Natriuretic Peptide System

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Natriuretic Peptide System

• Ri ???/P ???

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History

• 1981, de Bold et al. first reported a potent
  diuretic and natriuretic factor in rat atrial
  extracts
• 1984, Kangawa et al. identified atrial
  natriuretic peptide (ANP)
• 1988, B-type or brain natriuretic peptide (BNP)
• 1990, C-type natriuretic peptide (CNP)
• Natriuretic peptide family ANP, BNP, CNP,
  DNP(dendroaspis), Urodilatin
• Shares a common 17-amino acid disulfide ring

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Molecular biology - ANP

• 28 a.a peptide hormone
• Produced primarily in the cardiac atria
• Some is produced by ventricular tissue of fetus,
  neonate and hypertrophy
• Increased atrial-wall tension, increased
  intravascular volume, is the dominant stimulus
  for its release
• Several hormons and neurotransmitters directly
  stimulate the secretion of ANP

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Molecular biology - BNP

• 32 a.a peptide hormone
• Initially isolated from porcine brain
• Primarily derived from the cardiac ventricle
• Secreted primarily in response to increasing
  cardiac wall tension

ANP- burst- acute change of atrial pressure BNP-
gene- chronically increased pressure
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Curr Probl Cardiol, December 2004
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Molecular biology - CNP

• 22 a.a peptide hormone
• Predominates in the central nervous system,
  anterior pituitary, kidney, vascular , and
  endothelial cells
• Believed to be an endothelial derived peptide
  participating in an autocrine/paracrine role to
  regulate vascular structure and tone

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Molecular biology DNP, Urodilatin

• DNP 38 a.a peptide hormone
• First isolated from the venom of the green mamba
  snake
• Physiologic role in unclear

• Urodilatin 32 a.a peptide hormone
• Alternative processing of the ANP precursor in
  the kidney
• Intrarenal paracrine regulator of sodium and
  water homeostasis
• Secreted into the distal nephron to exerts its
  effects in the medullary collecting duct

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Most effects of the NPs are mediated through
binding to NP receptors, which activate
particulate guanylyl cyclase and produce the
second messenger, cyclic guanosine monophosphate
(cGMP)
The New England Journal of medicine Volume 339
Number 5, 1998
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Cardiovascular Effects

• Increase venous capacitance
• Promotes natriuresis in kidney
• Suppresion of RAA system

Reduce cardiac preload
Reflex tachycardia and vasocontriction
Lower the activation threshold of vagal afferent
Suppress the release of catecholamine from
autonamic nerve ending
Dampen baroreceptors
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Renal Effects

• Afferent renal arteriole ? relaxation
• Efferent renal arteriole ? constriction
• Relax mesangial cell ? surface area ?
• Production of Urodilatin ? paracrine effect
• Proximal tubule ? Inhibit angiotensin ?
• Cortical collecting duct ? Antagonize
  vasopression
• Medullary collecting duct?Block sodium absorption

GFR ?
Promote sodium and water excretion
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Central Nervous System Effects

• The actions of natriuretic peptides in brain
  reinforce those in the periphery

• Inhibit salt appetite and water drinking
• Inhibit the secretion of vasopressin?corticotropin
  
• Act in the brain stem to decrease sympathetic tone

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The New England Journal of medicine Volume 339
Number 5, 1998
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Anti-Remodeling Effects

• Inhibit the growth of cardiac fibroblast
• Retard the deposition of collage
• Induce cardiac myocyte aptosis

• Inhibit transforming growth factor (TGF-ß)
  induced fibrosis
• Limit the myocardial porliferative or
  hypertrophic response to injury or ischemia

Anti-remodeling and Anti-fibrotic properties
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NPs
NTG

• Randomized study in 60 patients with first
  anterior myocardial infarction
• Present with TIMI grade 0 or 1 by coronary
  angiography
• Prolong chest pain (gt30min) ST elevation (gt2mV,
  gt 2 precordial leads) successful infused (gt24
  hr.)
• Then all give ACEI(enalapril)
• Repeat cardiac catheterization one month later

Journal of the American College of Cardiology
Vol. 37, No. 7, 2001
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Clinical application of BNP in the emergency
diagnosis of heart failure
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Unloading of high-pressure baroceptors
The New England Journal of medicine August 19,
1998
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Response of NPs to heart failure

• Myocardial failure with hypertrophy
• Stretching of the failing atrial and ventricular
  myocardium
• Elevated plasma concentration of Angiotensin ?

Increased production of BNP ? ANP
The concentrations are correlated with the extent
of ventricular dysfunction

• Catecholamines ?
• Anigotensin ? ?
• Aldosterone ?
• Systemic vascular resistance ?
• Systemic volume ?

Myocardial performace ?
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110225 pg/ml 346390 pg/ml 675450 pg/ml

• Total of 1586 pt from seven sites enrolled from
  April 1999 December 2000
• Came to the emergency department with acute
  dyspnea
• Exclude patient under 18 y/o, those whose dyspnea
  was clearly not secondary to CHF, and those with
  AMI or renal failure
• BNP was measured
• The CHF was diagnosed by two independent
  cardiologists who were blind to the result of BNP

The New England Journal of medicine Volume 347
July 18, 2002
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The New England Journal of medicine Volume 347
July 18, 2002
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Predictors of Congestive Heart Failure

• A major challenge of heart failure is timely and
  accurate diagnosis
• The best clinical predictor of congestive heart
  failure was as increased heart size on chest
  X-ray (accuracy, 81)
• Followed by a history of congestive heart failure
  (accuracy, 75)
• Rales found on physical examination (accuracy,
  69)
• History of paroxysmal nocturnal dyspnea
  (accuracy, 60)

What about BNP? What is the best cut-point?
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The New England Journal of medicine Volume 347
July 18, 2002
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The New England Journal of medicine Volume 347
July 18, 2002
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Cardiovasc Rev Rep 25(3)100-104, 2004
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Thank You For Your Attension!!
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Conclusion

• B-type natriuretic peptide levels by themselves
  were more accurate than any other finding in the
  history, physical finding, or laboratory value in
  delineating the cause of dyspnea

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 70
NUMBER 4 APRIL 2003
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• Heart failure
• Pulmonary hypertension
• Atherosclertic vascular disease

When dose BNP increase?

• Biomarker in patient with heart failure and
  other cariovascular diasease
• Early warning system to help to identify patients
  at high risk for cardiac events
• Recombinant ANP (carperitide) and BNP
  (nesiritide) are useful for management of acutely
  decompensated HF
• Investigated for myocardial and renal protection
  in the setting of cardiac surgery
• Prevention of cardiac remodeling

Clinical application of BNP
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• Age
• Renal dysfunction BNP level ?
• Women
• Obese BNP level ?