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Cardiovascular Physiology
Vascular Control
1. What is the role of Natriuretic Peptide?
Natriuretic peptides are a family of ring shaped vasoactive hormones.
  • Antagonists to the renin-angiotensin-aldosterone system
  • ANP - Promotes potent natriuresis, diuresis, vasodilation (arterial and venous dilation), suppression of the renin-angiotensin-aldosterone axis, reduces sympathetic tone, lowers the activation threshold of vagal afferents, inhibits secretion of vasopressin, antimitogenic, inhibits growth of fibroblasts and retarding collagen deposition
    • BNP has cardiovascular effects similar to ANP
    • CNP is a more potent dilator of veins than the other two.
  • Diuresis occurs due to:
    • Increase in glomerular filtration pressure (due to constriction of glomerular efferent arterioles and dilation of afferent arterioles)
    • Direct tubular action - antagonizes vasopressin thus inhibits water transport in the cortical collecting ducts
    • Inhibit angiotensin II - stimulated aldosterone secretion
  • C-type NP inhibits aldosterone secretion but has little effect on arterial pressure or salt and water excretion
  • Urodilatin - the unique renal ANP (see below)
    • Stimulates diuresis and natriuresis at doses lower than doses of ANP
    • More resistant to endopeptidase inactivation
There are 4 natriuretic peptides (NP), named A-D
  • ANP
    • Atrial natriuretic peptide
    • Discovered by de Bold in 1981 from Kingston Ontario
    • Stored in secretory granules in the atria as a 126 amino acid pro hormone (proANP)
    • This is cleaved, by a membrane-bound endonuclease [Corin] in association with exocytosis, into 2 fragments
      • An N-terminal fragment called proANP1-98 or NT-proANP
      • The major biologically active hormone called C-terminal peptide ANP 99-126 (or ANP1-28)
      • These fragments are produced in equal amounts
    • The ANP gene is very actively expressed in the fetal and neonatal ventricle. Soon after birth, the ANP expression in the ventricles decreases to very low levels, but it can be re-induced by increased ventricular load.
    • Release of ANP from the atrial myocardium - occurs in response to
      • Atrial stretch due to volume overload
      • Hypoxia
      • Endothelin 1
      • Catecholamines
      • Angiotensin
      • Arginine vasopressin
      • Prostaglandins
      • Glucocorticoids
      • Thyroid hormones
    • The ANP gene is also expressed in the kidney where a 32 amino acid peptide is produced called urodilatin - a local regulator of sodium and water handling in the kidney.
    • ANP is elevated in congestive heart failure
  • BNP
    • Brain natriuretic peptide
    • Originally identified in extracts of porcine brain
    • Considerably more comes from the ventricles
    • Pro-BNP contains 108 amino acids
    • Cleavage releases BNP (32 amino acid molecule) and an N-terminal fragment
    • Both are elevated in CHF and ventricular concentric hypertrophy
  • C-type natriuretic peptide (CNP)
    • Two molecules have been identified - a 22 and 53 amino acid moiety
    • Begins as a pro-C-type NP precursors
    • The 22 amino acid peptide is contained within the carboxy-terminal portion of the 53 amino acid moiety. The 22 amino acid form is more potent than the 53 aa form.
    • Produced in the brain more so than the other 2 NPs
  • D-type natriuretic peptide (DNP)
    • 38 amino acids
    • Very little is know relative to its role
  • Natriuretic Peptide Receptors
    • There are 3 receptors - A, B, C
    • NPR-A and NPR-B - linked to cGMP dependent signaling cascade and structurally similar
      • Single membrane-spanning segment
      • The intracellular portion contains a kinase-like domain linked to the guanylyl cyclase catalytic unit. Binding to the receptor activates cGMP.
    • NPR-A:
      • Binds ANP and BNP with preference for ANP
      • Most abundant in large vessels
    • NPR-B:
      • Binds CNP
      • Predominates in the brain
    • NPR-C:
      • Involved in the clearance of the peptides
      • The NPs bind to receptor - internalized and enzymatically degraded
      • Single membrane-spanning segment
  • Neutral endopeptidases
    • Cleave circulating NPs - inactivation

    Role of NPs in Cardiovascular Disease:

    • There is increased ventricular production of ANP and BNP and there release into the plasma is increased by stretching of the failing atrial and ventricular myocardium and by elevated plasma concentrations of angiotensin II and endothelin-I
    • ANP and BNP become elevated in CHF - the degree of elevation is related to the severity of disease. They predict:
      • Development of cardiac arrhythmias
      • The degree of hemodynamic dysfunction
      • Long term survival
      • BNP is a stronger predictor than ANP
      • C-type NP may not be related to heart disease
    • The renal responsiveness to NPs decreases as heart failure worsens despite an increase in plasma levels of NPs due to:
      • Changes in renal hemodynamics
      • Receptor down-regulation
      • Increased cGMP phosphodiesterase activity
    Therapeutic considerations:
    • ANP as anaritide (synthetic ANP) - assessed in renal failure - not useful
    • Neutral endopeptidase inhibitors
      • Inhibit the degradation of ANP
      • Also inhibit the degradation of angiotensin II
      • May be useful if used with an ACE inhibitor or Angiotensin II receptor blocker
      • Likely overall of little value in the management of cardiovascular disease
    • Nesiritide (synthetic BNP) has been used to treat acute congestive heart failure in people
    NPs in domestic animals:
    • NT pro-BNP appears to be the most useful diagnostic NP in domestic animals
      • Biologically inactive
      • Longer half life than active BNP
      • Levels are higher in heart failure than active BNP
      • In dogs: Cardiopet NT-proBNP (Idexx)
        • > 900 pmol/l indicative of heart disease
      • In cats: Cardiopet NT-proBNP (Idexx)
        • > 50 pmol/l indicative of heart disease
  • production