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Cardiovascular Pathobiology And Treatment > Reninangiotensin System, Vasopressin Ad Endothelin > Flashcards

Reninangiotensin System, Vasopressin Ad Endothelin Flashcards

1
Q

What is the purpose of the RAAS system

A

Maintenance of circulatory volume and arterial pressure
Central role in regulation of sodium excretion and body fluid volume

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2
Q

What is the site of angiotensin 2 production

A

Lung

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3
Q

Describe the lung and angiotensin 2 production

A

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

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4
Q

Describe the juxtaglomerular apparatus

A

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

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5
Q

Renin secretion is stimulated in 3 ways…

A

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

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6
Q

RAAS system direct and indirect response to reduced plasma volume

A

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

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7
Q

Mechanism of action of aldosterone

A

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

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8
Q

Mechanism of action of vasopressin

A

‘Free water balance is couples to sodium balance to maintain osmotic equilibrium
Diagram

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9
Q

Mechanism of action for controlling water permeability of collecting duct

A

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

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10
Q

Local tissue (auto/paracrine) RAAS

A

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

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11
Q

Physiological functions of angiotensin 2

A

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

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12
Q

Angiotensin 2 maintains…..

A

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))

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13
Q

Describe angiotensin 2 and renal artery stenosis

A

Maintains glomerular filtration but restricts blood flow to tubule (ischaemia), puts more strain on the kidney

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14
Q

AT1 receptor:
Agonist potency location function

A

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

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15
Q

AT2 receptor
Agonist potency; location; function

A

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

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16
Q

Actions of aldosterone

A

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

17
Q

Cause and effect of excess aldosterone levels

A

Cause: primary (Adenoma, bilateral adrenal hypertrophy) or secondary to increased renin (renal artery stenosis)
Effect: hypokalaemia, alkalosis, increased Na, extracellular fluid, increased BP

18
Q

Cause and effect of deficiency in aldosterone

A

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

19
Q

Abnormal activity of RAAS development of hypertension due to:

A

Sodium retaining effects
Vasoconstrictor effects
Structural remodelling

20
Q

Action of pharmacological suppression of RAAS system

A

Vasodilation (and attenuated remodelling) -> decr peripheral vascular resistance-> decr BP
Decr Na retention -> decr blood volume -> decr blood pressure

21
Q

Protective actions of ANG1-7

A

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

22
Q

Describe the biology of vasopressin

A

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

23
Q

Actions of vasopressin (receptors)

A

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

24
Q

Clinical applications of vasopressin and analogues

A

Diabetes insipidus
Nocturnal enuresis in older children
Prophylaxis against bleeding in haemophilia and persistent bleeding on tooth extraction
Vasoconstrictor added to local anaesthetics

25
Q

Clinical application of vasopressin antagonists

A

Conivaptan (non-selective), Tolvaptan (V2 selective)
For hyponatraemic hypervolaemia associated with inappropriate vasopressin secretion
Short-term benefit in acute exacerbation of HF

26
Q

3 iOS forms of endothelium peptide family

A

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

27
Q

ET-1 released..

A

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

28
Q

Endothelium actions

A

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)

29
Q

Classification of endothelin receptors

A

2 receptor subtypes ETA and ETb distinguished according to agonist affinity

30
Q

Agonist affinity of ETA

A

Affinity of ET-1 (and ET-2) > ET-3

31
Q

Agonist affinity of ETb

A

Affinity of ET-1 (and ET-2) = ET-3

32
Q

ETA and ETb can be differentiated by

A

Selective antagonists
ETA receptor selective = BQ123, ambrisentan
ETb receptor selective = BQ788, A192621

33
Q

ET-1 increases the ….

A

Total mass of cellular protein by stimulating de novo synthesis in ventricular cardiomyocytes
Can also measure gene expression at RNA, protein level etc

34
Q

Increased plasma levels correlate with….

A

Chronic heart failure severity, hospitalisation, mortality

Cardiovascular Pathobiology And Treatment (13 decks)

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