Renin-Angiotensin System Flashcards
Describe the classifical loop of the renin angiotension system
Ok so angiotensinogen is released from the liver (a 14-mer), the last 4 carboxyl groups are cleaved by renin to produce a 10mer called angiotensin 1. Renin is released from the juxtaglomerular cells of the liver, these cells secrete renin in response to decreased NA in the blood, decreased blood pressure (sensed by decreased blood volume) and they also secrete it based on sympathetic stimulation (NA acts on b1 on the JG cells). Renin is produced from the peptide prorenin into the active form of renin where it cleaves angiotensinogen. Angiotensin 1 (10mer) then circulates in the blood stream until it meets ACE; ACe is anchored to cell membrane, particulary in the endothelium layer in the lung and cleaves the last 2 carboxy residuces of angotensin 1 to produce antiotension 2 which is the activate hormone (an 8mer). angiotensin 2 then acts on AT1R and AT2R (to a lesser extent)
What is the effect of angiotensin 2 acting on the AT1 receptor?
This receptor is coupled to the gq protein cycle so when activated leads to increased calcium. Angiotensin 2 acts on these receptors on the promixmal renal tubules which leads to increased activation of the sodium hydrogen exchanger and leads to increased sodium. It also acts on these receptors located on the adrenal cortex and leads to the production of aldosterone, aldosterone that acts on nuclear receptors in the cells of the distal renal tubules and causes sodium channels to be inserted in the basal lateral membrane - this leads to an increase in the uptake of sodium and with it ocmes water this then raises blood pressure and raises blood volume. When this system is overactive e.g. in hypertension the at1r receptors activate fibroblasts which leads to fibrosis and scarring. Also at1r causes hypertrophy of cardiac mycoytes by stimulating them so they enlarge which leads to damage to the heart. Activation of at1r also leads to ROS pr oduction and therefore oxidative stress damage. The At1 receptor is also thought to be linked to b arrestin which is involved in the phosphylation and desensitsation of receptors.
What happens when angiotensin 2 binds o the at2 receptor?
It causes the opposite effects on the AT1 receptor by causing vasodilation through the release of NO. it is a foetal receptor that is switched off at birth but is switched back on in disease.
Describe the negative feedback system in place?
When the Na level in the blood raises and the blood volume raises as a consequence then the JG cells will stop producing renin as there signals become depleted
Aliskiren
A renin inhibitor that has therpeutic potentil in hypertension - reduces symptoms but only problem is it does not block intrarenal renin production
Pronanolol
A B adrenergic blockers that blocks the b receptors of the juxtaglomurular cells that are stimulated by sympathetic nervous activity - only problem is does not block intrarenal production
Captopril
An ace inhibitor (most widely used drugs in the world)
Used to treat hypertension and has been found to have some therapeutic effect after someone has had an acute MI. Blocks ACE, the carboxyl group of the drug binds othe zinc ion in the sctive site of the ACE and stops it from converting angiotensin 1 to 2 and therefore reduces angiotensins effect on AT1R receptors. Problem is that ACE also breaks down bradykinin and if block bradykinin builds up a nd stimulates sensory nerves leading to an irritant cough. Also captopril has a short half life which requires 2-3 treatments a day and therefore patient compliance is an issue (now have enalapril which is a propdrug with a longer half life but still same irritant cough property)
Losartan
An AT1R blocker that can be used in hypertension and heart failure has no irritant cough like captopril and enalapril. Has lead to the intrest in creating biased arbs that do not block the b-arrestin pathway which can have some therpeutic effect
Describe the counter regulatory axis of the renin-angiotensin system
Angiotensin 1 can be converted to Ang1-9 by ACE2 where it can then be converted by originial ACE into the active hormone ang1-7. Angiotensin 2 can also be converted directly by ACE2 to ang1-9. Ang1-7 then acts on Mas receptors - Mas actions antagonist the effect of angiotensin 2 on AT1R so are therpatuic - they have anti-hypertrophic and anti-fibrotic effects
Based on the counter regulatory axis what drugs are currently being developed that coudld be therapetuic in CVD?
Human recombinant ARBS
XNT which is asmall molecule activtor of ACE2
Describe domain selective ACE inhibitors
Well since the C domain is the one that breaks up angiotensin 1 to 2 it count be targetted and that leaves the N domain that breaks down bradykinin free and therefore prevents the irritant cough
