Natriuretic Peptides

Question 1

How many classes of NPs are there and what are they?

Answer 1

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)

Question 2

Structure of NPs

Answer 2

Oddly structured peptides, with a circular element at 1 end and 2 tails coming out the other (except for CNP which has only 1)

Question 3

Synthesis of NPs

Answer 3

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

Question 4

Distribution of NPs

Answer 4

Two elements in the atrium (large and small granules) Both ANP and BNP released in a linked manner

Question 5

Major tissue distributors of NPs

Answer 5

Generally associated with atrial myocytes (ANP & BNP)
But also BNP in ventricular and C in vasculature
Urodilatin in renal

Question 6

Biological effects of NPs

Answer 6

Vasodilators, natiuresis and diuretic
Antagonistic properties to RAS
BENEFICIAL

Question 7

Elimination system for NPs

Answer 7

Dual elimination system:

1. C-receptors
2. Neurol endopeptidases (NEP)

Question 8

Release of ANP & BNP

Answer 8

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

Question 9

Release of CNP

Answer 9

CNP is released by endothelium in response to shear stress and cytokines

Question 10

Effect of ANP and BNP

Answer 10

• Increased natriuresis
• Reduced BP (through peripheral vasodilation)
• Increased urinary cGMP

Question 11

Effect of CNP

Answer 11

• Little or no effect on natriuresis or BP

* Does exert vasodilator effects in some circulations

Question 12

Receptors for NPs

Answer 12

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

Question 13

Metabolism of NPs

Answer 13

1. 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
2. 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

Question 14

Action of NEP inhibitor and example

Answer 14

Candoxatrilat

Can increase levels of NP by inhibiting breakdown

Question 15

NPR-C ligand action and example

Answer 15

C46542

Can also increase levels of NP by inhibiting clearance

Question 16

Where is NEP present?

Answer 16

Mainly in the brush-border membrane of renal tubules but also lungs, intestine, adrenal, brain, heart and peripheral blood vessels

Question 17

Action of NEP

Answer 17

Catalyses breakdown of ANP, BNP and CNP
Also degrades other peptide hormones
Cnverts pro-endothelin into endothelin
and AngI into Ang (1-7)

Question 18

Physiology of NPs

Answer 18

↓BP
↓Vascular growth (reduced hyperplasia etc., which may cause increase resistance and hence increase BP)
↑Na+ and H2O excretion

Question 19

NPs in disease?

Answer 19

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

Question 20

Responses to ANP/BNP in CHF

Answer 20

BLUNTED

Thought to be due to desensitisation

Question 21

Biomarkers in AF

Answer 21

• 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)

Question 22

NP in AF and why

Answer 22

↑NP with AF, largely due to distension of the atrium itself May also be secondary changes due to more wide ranging cardiac dysfunction

Question 23

Combining biomarkers in AF

Answer 23

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

Question 24

Possible uses of NPs

Answer 24

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

Question 25

Role of NPs currently

Answer 25

Not quite diagnostic yet but helps with echo etc

Question 26

BNP vs NT-proBNP

Answer 26

The in-vivo half-life of BNP is ~20 min
In vivo half-life of NT-proBNP is 2 hours
We measure NT-proBNP due to its greater stability