Reninangiotensin System, Vasopressin Ad Endothelin Flashcards
What is the purpose of the RAAS system
Maintenance of circulatory volume and arterial pressure
Central role in regulation of sodium excretion and body fluid volume
What is the site of angiotensin 2 production
Lung
Describe the lung and angiotensin 2 production
Lung has large surface area of vascular endothelium
Does not possess angiotensinases to metabolism angiotensin 2 like other tissues
Contribution of other tissues (and cell types) to angiotensin 2 production previously underestimated?
Most A1 to A2 conversion occurs in vascular beds including renal, coronary
Describe the juxtaglomerular apparatus
In the renal cortex
Unique segment of the nephron
Macula dense specialised in thick ascending limb which makes contact with vascular elements of the JGA
Vascular elements of the JGA cont modified smooth muscle cells of arterioles (granular cells) which contain secretory granules that synthesise and secrete the enzyme renin
A second group of JGA (lacis or mesangial cells) are not granular but also secrete renin
Renin secretion is stimulated in 3 ways…
Increased activity of renal sympathetic nerves (Beta 1 adrenoreceptor)
Pressure-sensitive renin-secreting cells respond to decreased renal arterial pressure
Decreased delivery of sodium to macula densa cells
RAAS system direct and indirect response to reduced plasma volume
Increased angiotensin 2
Direct:
-AT1 receptor in PCT incr tubular reabsorption of NA, decor sodium excretion
Indirect
AT1 receptor in adrenal cortex, incr aldosterone secretion, increase aldosterone, aldosterone receptor in DCT - increase Na reabsorption and decr sodium excretion
Negative feedback loop
Mechanism of action of aldosterone
Aldosterone = mineralocorticoid
Synthesis of exchange/channel proteins
Activators of Na and K channels (silent channels become fucntional)
Proteins regulating mitochondrial ATP production
Outcome incr capacity for Na reabsorption and increased K and H secretion
Mechanism of action of vasopressin
‘Free water balance is couples to sodium balance to maintain osmotic equilibrium
Diagram
Mechanism of action for controlling water permeability of collecting duct
Vasopressin bind to G protein-coupled V2 recent=ProRes on basolateral membrane of principal cells in collecting duct
This, via Aden your cyclase and protein kinase A, leads to migration of vesicles containing preformed water channels (aquaporin-2; AQP-2) to apical membrane
AQP-2 channels released from vesicles and inserted into membrane, increasing water permeability
Channels of aquaporin-3 and -4 types (AQP-3, AQP-4) in basolateral membrane allow passage of water into hyperosmolar medullary interstitium
Local tissue (auto/paracrine) RAAS
Angiotensin and renin-like enzymes present in many arteries, veins
Myocardium, renal proximal tubule and glomerulus, CNS, adrenal gland, gut, inflammatory cells also synthesise angiotensin 2
Localised fluctuations in peptide levels
Physiological functions of angiotensin 2
Potent vasoconstrictor - incr TPR and BP
Aldosterone (adrenal cortex)/ Vasopressin (pituitary) release - retention of Na/Water
Central effects - thirst/salt appetite
Growth/remodelling effects - vasculature, heart, kidney
Generation of ROS
Pre-synaptic facilitation of noradrenaline release
Negative feedback regulation of renin secretion
Angiotensin 2 maintains…..
Glomerular filtration
In addition to general systemic vasoconstriction
Also controls renal efferent arterioles
Important in Pathophysiological conditions
Contracts renal mesangial (reduces filtration area (increases pressure))
Describe angiotensin 2 and renal artery stenosis
Maintains glomerular filtration but restricts blood flow to tubule (ischaemia), puts more strain on the kidney
AT1 receptor:
Agonist potency location function
Ang2>Ang3
Lung, liver, brain, kidney, blood vessels, heart; adrenal and pituitary glands
Vasoconstriction;cardiac contractility; remodelling of heart vessels ; release of aldosterone and vasopressin; drinking/thirst; noradrenaline release; negative feedback on renin release
AT2 receptor
Agonist potency; location; function
Ang2=Ang3
Mainly in brain, reproductive tissues, heart? Foetal tissues?
Largely unknown? Embryogenesis? Anti-proliferative effects? CNS influence on BP (ANG3) via stimulation of ADH, SNS
Actions of aldosterone
Promotes K loss (prevent hyperkalaemia)
Conserves sodium by kidney (also by gastrointestinal tract, sweat glands)
(In)direct vasoconstrictor action on vasculature
Raises BP
Promotes collagen synthesis and chronic vascular and target organ remodelling in ischaemia and haemodynamic stress
Cause and effect of excess aldosterone levels
Cause: primary (Adenoma, bilateral adrenal hypertrophy) or secondary to increased renin (renal artery stenosis)
Effect: hypokalaemia, alkalosis, increased Na, extracellular fluid, increased BP
Cause and effect of deficiency in aldosterone
Cause: primary (Addison’s disease, damage to adrenal cortex) or secondary to decreased renin
Effect: hyperkalaemia, acidosis, decreased Na, extracellular fluid, urine output, postural hypotension
Abnormal activity of RAAS development of hypertension due to:
Sodium retaining effects
Vasoconstrictor effects
Structural remodelling
Action of pharmacological suppression of RAAS system
Vasodilation (and attenuated remodelling) -> decr peripheral vascular resistance-> decr BP
Decr Na retention -> decr blood volume -> decr blood pressure
Protective actions of ANG1-7
Incr insulin like effects
Decr inflammation
Decr angiotensin 2 levels
Decr angiotensin 2 signalling
Cardio protection
Renoprotection
Decr fibrosis
Brain protection
Decr trombosis
Increased endothelial function
Describe the biology of vasopressin
Released from pituitary due to increased plasma osmolarity or decreased circulatory volume
Excess associated with hypervolaemia, hyponatraemia
Deficient secretion/action - diabetes insipidus
Alcohol inhibits release - causes diuresis
Actions of vasopressin (receptors)
V2 - water retention, stimulates van Willibrands factor release from endothelium, promotes coagulation, stabilises fibrin Clot
V1a - vasoconstriction, LVH
V1b - ACTH secretion (regulates cortisol)
Desmopressin V2 selective and less susceptible to degradation
Clinical applications of vasopressin and analogues
Diabetes insipidus
Nocturnal enuresis in older children
Prophylaxis against bleeding in haemophilia and persistent bleeding on tooth extraction
Vasoconstrictor added to local anaesthetics
Clinical application of vasopressin antagonists
Conivaptan (non-selective), Tolvaptan (V2 selective)
For hyponatraemic hypervolaemia associated with inappropriate vasopressin secretion
Short-term benefit in acute exacerbation of HF
3 iOS forms of endothelium peptide family
Each encoded by distinct gene
Processed from larger big-ET precursor peptides by ECE
ET2 and ET3 differ from ET1 by 2 and 6 amino acids
ET-1 released..
Mainly from the endothelium
In response to RAAS, vasopressin, noradrenaline, thrombin, hypoxia and low sheer stress
Inhibited by NO, prostacyclin, high sheer stress, natriuretic peptides
Endothelium actions
Sustained vasoconstriction of arteries and veins
Positive ionotropic and chronograph effects
Secretion of aldosterone, adrenaline
Proliferation of vascular smooth muscle cells
Cardia hypertrophy, fibrosis and remodelling
Pathophysiological role - pulmonary hypertension and HF?
Endothelium-dependent relaxation - NO release, -ve feedback, regional vasodilation
Natriuretic, diuresis (action in CD)
Classification of endothelin receptors
2 receptor subtypes ETA and ETb distinguished according to agonist affinity
Agonist affinity of ETA
Affinity of ET-1 (and ET-2) > ET-3
Agonist affinity of ETb
Affinity of ET-1 (and ET-2) = ET-3
ETA and ETb can be differentiated by
Selective antagonists
ETA receptor selective = BQ123, ambrisentan
ETb receptor selective = BQ788, A192621
ET-1 increases the ….
Total mass of cellular protein by stimulating de novo synthesis in ventricular cardiomyocytes
Can also measure gene expression at RNA, protein level etc
Increased plasma levels correlate with….
Chronic heart failure severity, hospitalisation, mortality
