Natriuretic Peptides Flashcards
(26 cards)
How many classes of NPs are there and what are they?
5
1. Atrial natriuretic peptide (ANP/CDD)
23aa
2. Brain natriuretic peptide (BNP)
32aa
3. C-type natriuretic peptide (CNP)
22 aa (circulating) and 53 aa (tissue) peptides
4. Urodilatin (proANP 95-126)
5. Dendroaspsis natriuretic peptide (DNP)
38aa isolated
from green mamba venom (present in plasma)
Structure of NPs
Oddly structured peptides, with a circular element at 1 end and 2 tails coming out the other (except for CNP which has only 1)
Synthesis of NPs
Essentially similar process for BNP & CNP except coded for by separate genes nearby on the same chromosome (mouse 1, human 2) - geographically close on chromosome
Multistep process for synthesis of ANP:
Start with gene producing large peptides
These peptides are gradually broken down, folded and processed to produce the active protein
Distribution of NPs
Two elements in the atrium (large and small granules) Both ANP and BNP released in a linked manner
Major tissue distributors of NPs
Generally associated with atrial myocytes (ANP & BNP)
But also BNP in ventricular and C in vasculature
Urodilatin in renal
Biological effects of NPs
Vasodilators, natiuresis and diuretic
Antagonistic properties to RAS
BENEFICIAL
Elimination system for NPs
Dual elimination system:
- C-receptors
- Neurol endopeptidases (NEP)
Release of ANP & BNP
ANP and BNP are released by the heart in response to atrial and ventricular (BNP) stretch Note: not due to increased pressure, but increased volume
Release of CNP
CNP is released by endothelium in response to shear stress and cytokines
Effect of ANP and BNP
- Increased natriuresis
- Reduced BP (through peripheral vasodilation)
- Increased urinary cGMP
Effect of CNP
- Little or no effect on natriuresis or BP
* Does exert vasodilator effects in some circulations
Receptors for NPs
NPR-A: ANP & BNP
NPR-B: Only CNP
NPR-C: Internalisation and clearance receptor
NEP: (Neutral endopeptidase aka neprilysin) Clearance receptor. Has become a target for therapeutic manipulation. Block of NEP enzyme, to promote beneficial effector system
Metabolism of NPs
- Neutral endopeptidase (NEP) (EC24.11)
Metabolises CNP>ANP>BNP (metabolises CNP more actively than the other two, although we are not sure why) Largely present in renal tubular and vascular smooth muscle - NPR-C (clearance receptor): NPR-C has lower affinity for BNP accounting for its longer half-life than ANP
Gives BNP a longer half-life, more slowly cleared from the body, more stable - hence is a better marker to use clinically
Action of NEP inhibitor and example
Candoxatrilat
Can increase levels of NP by inhibiting breakdown
NPR-C ligand action and example
C46542
Can also increase levels of NP by inhibiting clearance
Where is NEP present?
Mainly in the brush-border membrane of renal tubules but also lungs, intestine, adrenal, brain, heart and peripheral blood vessels
Action of NEP
Catalyses breakdown of ANP, BNP and CNP
Also degrades other peptide hormones
Cnverts pro-endothelin into endothelin
and AngI into Ang (1-7)
Physiology of NPs
↓BP
↓Vascular growth (reduced hyperplasia etc., which may cause increase resistance and hence increase BP)
↑Na+ and H2O excretion
NPs in disease?
Usually look at BNP
Easer to do and has a much longer half-life, hence gives a more stable picture as it persists for longer
Responses to ANP/BNP in CHF
BLUNTED
Thought to be due to desensitisation
Biomarkers in AF
• Impaired cardiac function (NPs)
• Atrial fibrosis (markers of inflammation)
• Altered haemodynamics (NPs, renal function)
• Atrial dilatation (NPs)
• Myocyte damage (troponin)
• Electrical remodelling (electrophysiology)
• Prothrombotic state (markers of coagulation e.g. D-
dimer)
• Vascular pathology (markers of inflammation, renal
function, endothelial function)
NP in AF and why
↑NP with AF, largely due to distension of the atrium itself May also be secondary changes due to more wide ranging cardiac dysfunction
Combining biomarkers in AF
Combined to get a better picture of prognosis and function. NT-proBNP and Troponin I together show high percentage of yearly CV events (stroke, HF, MI) compared to the two separately
Possible uses of NPs
Most commonly used to confirm diagnosis of several cardiomyopathies associated with HF
- Prediction of cardiovascular risk
- Assessment of severity of congestive heart failure
- Monitoring of therapy in congestive heart failure
- Detection of LV diastolic dysfunction
- Screening for mild heart failure
- Evaluation of LV systolic dysfunction
- Identification of LV hypertrophy in hypertension
- Recognition of obstructive hypertrophic
cardiomyopathy
- Estimation of infarct size after myocardial
infarction
- Prognostic outcome after myocardial infarction
