Sympathetic nervous system and renin-angiontensin system Flashcards
How do baroreceptors lead to change in heart rate?
They detect pressure - increased baroreceptor firing leads to a decrease in sympathetic activity which reduces pressure and heart rate
Where are baroreceptors found?
aortic arch
carotid arteries
Give examples of 2 catecholamines and the difference in their structures
Adrenaline and noradrenaline
Adrenaline has a – CH3 attached to the N atom
Where is noradrenaline synthesised in the neurone?
In the terminal varicosity – nodule at end of nerve
What is the process of noradrenaline synthesis?
- Tyrosine enters neurone
- Converted to DOPA (tyrosine hydroxylase)
- DOPA to dopamine (DOPA decarboxylase)
- Dopamine enters vesicles
- Dopamine to noradrenaline in vesicles(Dopamine beta hydroxylase)
How does noradrenaline leave the axon terminal?
Exocytosis using ATP
Which two places can recycled noradrenaline be taken?
Return into the neurone where it was released from
It can be up taken by extra neuronal cells
Which two enzymes break down noradrenaline?
- COMT (Catechol-O-Methyl Transferase)
* MAO (Monoamine Oxidase)
How are adrenoreceptors sub classed?
- Excitatory on smooth muscle - alpha adrenoreceptor mediated
- Relaxant on smooth muscle + stimulatory effect on heart beta adrenoreceptor mediated
What does a stimulatory effect on the heart mean?
Increase in the force of contraction (inotropic effect) and increase in heart rate (chronotropic effect)
What is inotropic?
Increase in the force of contraction
What is chronotropic?
Increase in heart rate
What are the different subdivisions of BETA-receptors?
- Beta 1
- Beta 2
- Beta 3 – imp in bladder function and thermogenesis
Where are beta 1 receptors found?
Cardiomyocytes
Smooth muscle of GI tract
Where are beta 2 receptors found?
Vasculature
Bronchi
Uterine smooth muscle
Where are beta 3 receptors found?
Fat cells
smooth muscle of the GI tract
What are the different subdivisions of ALPHA - receptors?
Alpha 1
Alpha 2
Where are alpha -1 receptors located?
Post-synaptic (mostly on effectors)
Where are alpha 2- receptors located?
- Pre-synaptic nerve terminal
* Some are post synaptic on vascular smooth muscle
What is the importance of alpha-1 receptors?
Constriction of resistance vessels
What is the importance of alpha -2 receptors?
- Pre-synaptic - their activation causes negative feedback inhibition of further transmitter release
- Post-synaptic ones cause vasoconstriction
How does the activation of Alpha 1 adrenoreceptors lead to muscle contraction?
- G linked protein receptors
- Receptor activation leads to the activation of PLC
- PLC converts PIP2 to IP3 which leads to a release of calcium from intracellular stores
- Increase in intracellular calcium in a muscle cell causes CONTRACTION
What is the role of cAMP in smooth muscles and platelets?
cAMP is an inhibitor, so it prevents activation, makes smooth muscle relax and prevents platelet activation
What is the role of cAMP in cardiomyocytes?
Increase in cAMP, like calcium, activates the cell - this is unique to cardiomyocytes
What is anaphylaxis?
An extreme allergic reaction where you get release of vasodilators and bronchoconstriction
Why can adrenaline be used during anaphylaxis?
It binds to all adrenoreceptors so will activate all the receptors you need
What can isoprenaline be used as a treatment for?
Asthma
Which adrenoreceptors can dopamine work on?
alpha 1 and beta 1 receptors
In which parts of the body does dopamine have its own receptors?
Vasculature and kidneys
Which adrenoreceptors does isoprenaline bind to?
Beta 1 and beta 2
Which adrenoreceptor does phenylephrine bind to?
Alpha 1 receptor
What are two synthetic catecholamines?
Isoprenaline and phenylephrine
What three things regulate renin release?
- Amount of sodium that reaches the macula densa - the less sodium there is, the more renin will be released
- Blood Pressure - depends on the pressure within the preglomerular vessels - the lower the blood pressure, the more renin is released
- Beta Receptor Activation - sympathetic response in the kidneys the more beta receptors are activated, the more renin is released
How can drugs be used to affect the renin- angiotensin system?
- Angiotensin II receptors can be blocked
- ACE inhibitors can partially block the production of angiotensin II
- Beta blockers stop renin release in the kidneys
- NSAIDs can increase renin release (unwanted effect)
Which type of receptors are angiotensin II Type 1 Receptors (AT1)
G-protein coupled receptors (Gi and Gq)
Where are angiotensin II type 1 receptors located?
Blood Vessels Brain Adrenals Kidney Heart
What is the role of activated AT1 receptors?
To increase blood pressure
What are the effects of angiotensin II on the kidneys?
- Increase sodium reabsorption in proximal tubule
- Renal vasoconstriction
- Enhanced noradrenaline effects in the kidney
What are the effects of angiotensin II on peripheral resistance?
- Vasoconstriction
- Enhanced action of noradrenaline – more release and less uptake
- Increased sympathetic discharge
How long does angiotensin II take to increase peripheral resistance?
Rapid
How long does angiotensin II take to have renal/adrenal effects?
Weeks and months
How can we pharmacologically manipulate the Renin-Angiotensin System?
Renin Inhibitor
ACE inhibitors
Angiotensin II receptor blockers
What is an alternative pathway for angiotensin II production?
Chymases are enzymes which produces angiotensin II from angiotensin I and even from angiotensinogen
How can ACE inhibitors affect bradykinin and what is its role?
- ACE breaks down bradykinin (main product of kinin system)
- If you block ACE then you’ll have less angiotensin II and more bradykinin
- Bradykinin is a vasodilator
What do angiotensin II Type 1 receptor antagonists do?
They block:
• Pressor effects (blood pressure effects)
• Stimulation of noradrenaline system
• Secretion of aldosterone
• Effects on renal vasculature
• Growth-promoting effects of cardiac and vascular tissue
• Uricosuric effect (high amounts of uric acid)
What are the main triggers for increased aldosterone production?
Increased Potassium
Angiotensin II
What are the pathophysiologic effects of aldosterone in cardiovascular disease?
- Potassium and magnesium loss
- Sodium retention
- Ventricular arrhythmias
- Inflammation, vascular fibrosis and injury
- Myocardial fibrosis and necrosis
- Prothrombotic effects
- Central hypertensive effects
- Endothelial dysfunction
- Autonomic dysfunction – decreased HR variability
What causes primary hyperaldosteronism?
benign tumours of the adrenal cortex
What causes secondary hyperaldosteronism?
Excessive response of the body in heart failure and liver failure
What are the phenotypes of the two types of hyperaldosteronism?
- Primary = high blood pressure + no oedema
* Secondary = low/normal blood pressure + lots of oedema
Which roles do the sympatho-adrenal and renin-angiotensin systems share?
Activation of both systems leads to: increased blood pressure, increased heart rate and increase in sodium/water retention
How do the sympatho-adrenal and renin-angiotensin systems decrease fluid loss?
- Increased coagulation
- Decreased fibrinolysis
- Increased platelet activation
What is an example of a stressor that activates the sympatho-adrenal and renin-angiotensin system?
Fluid loss
What is the sympatho-adrenal system?
Sympathetic nervous system sends impulses to the adrenal glands, stimulating them to produce catecholamines (adrenaline and noradrenaline)
What are the effects of noradrenaline on systolic and diastolic BP, mean BP and heart rate?
- Increases systolic BP
- Increases diastolic BP
- Increases blood pressure
- Decreases heart rate – reflex bradycardia
What is reflex bradycardia?
Vasoconstriction causes BP to increase, so more firing of the baroreceptors leading to the deactivation of the sympathetic innervation of the heart and increased activity of the Vagus nerve leading to a reduced heart rate
What are the effects of isoprenaline on systolic and diastolic BP, mean BP and heart rate?
- Increases systolic BP
- Decreases diastolic BP
- No real change in mean BP
- Increases heart rate
How does angiotensin 2 affect expression of proto-oncogenes, growth factors and ECM synthesis?
- Increased expression of proto-oncogenes
- Increased production of growth factors
- Increased synthesis of extracellular matrix proteins
How does angiotensin II affect preload and afterload and vascular wall tension?
- Increased preload and afterload
* Increased vascular wall tension
Why are the effects of isoprenaline limited?
No vasoconstriction so no resistance change (it is a pure beta agonist)
Why is the distribution of receptors not uniform?
vascular beds in different areas express different receptors and so will have different vascular responses
Is isoprenaline a vasodilator or a vasoconstrictor?
Vasodilator
What are the effects of adrenaline on systolic, diastolic, mean blood pressure and heart rate?
• Increases systolic BP
• Decreases diastolic BP
• Increases mean BP
• Increases heart rate - potent effect on beta receptors on cardiomyocytes
Lesser effects than isoprenaline as has both beta and alpha effects
How do adrenaline and isoprenaline change heart rate?
Directly
Coupling of Beta adrenoreceptors and Alpha 2 adrenoreceptors
They are G protein linked receptors, they increase the levels of cAMP
cAMP is a stimulant in the heart (normally an inhibitor) and increases levels of intracellular calcium
What does isoprenaline do?
It works on the heart to increase the force and rate of the heart contractions. Hence BP increases. Useful for STM treatment of heart block (heart beats too slowly) and shock.
