efferent glomerular arteriole

Atrial natriuretic peptide

Atrial natriuretic peptide (ANP), atrial natriuretic factor (ANF), or atriopeptin, is a protein (polypeptide) hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water, sodium, potassium and fat (adiposity). 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.

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 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 Kingston, Canada 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.

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 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:

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.

Receptors

Three cell surface receptors have so far been identified on which ANP act, and these are designated ANPA, ANPB and ANPC. The ANPA and ANPB receptors have guanylate cyclase activity and mediate the biological effects by producing cGMP. The ANPC receptor functions mainly as a clearance receptor by binding and sequestering ANP from the circulation. All natriuretic peptides are bound by the ANPC receptor. Atrial natriuretic peptide and brain natriuretic peptide act through the ANPA and C-type natriuretic peptide through the ANPB receptor

Physiological effects

ANP binds to a specific set of receptors - ANP receptors. Receptor-agonist 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.

Renal

  • 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.

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.

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 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, although 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), two others have been isolated. Tervonen (1998) described a salmon natriuretic peptide, named Salmon cardiac peptide, with similar structure and properties. As well, dendroaspis natriuretic peptide (DNP) was discovered in the venom of the green mamba.

Diagnostic Use

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.

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

References

External links

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