.
4. It may be associated with isolated atrial amyloidosis.

Adipose Tissue

1. Increases the release of free fatty acids from adipose tissue.
2. Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans.
3. Activates adipocyte plasma membrane type A guanylyl cyclase receptors NPR-A.
4. 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).

Degradation

Regulation of the effects of ANP is achieved through gradual degradation of the peptide by the enzyme neutral endopeptidase (NEP). 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 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.

Pharmacological  Modulation Of Atrial Natriuretic Peptide

1. Neutral endopeptidase (NEP) is the enzyme that metabolizes natriuretic peptides.
2. Several inhibitors of NEP are currently being developed to treat disorders ranging from hypertension to heart failure.
3. Most of them are dual inhibitors.
4. Omapatrilat (dual inhibitor of NEP and angiotensin-converting enzyme) developed by BMS did not receive FDA approval due to angioedema safety concerns.
5. Other dual inhibitors of NEP with ACE/angiotensin receptor are currently being developed by pharmaceutical companies.

NPR-A

Endogenous agonists          ANP (NPPA, P01160)  (Selective)

Selective agonists                sANP

Selective antagonists          A-71915, [Asu7,23']β-ANP-(7-28), anantin

NPR-B

Endogenous agonists           CNP (NPPC, P23582) (Selective)

Selective antagonists            [Ser11](N-CNP,C-ANP)pBNP2-15

NPR-C

Endogenous agonists             Osteocrin (OSTN, P61366) (Selective)

Selective agonists                   cANF4-23

Selective antagonists              AP811, M372049