The Sympathetic Nervous System and the Renin-Angiotensin System Flashcards
REMEMBER: parasympathetic comes from the ………………… region and sympathetic comes from the ……………….. region
BARORECEPTORS are pressure sensors - increased baroreceptor firing leads to a decrease in ……………….. activity which reduces pressure and heart rate
Baroreceptors are found in the ………. ………. and in the ……………….. ………………..
NOTE about Autonomic Effector Nerves: all parasympathetic nerve terminals release ………………..
In the paravertebral sympathetic ganglion, the transmitter is ALWAYS ………………..
At the effector end of the sympathetic arm the transmitter is ………………..
Except in the special case of the adrenal medulla which acts as a specialised post-ganglionic neuron and releases mainly adrenaline (80%) and noradrenaline (20%)
Post-ganglionic fibres to the sweat glands release ………………..
REMEMBER: parasympathetic comes from the craniosacral region and sympathetic comes from the thoracolumbar region
BARORECEPTORS are pressure sensors - increased baroreceptor firing leads to a decrease in sympathetic activity which reduces pressure and heart rate
Baroreceptors are found in the Aortic Arch and in the Carotid Arteries
NOTE about Autonomic Effector Nerves: all parasympathetic nerve terminals release acetylcholine
In the paravertebral sympathetic ganglion, the transmitter is ALWAYS acetylcholine
At the effector end of the sympathetic arm the transmitter is noradrenaline
Except in the special case of the adrenal medulla which acts as a specialised post-ganglionic neuron and releases mainly adrenaline (80%) and noradrenaline (20%)
Post-ganglionic fibres to the sweat glands release acetylcholine
Where does the synthesis of noradrenaline occur?
Synthesis of the noradrenaline occurs in the TERMINAL VARICOSITY - this is a small nodule at the end of the sympathetic nerve
Except for the special case of the adrenal medulla, the transmitter is Noradrenaline
It is stored in granular vesicles and is exocytosed - this is an ACTIVE process (requires ATP)
Then you get reuptake and removal of the transmitter
What are the two methods noradrenaline can be removed from the cleft?
There are TWO enzymes that are responsible for the subsequent breakdown of the transmitter.
Name these enzymes
Noradrenaline can be removed from the cleft by two methods:
Uptake 1 = goes back to the neurone that released it
Uptake 2 = taken up by extraneuronal cells
There are TWO enzymes that are responsible for the subsequent breakdown of the transmitter:
COMT (Catechol-O-Methyl Transferase)
MAO (Monoamine Oxidase)
What type of adrenoreceptor has Excitatory effects on smooth muscle?
What type of adrenoreceptor has relexant effects on smooth muscle and stimulatory effect on the heart?
Subdivision of Adrenoreceptors
It was divided based on the TWO groups of effects:
EXCITATORY effects on smooth muscle:
ALPHA adrenoreceptor mediated
RELAXANT effects on smooth muscle + STIMULATORY effect on heart
BETA adrenoreceptor mediated
NOTE: by stimulatory effect on the heart it means that it increases the force of contraction (inotropic effect) and increases heart rate (chronotropic effect)
Where are Beta 1- adrenoreceptors located?
Where are Beta 2- adrenoreceptors located?
Where are Beta 3- adrenoreceptors located?
Where are alpha 1- adrenoreceptors located?
Where are alpha 2- adrenoreceptors located?
Subdivision of ALPHA receptors
Alpha 1 receptors are located POST-SYNAPTICALLY (predominantly on effector cells)
These are important in mediating CONSTRICTION of resistance vessels in response to sympathomimetic amines
Alpha 2 receptors are located on PRE-SYNAPTIC nerve terminal membrane
Their activation by released transmitter causes NEGATIVE FEEDBACK inhibition of further transmitter release
Some are post-synaptic on vascular smooth muscle (these, like alpha 1, cause vasoconstriction)
Alpha 1 adrenoreceptors
This is the signal transduction mechanism of alpha 1 adrenoreceptors via ………………..
When the receptor is activated, this causes the activation of ………………..
PLC converts ……………….. to ……………….. which leads to a release of calcium from intracellular stores
An increase in intracellular calcium in a muscle cell causes ………………..
So activation of these receptors increases calcium levels and causes contraction
Alpha 1 adrenoreceptors
This is the signal transduction mechanism of alpha 1 adrenoreceptors via G proteins
When the receptor is activated, this causes the activation of Phospholipase C
PLC converts PIP2 to IP3 which leads to a release of calcium from intracellular stores
An increase in intracellular calcium in a muscle cell causes CONTRACTION
So activation of these receptors increases calcium levels and causes contraction
Beta receptors are coupled with………………. ……………. which increases the levels of ………….
In SMOOTH MUSCLE and PLATELETS = …………. is an INHIBITOR so it prevents activation, makes smooth muscle ………….. and prevents platelet activation
In CARDIOMYOCYTES = increase ………….., like calcium, ACTIVATES the cell - this is unique to cardiomyocytes
Alpha 2 receptors are also ………………… releasing receptors but this is more to do with inhibition of ………………. ………………
You reduce intracellular levels of cAMP and therefore oppose the effects of calcium (because calcium isn’t released from intracellular stores)
Beta receptors are coupled with Adenylate Cyclase which increases the levels of cAMP
In SMOOTH MUSCLE and PLATELETS = cAMP is an INHIBITOR so it prevents activation, makes smooth muscle RELAX and prevents platelet activation
In CARDIOMYOCYTES = increase cAMP, like calcium, ACTIVATES the cell - this is unique to cardiomyocytes
Alpha 2 receptors are also calcium releasing receptors but this is more to do with inhibition of adenylate cyclase
You reduce intracellular levels of cAMP and therefore oppose the effects of calcium (because calcium isn’t released from intracellular stores)
Anaphylaxis is an extreme allergic reaction where you get release of vasodilators and bronchoconstriction
What molecule will counteract this and why?
What receptors does noradrenaline activate?
What receptors does Adrenaline activate?
What receptors does isoprenaline activiate?
What receptors does Phenylephrine activate?
Anaphylaxis is an extreme allergic reaction where you get release of vasodilators and bronchoconstriction - adrenaline (as it binds to all adrenoreceptors) will activate all the receptors you need to counteract this
Dopamine is a precursor for the catecholamines has some effects on alpha 1 and beta 1 receptors and has its own receptors in the vasculature and the kidneys
There are two synthetic drugs which have been designed to examine what the receptors do though isoprenaline is used as a treatment for asthma
As isoprenaline and phenylephrine bind to different receptors, you can use them to determine the different contributions of the receptors to the cardiovascular changes
Why does noradrenaline massively increase BP?
Why does adrenaline have a similar effect to noradrenaline but to a lesser extent?
Why does resistance not change of Isoprenaline?
Why does adrenaline decrease diastolic BP?
Why does noradrenaline cause decrease heart rate?
Noradrenaline massively increases blood pressure because it is a VASOCONSTRICTOR
As blood pressure is determined by cardiac output and total peripheral resistance and noradrenaline massively increases TPR, the blood pressure rises
Adrenaline will have similar effects but to a lesser extent and it also has beta effects which sort of counteract the alpha effects
Isoprenaline is a pure BETA AGONIST but the effects are limited because it isn’t going to cause any vasoconstriction and hence resistance won’t change
Adrenaline has quite potent vasodilator properties which means that is decreases diastolic blood pressure
Isoprenaline has entirely vasodilator properties and so will reduce blood pressure even more
With noradrenaline you may get REFLEX BRADYCARDIA - this occurs because of the baroreceptor loop - vasoconstriction causes an increase in blood pressure which increases the firing frequency 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
This is not a direct effect on the heart by noradrenaline itself
Adrenaline has a potent effect on beta receptors on cardiomyocytes and will increase the heart rate
Summary:
Noradrenaline = Reflex Bradycardia
Adrenaline = Direct increase in heart rate
Isoprenaline = More direct increase in heart rate (not counteracted at all by alpha effects peripherally)
IMPORTANT NOTE: the distribution of receptors is NOT UNIFORM - vascular beds in different areas express different receptors and so will have different vascular responses
Response of major vascular beds to catecholamines
Renin release is regulated by THREE major elements:
Name them and the location where they are sensed?
Renin release is regulated by THREE major elements:
Amount of sodium that reaches the macula densa (near the glomerulus) - 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
These all increase renin release in response to stress situations - low sodium reaching kidneys, reduced blood pressure, sympathetic activity throughout the body
This response is likely if you have experienced volume loss from the circulation (e.g. due to dehydration or acute haemorrhage)
Angiotensin II receptors can be blocked
ACE inhibitors can partially block the production of angiotensin II although there are other pathways of angiotensin II production which are insensitive to ACE inhibitors
Beta blockers stop renin release in the kidneys
NSAIDs can increase renin release - this is an unwanted effect
What happens when BP goes down?
RAAS
What type of receptors are Angiotensin II Type 1 Receptors (AT1) ?
What are they also coupled with?
Where are they located? (5 places)
Activation of AT1 receptors work to INCREASE BLOOD PRESSURE
Angiotensin II Type 1 Receptors (AT1)
G-protein coupled receptors (Gi and Gq)
Also couples with Phospholipase A2
Located in:
Blood Vessels
Brain
Adrenals
Kidney
Heart
Activation of AT1 receptors work to INCREASE BLOOD PRESSURE
What effect does ANG II have on peripheral resistance and how?
What type of response is it?
Peripheral Resistance - RAPID PRESSOR RESPONSE
Direct vasoconstriction
Enhanced action of peripheral noradrenaline
The is increase noradrenaline release and decreased uptake
Increased sympathetic discharge
If the sympathetic nervous system and RAS work together they go in the same direction to increase blood pressure
Release of catecholamines from the adrenal gland
What effect does ANG II have on renal function? (list 4)
What type of response is this?
Renal Function - SLOW PRESSOR RESPONSE
This happens over weeks or months
Direct effect is to increase sodium reabsorption in proximal tubule
Synthesis and release of aldosterone from the adrenal cortex
Altered renal haemodynamics:
Renal vasoconstriction
Enhanced noradrenaline effects in the kidney
What effects does ANG II have on the CVS?
List 2 haemodynamic effects?
List 3 Non-Haemodynamic groups?
Haemodynamic Effects
Increased preload and afterload
Increased vascular wall tension
Non-Haemodynamic Effects
Increased expression of proto-oncogenes
Increased production of growth factors
Increased synthesis of extracellular matrix proteins
Pharmacological Manipulation of the Renin-Angiotensin System
X marks the points where you can pharmacologically block it
There is a direct renin inhibitor which inhibits the enzymatic effect of the enzyme and hence blocking the formation of angiotensin I
There are ACE inhibitors which block the conversion of angiotensin I to angiotensin II
You can also get angiotensin II receptor blockers
There are other pathways for making angiotensin II - CHYMASES are a family of enzymes which produces angiotensin II from angiotensin I and even from angiotensinogen and we don’t have a way of blocking them at the moment
What is the main product of the kinin system and what is it effect?
What happens if you block ACE?
Left is the angiotensin system and on the right is the kinin system
Main product of the kinin system is an octapeptide called bradykinin
Bradykinin is a vasodilator which does pretty much the opposite of angiotensin II
ACE used to be called kininase II because one of the things it did was to break down bradykinin
If you block ACE then you’ll have less angiotensin II and more bradykinin
Angiotensin II Type 1 Receptor Antagonists
No effects on the bradykinin system
Selectively block these effects of the Angiotensin II:
List 5 effects
Angiotensin II Type 1 Receptor Antagonists
No effects on the bradykinin system
Selectively block these effects of the Angiotensin II:
Pressor effects
Stimulation of noradrenaline system
Secretion of aldosterone
Effects on renal vasculature
Growth-promoting effects of cardiac and vascular tissue
Uricosuric effect
You can get angiooedema - this is similar to anaphylaxis but not as bad - it was thought to be due to the accumulation of bradykinin
Higher levels of potassium switches on the synthesis and release of …………….
Effect of Aldosterone = lose ……………….. through the kidneys but retain sodium and water
What are the 3 main tiggers for aldosterone release>=?
Angiotensin is one of the main elements which increases the synthesis and release of aldosterone (potassium is the other)
Higher levels of potassium switches on the synthesis and release of aldosterone
Effect of Aldosterone = lose potassium through the kidneys but retain sodium and water
This leads to an increase in blood pressure
A large amount of aldosterone isn’t good because it aggravates heart failure
Main triggers for increased aldosterone production:
Increased Potassium
Angiotensin II
Minor effect from ACTH
It used to be thought that aldosterone only works in the kidneys but it has recently been discovered that there are aldosterone receptors in the brain, heart and blood vessels
What is primary hyperaldosterone and what is its phenotype?
What is secondary hyperaldosterone and what is its phenotype?
Pathophysiologic Effects of Aldosterone in Cardiovascular Disease
Primary Hyperaldosteronism - associated with benign tumours of the adrenal cortex - this is associated with hypertension
Secondary Hyperaldosteronism - excessive response of the body in heart failure and liver failure - the phenotype is completely different
Phenotypes of Hyperaldosteronism:
Primary = high blood pressure + NO oedema
Secondary = low/normal blood pressure + LOTS of oedema
The sympatho-adrenal and renin-angiotensin systems are a response to STRESS
A particularly potent stressor is FLUID LOSS
Activation of both systems leads to:
List 3 things
There are also effects to decrease fluid loss:
list 3 things
The sympatho-adrenal and renin-angiotensin systems are a response to STRESS
A particularly potent stressor is FLUID LOSS
Activation of both systems leads to:
Increased Blood Pressure
Increased Heart Rate
Increase Sodium/Water Retention
There are also effects to decrease fluid loss:
Increased Coagulation
Decreased Fibrinolysis
Increased Platelet Activation
All of this is about MAINTAINING EXTRACELLULAR CIRCULATORY VOLUME
The problem is that these effects could lead to heart failure and hypertension
