Angiotensin, natriuretic peptides, endothelin Flashcards Preview

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Flashcards in Angiotensin, natriuretic peptides, endothelin Deck (34)
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natriuretic peptide family:

Urodilatin (proANP)
Dendroaspsis natriuretic peptide (DNP)

--- 5 members


where are natriuretic peptides synthesised?

ANP - synthesised and stored and released by atrial myocytes
BNP - synthesised in the ventricles (and in atria)
CNP - released by vascular endothelium, also CNS
Urodilatin - from renal tubule


Regulation of ANP release

Stimulated by:
1) atrial distension - in fluid overload and CHF
2) Angiotensin II
3) Endothelin
4) Sympathetic stimulation (beta1-AR)


regulation of BNP release:

stimulated by atrial and ventricular stretch


Effects of ANP and BNP

1) increased natriuresis and diuresis (potassium sparing)
2)Vasodilation (activates guanylyl cyclase in VSMCs and increases cGMP) and attenuates vascular sympathetic tone
3) increased urinary cGMP, increases GFR
4)decreases aldosterone release, decreases renal release and thus decreases AngII levels
ANP is a counter-regulatory system for the RAAS


metabolism and clearance of natriuretic peptides

1)NPR-C (clearance receptor) : has lower affinity for BNP
2)Neutral endopeptidases largely in renal tubules and VSMCs


CNP regulation and effects

CNP released by endothelium in response to shear stress and cytokines.
little or no effect on natriuresis or BP.


Neutral endopeptidases: location, actions, tharapeutics

1) present mainly in the brush border membrane of renal tubules, also vascular endothelium
2) catalyses the breakdown of ANP, BNP, CNP
3) also degrades other peptide hormones: bradykinin, urodilatin, adrenomedullin
4) converts pro-endothelin into endothelin, and AngI into Ang(1-7)

OVERTURE: NEP inhibitor showed no superiority to ACEi, and worse Side Effect profile



BNP is released as prohormone, cleaved into BNP and NT-pro-BNP in EQUIMOLAR amounts

In vivo half-life of BNP is 20min, NT-pro-BNP is 2h


therapeutic manipulations of natriuretic peptides:

ANP and BNP infusion:
Decreases RA and pulmonary capillary pressure, and decreases [Renin] and [aldosterone]. Increases urinary Na and H2O excretion

recombinant hBNP (Nesiritide) approved by FDA in acute decompensated CHF: decreases cardaic filling, improves cardiac index &diuresis/natriuresis

NPR-C ligands can increase levels of natriuretic peptides by inhibiting their clearance

NEP inhibitors --> elevates ANP --> reinforces the effects of ACEi (or ARBs)


how is angiotensin II produced?

Released from the juxtaglomerular cells Renin cleaves angiotensinogen producing angiotensin I, which is then converted to angiotensin II by ACE. ACE is present in the vacular endothelium, particularly the lungs.

can be produced via alternative pathways involving VHYMASES


how is renin regulated?

SNS stimulation of the kidneys (via B1-AR), renal artery hypotension, decreased Na delivery to the distal tubules (usually due to reduced GFR secondary to refuced renal perfusion) stimulate the release of renin into the circulation.

Renin is formed within the juxtaglomerular cells associated with afferent and efferent arerioles of the renal glomeruli, which are adjacent to the MACULA DENSA cells of the distal tubule segments that sense Na and Cl concentrations in the distal tubules.


what are the Angiontensin receptors and their ligands?

AT1 - Ang II
AT2 - Ang II
Mas - Ang (1-7)
AT4 - Ang II, Ang 3-8


Functions of AT1 receptor

Ang II binds to the receptor which is mediated by G protein-coupling, Ca, and IP3 signalling. Produces:
1) vasoconstriciton
2) cardiac and vascular fibrosis
3) cardiac and vascular hypertrophy
4) inflammation

5) facilitates NA release from sympathetic nerve endings and inhibits NA reuptake
6)increases the release of aldosterone ---> increases Na and fluid retention
7) stimulates thirst centres in the brain


Functions of AT2 receptor

largely FUnctionally antagonises the effects of AT1:
1)produces vasodilaation via bradykijnin, NO, cGMP
2) antifibrotic
3) anti-proliferative
4) anti-inflammatory

5 inhibits renin release by acting directly on juxtaglomerular cells


How is Ang (1-7) produced and how does it act?

Produced by ACE2 cleaving angiotensin II.
acts on Mas receptors producing similar effects to AT2 receptor:
1)produces vasodilation
2) antifibrotic
3) anti-proliferative
4) anti-inflammatory


what is ACE2 and what are its properties

A carboxypeptidase with 40% identity to ACE
converts AngII to Ang 1-7, metabolises various peptides includin neurotensin, kinetensin but NOT BRADYKININ
expressed in heart, kidney, endothelium, VSMCs, testis
not inhibited by classical ACEis
Expression upregualted by inhibition of AT1 receptors
Acts as a receptor for SARS
ACE2 overexpression causes cardiac conduction disturbances and SCD in mice/


Local RAS

classicaly plasma renin was thought to account for conversion of angiotensinogen to angiotensin I but BP correlates poorly with plasma renin activity
action of AngII requires levels that rarely if ever occur in circulating blood,

venous blood levels of AngII exceed those expected on the basis of arterial blood levels

mRNA and protein for renin and angiotensinogen are present in a number of tissues.

exact roles of local RAS is not yet understood


what is renin:

aspartic protease with only one known substrate, angiotensinogen
produced by juxtaglomerular cells
exists in pro-, active, and inactive forms.
prorenin, the inactive precuros, circualtes in plasma at 100-fold higher concentrations and can be activated by proteolysis, low pH and low temperatures


Prorenin receptors. which ? action?

Prorenin and renin can bind two distinct receptors: 1) (pro) renin receptors and 2) Mannose-6-phosphate receptors

binding of prorenin to PRR causes:
enzymatic activation of prorenin allowing conversion of angiotensinogen into Ang I without cleavage of prorenin
induces cellular signalling via MAP kinase pathways

ohysiological role of PRR unknown. present in VSMCs.


the endothelin peptide family and members:

three members of 21-amino acid long isopeptides
ET-1, ET-2, ET3
each encoded by a separate gene


which endothelin is of major importance in CVS?



Where is endothelin produced?

- endothelial cells (major source)
- Most nephron segments
- Neurons in CNS, postganglionic neurons of SNS


how is endothelin produced?

produced by a series of proteolytic cleavages
final step is by Endothelin converting enzyme (ECE)

ECE ahs two major isoforms
ECE1 and ECE2

they are membrane bound zinc metalloproteases


endothelin receptors and what were the clues for subtype existence?

the existence of multiple ET receptor subtypes was first hinted at by the characteristic biphasic BP response to ET-1 in rats

Receptors known: ETA and ETB


ET receptor potencies and mechanisms

ETA: ET-1=ET-2>>ET-3

ETB: all ETs equally

they are heptahelical G protein coupled receptors - couple to multiple classes of G proteins, and couping varies depending on the receptor subtype and the lignad bound to the R in question


What are the actions of endothelin on VSCM?

both ETA and ETB are located on VSCMs and both mediate VASOCONSTIRCTION when ET-1 binds them

the pathway involves phospholipase C (PLC) activation --> increase in IP3 --> increase in [Ca].


What are the actions of endothelin on the endothelial cells?

ETB on the endothelial cells leads to increased NO and vasodilator metabolites ---> VASORELAXATION


relative roles of ETB and ETA on vascular tone

acute ETA blockafe produces either a small drop in BP or no change --> ETA plays a small role in determining the basal vascualr toen in healthy individuals

ETB blockade --> increase in BP due to loss of ETB mediated vasodilation and increased ETA activation

endogenous ET-1 in healthy humans contributes little to vascular tone by providing some vasoconstriciton: systemic administration of both ETA and ETB antagonists produced mild reduction in TPR and BP


Actions of ETA

In VSCM mediates vasoconstriction
also promotes growth and proliferation of VSCMs via activation of MAP kinases and epidermal growth factors receptor
Stimualtes Oxidative Stress

Promotes cardiac hypertrophy via activating PKC taht activates Ras which then activates Raf-MKK1/2 - ERK1/2 pathway in which the transcription of pro-hypertrophic genes is promoted

also induces Macrophage cytokine production, increases ROS via increased NADPH oxidase activity, and increases adhesion molecule expression ==== implicated in PAH and atherosclerosis