Renin-Angiotensin System Flashcards
What is the renin-angiotensin system?
- Regulates blood pressure and blood volume
- Effects mediated by angiotensin II (Ang II)
- Ang II also stimulates aldosterone
What does angiotensin II do?
- Vasoconstrictor of small arteries and arterioles
What does aldosterone do?
Volume-expanding hormone
What is angiotensinogen?
- Primary precursor inactive protein (453 amino acids long)
- Constitutively secreted by liver
- Amino acid sequence contains sequence for Ang I and II so enzymatically cleaved for desired protein
Which parts of the amino acid sequence are Ang I and II?
- Ang I- first 10 amino acids
- Ang II- first 8 amino acids
What is renin?
- Enzyme secreted by the kidney
- Secreted by juxta glomerulus apparatus- cells in and around glomerulus
- Release is primary determinate of RAS activated- regulate part
What stimulates the response of renin?
- Released in response to blood pressure
- Sympathetic activation
What does renin do?
- Cleave angiotensin to make Ang I
- No physiological activity
What is the juxtaglomerular apparatus?
- Afferent arteriole –? filtration –> efferent arteriole
- Cells surrounding afferent arteriole release renin
What does ACE stand for?
- Angiotensin Converting Enzyme
What does ACE do?
- Peptidase
- Cleaves peptide bonds
- Converts inactive Ang I to active Ang II by cleaving off 2 amino acids
How is ACE expressed?
- Constitutively expressed
- Mainly in the endothelium of lung
- Also found in other tissues
What is bradykinin?
- Vasodilator broken down by ACE
- Causes pain, redness and increase in permeability
How is ACE important clinically?
- ACE inhibitor drugs
- Promote vasodilation
- Also promote bradykinin
Describe the mechanism of Ang II
- Vascular smooth muscle (Vasoconstriction)
- Adrenal cortex (aldosterone release)
- Sympathetic nerves (increase noradrenaline)
- Kidney (promoting Na+ retention)
What is the overall effect of Ang II?
- Affects blood pressure and blood volume
- Promotes vasoconstriction and salt and water retention
What breaks down Ang II?
- Amino peptidases
- In blood cells in peripheral tissues
What products result from angiotensin II breakdown?
- Limited activity for some products
- Ang III (Ang2-8) limited vasoconstriction
- Ang 1-7 vasodilator acting at MAS receptors
What is the endocrine renin system?
- Circulating renin originates in the kidneys mainly
- Physiological actions all around the body
What is the paracrine renin system (local)?
- All components are present in a tissue
- E.g. kidneys
- Heart and blood vessel walls
- Various parts of the brain
What factors increase renin release?
- Low arterial blood pressure
- Low blood volume
- Altered sodium handling
How does low arterial blood pressure increase renin release?
- SNS activation via baroreceptor reflex
- Internal stretch receptor (juxtaglomerular cells)
- Trigger release of renin
How does low blood volume increase renin release?
- SNS via low pressure receptors
- Arterial stretch
How does altered sodium handling increase renin release?
- Detected by intrarenal mechanism (macula densa)
What factors decrease renin release?
- Negative feedback
- Increased arterial pressure- decreased SNS activation
- Increased blood volume- increases afferent arteriole stretch
- Angiotensin II- negative feedback mechanism
How is RAS regulated?
- Renin is the point of regulation
- Liver continuously produces angiotensin- not rate limiting
- ACE constitutively expressed on lung endothelium
- Renin release controlled by BP
What are the 2 Ang II receptors?
- AT1 receptors
- AT2 receptors
Describe AT1 receptors
- Mitogenic, pro-fibrotic (pathologically importnat), vasoconstriction
- Predominant receptor
Describe AT2 receptors
- Anti-mitogenic, anti-fibrotic, vasodilatory and decrease BP
What are the mediated actions of AT1 receptors?
- Control of blood pressure
- Vasoconstriction
- Aldosterone release from adrenal cortex- leads to Na+ retention, increased osmolality of plasma
Describe how vasoconstriction occurs with AT1 receptor stimulation
- Direct action on vascular smooth muscle
- Release of ADH and endothelia
- Potentiation of SNS
- Blockers of RAS referred to as sympatholytic
- Multiple vasoconstrictors released
Where are AT1 receptors found and what do they do with noradrenaline?
- Potentiate noradrenaline release
- Block reuptake
- Increase noradrenaline synthesis
What are the other sites of action for Ang II?
- Central control mechanisms in medulla of brain
- Catecholamine release from adrenal medulla
- Overall effect is increased SNS activity
Describe the mechanism of Ang II action on receptor
- Ang II act on nerve ending AT1
- Potentiation of sympathetic system
- Noradrenaline
- Αlpha receptors on blood vessels
- Vasoconstriction
Describe the action of aldosterone
- Release regulated by Ang II and also high K+ conc
- Promotes water retention
- Also drives potassium secretion
How does aldosterone promote water retention?
- Osmotic effect of increasing sodium retention in kidney and gut
- Increased ADH
- Potent dipsogen (promotes thirst)
What are the other actions that occur via AT1 receptors?
- Drives a lot of remodelling changes
- Mitotic- fibroblasts and smooth muscle
- Hypertrophy particularly cardiomyocytes
- Profibrotic- inhibits collagen breakdown
- These effects are associated with pathological changes in heart failure and chronic kidney disease
What are the mediated actions that occur at AT2 receptors?
- Stimulates vasodilation
- Increases activity of collagenases- decreasing collagen activity and fibrosis
- Decrease growth factor expression and inhibition of tissue growth
- Induction of apoptosis
How is vasodilation stimulated via AT2 receptors?
- Through NO release
- Increased tissue bradykinin production
What is the equation for cardiac output and peripheral resistance?
MAP = CO X TPR
How is TPR regulated?
- Regulated by vascular tone
- Depends on level of constriction
- Small change in radius leads to big change in vasoconstriction
What is the relationship between CO and stroke volume?
CO = HR x SV
- Heart rate increased by SNS
What is stroke volume determined by?
- Preload- if we expand volume- stretch myocardium and it responds with more force
- Contractility
- Afterload
How does Ang II action affect vasculature?
- Fast-acting short response
- Direct vasoconstriction will increase TPR (resistance)
- Interaction with SNS and endothelia release
How does Ang II action affect blood volume?
- Slower acting, long term
- Salt and water retention via direct action and stimulation aldosterone
- Increase in venous return (preload) and therefore CO
Whats the link between Ang II and heart failure in remodelling?
- Falling BP, baroreceptors constantly not firing, little stimulation, a lot of sympathetic stimulation, a lot of renin
- Leads to Ang II release
- Profibrotic/mitotic effects- leads to increased cardiac modelling
What is the link between Ang II and chronic kidney disease in remodelling?
- Promotes mesangial proliferation and hypertrophy
- Promotes synthesis of TGF-β and collagen
- Degenerative process elating to glomerulosclerosis
List the blockers of RAS
- β-blockers
- Renin inhibitors
- ACE inhibitors
- Angiotensin receptor antagonists
How do β-blockers work?
- Block SNS stimulation of secretion
How do renin inhibitors work?
- Drugs exist but are not routing clinical use as renin is the only regulator
How do ACE inhibitors work?
- Block conversion of Ang I to Ang II
How do angiotensin receptor antagonists work?
- Stop Ang II binding to AT1 receptor
Describe the mechanism of action of ACE inhibitors
- Block conversion of inactive Ang I to active Ang II
- Also inhibits breakdown of bradykinin
- Widely used in heart failure
- Captopril, ramipril
How do ACE inhibitors inhibit the breakdown of bradykinin?
- As a vasodilator, adds to lowering BP
- Basis of best known side effect- dry cough
- No other benefit
How do ACE inhibitors help with heart failure?
- Reduced preload and afterload
- Anti-fibrotic effects
When would AT1 receptor antagonists be prescribed?
- Persistent dry cough with ACE inhibitors
Give examples of AT1 receptor antagonists
- Losartan
- Candesartan
What is the difference between ACE inhibitors and AT1 receptor antagonists?
- Unlike ACE inhibitors, AT1 receptor antagonists do not affect AT2 receptors
- Seem equally good in terms of treating heart failure
