S3: Regulation of Cerebral Circulation

Question 1

Describe the special requirements of the brain

Answer 1

• Grey matter (mostly neuronal cell bodies) make up 40% of brain tissue and are intolerant to hypoxia. Without adequate levels of O2, neuronal damage will start to occur after several minutes and grey matter will die.
• Therefore the primary requirement of the brain is a constant O2 rich blood supply. Hypoxia in the brain = emergency situation.
• To function properly the brain has a high O2 consumption so it also requires high blood flow.
• The blood flow has the be regulated because brain activity is constantly and blood flow needs to match level of activity for proper local functioning. There has to be a ability to shift blood flow to areas that may need it more during certain tasks e.g. thinking and learning required high blood flow due to high O2 consumption.

Question 2

Describe adaptation of our brain (in terms of circulation)

Answer 2

• There is high O2 consumption relative to the brains size.
• There is also a high proportion of cardiac output to the brain compared to its small size. However, despite this, the brain is using a lot of oxygen so it is a actually underperfused in terms of how much blood it is receiving compared to how much oxygen it is using.
• To counteract this, our brains extract a greater amount of oxygen from the blood than other tissues, a resting O2 extraction of 35%.

Question 3

Why is the brain very affected if there is a blockage in cerebral vessels?

Answer 3

The brain is at high risk as it is already underperfused.

Question 4

Describe special structural features of the cerebral circulation

Answer 4

• The most major structure feature is the Circle of Willis. This is an arterio-arterial anastomosis and the purpose is to supply constant high rate of blood flow to the brain. The collaterals allow blood flow to be maintained even if one part gets stenosed or blocked (blood can be shunted from one area to another and blood flow maintained). The Circle of Willis therefore offers a protective function/adaptation.
• Another structural feature is we have high capillary density. Because of this, there is a very high area over which exchange can take place and thus brain achieves a high O2 delivery/extraction. A high number of capillaries also reduces the distance between the blood vessel and neurone (reducing x in Ficks law). This increases diffusion.
• Finally, is the presence of the blood brain barrier. This is formed of very tight endothelial junctions and allows the brain to be incredible selective over what comes in and goes out (continuous capillaries).

Question 5

What is an anastomosis?

Answer 5

Streams of arteries that branch out and then reconnect with one another.

Question 6

How does blood enter the Circle of Willis?

Answer 6

The internal carotid arteries and the basilar artery.

Question 7

Where is an embolus travelling up internal carotid artery likely to end up?

Answer 7

An embolus passing up the internal carotid artery is likely to enter and block the middle cerebral artery (because 80% of flow from internal carotid goes into middle cerebral artery). The other 20% goes tho the anterior cerebral artery.

Question 8

Describe special functional features of the cerebral circulation

Answer 8

• Brain controls and safeguards its own blood supply.
• Cerebral resistance vessels (arterioles) tend to be spared from baroreceptor reflex induced vasoconstriction. This allows blood flow to continue to the brain because other systemic vessels will be constricted while the cerebral ones are open.
• Auto-regulation (myogenic respose) is well developed in cerebral vessels. This is the intrinsic ability to maintain blood flow under different blood pressures.
• Local metabolic vasodilation is also well developed in cerebral vessels so when metabolite levels are increasing and activity is high, the vessels will vasodilate to accommodate for this.
• Tight BBB controls access and outflow of solutes.

Question 9

How does the brain control and safeguard the CVS system?

Answer 9

There is strong control over the heart and blood vessels which hence control blood pressure and blood flow (by modulating sympathetic mediated vasoconstriction).

• Carotid sinus baroreceptors which monitor cerebral perfusion pressure which defines blood flow. When BP goes down, it activates the baroreceptor reflex which vasoconstricts arterioles and increases CO to increase BP.
• Controlling heart/peripheral vasculature through reflexes (e.g. the heart receptors controlling blood volume, stretch and metaboreceptors in muscle).

Question 10

What are carotid sinus baroreceptors?

Answer 10

The carotid sinus baroreceptors are stretch sensitive mechanoreceptors that are sensitive to changes in blood pressure. Changes in blood pressure will cause them to change firing of their afferent fibres and at low pressures they will be inactive.

• At low BP there is no inhibitory signal from baroreceptors.
• At high BP baroreceptors stimulate inhibitory signals.

Question 11

Describe mechanism of carotid sinus baroreceptors during high blood pressure

Answer 11

• Carotid sinus baroreceptors is activated.
• An increase of blood pressure will cause increased firing in afferent fibres (carotid sinus nerve) to the NTS (in brainstem).
• NTS will send excitatory information to the CVLM which will send inhibitory signals to the RVLM (head of sympathetic system).
• RLVM has neurones that project down and can activate sympathetic neurones at the intermediolateral point. So, by turning down RLVM, there will be less activation of sympathetic nerves.
• This means there will be a decrease in HR, decrease in SV (lower force of contraction) and this reduces CO and then there is also reduced tone of arterioles reducing TPR. Together arterial BP drops.

Question 12

Describe mechanism of carotid sinus baroreceptors during low blood pressure

Answer 12

• Carotid sinus baroreceptor detects low blood pressure (due to decreased stretch).
• Drop in BP leads to less firing of the carotid sinus nerve.
• Less NTS.
• Less excitation of CVLM.
• Less inhibition of RVLM so RVLM activity increases.
• Parasympathetic activity will decreases and sympathetic activity increases.
• Blood pressure increases.

Question 13

Describe autoregulation to maintain local cerebral blood flow

Answer 13

• Without a myogenic response, we would expect that as arterial pressure increases, vessel gets more distended thus flow increases.
• In reality, the blood flow in vessels can stay the same with fluctuating BP.
• This is because when blood pressure initially increases, the vessel wall will distend and the blood vessel wall will respond by constricting.This constriction keeps flow the same, because essentially the pushing force has increased (pressure) but we have reduced the size to flow through in order to keep flow the same.
• When there is a drop in blood pressure the vessel will be less distended (i.e. more closed) which will reduce flow initially, but the vessel responds by increasing vessel diameter to maintain flow.
• However, there is a autoregulation range that when surpassed, BP will affect BF.
• Below range, despite the vessel being very distended (due to autoregulation), pressure is so low that there isn’t enough driving force and not enough perfusion.
• Above range, BP is too increased and vasoconstriction does not reduce it sufficiently so BF increases.
• Sympathetic stimulation helps increase the range of the autoregulation by enhancing it.

Question 14

What is hypotension of the cerebral vessels likely to lead to?

Answer 14

Mental confusion and syncope

Question 15

What is hypertension of the cerebral vessels likely to lead to?

Answer 15

Increases risk of bleeding

Question 16

Describe relationship of pCO2 to cerebral blood flow

Answer 16

• Normal levels of CO2 in our blood corresponds to normal cerebral blood flow.
• If someone starts asphyxiating (hypoventilation), their pCO2 will increased and this increases the acidity in blood vessels. The vessels will then vasodilate to try and blow off the CO2. So hypercapnia is linked to vasodilation and increased blood flow in cerebral vessels.
• If an individual hyperventilates and blows off their CO2, so their pCO2 is low in the blood and it becomes alkaline. So hypocapnia leads to vasoconstriction of cerebral vessels to reduce flow and removal of CO2.
• Thus, we can see that levels of CO2 in the blood heavily affect cerebral blood flow because they determine pH which will cause constriction of dilation and we want to keep the cerebral enviroment constant.

Question 17

What happens to cerebral blood flow when pO2 drops?

Answer 17

If O2 levels drop, cerebral blood flow will increase, as we would expect. This is because we want to try maintain oxygen delivery to brain tissue. This is occurs as hypoxia leads to release of certain metabolites like adenosine which are vasodilators.

Question 18

What is regional hyperaemia?

Answer 18

Localised changes of blood flow can be seen when doing different tasks, e.g. when resting, when doing a test etc. This is because of increased blood for to the areas involved in that task to provide oxygen (using more neurones). Thus regional hyperaemia can also be referred to as functional or metabolic hyperaemia.

Question 19

Describe autoregulation linked to regional hyperaemia

Answer 19

• This is occurs due to the relationship between neuronal firing and blood flow. As neuronal firing frequency increases, we see that the amount of blood flow to that area also increases.
• The reason is due to K+ in the ECF, [K+]ecf increases as neuronal firing frequency increases because to hyperpolarise the cell and fire again the K+ channels will open and K+ will efflux. - During high frequency firing there will be a lot of K+ coming out and building up in the ECF.
• The high K+ in the interstitial fluid causes blood vessels to dilate.
• This is what provides the link between: using area of the brain and increased blood flow to area.

Question 20

Are cerebral arteries innervated?

Answer 20

• Cerebral arteries that are outside the brain (outside brain parenchyma) but within the cranium receive dense innervation from sympathetic nerves.
• However cerebral arterioles within the brain have little innervation and instead are regulated by intrinsic auto-regulation, myogenic response and metabolic auto-regulation. Therefore the baroreflex has little effect on these cerebral arterioles.

Question 21

Describe the nervous control (including NT) of cerebral arteries

Answer 21

• 5 – Hydroxytryptamine (5-HT, serotonin) is a potent vasoconstrictor and is abundant in perivascular (sitting around blood vessels) nerves around the cerebral arteries. 5-HT provides physical antagonism of the vasodilation.
• The perivascular nerves consist of nociceptive fibres, parasympathetic vasodilator fibres and sympathetic vasoconstrictor fibres (little effect).
• The perivascular sensory fibres (nociceptive fibres) mediate the pain of vascular headaches in strokes and the later phase of migraine. They also have motor function and release dilators (substance P, CGRP) and reduce constrictors (5-HT).

Question 22

Describe mechanism of a migraine and solution

Answer 22

• A migraine involves a severe headache caused by vasodilation of extracerebral vessels like the middle meningeal artery, as well as inflammation around the vessel. This dilation is thought to be due to release of substance p and CGRP.
• Sumatriptan (a 5-HTB agonist) is used for migraine and causes constriction of blood vessels, this reduces inflammation induced vasodilation. This helps reduce the pain.

Question 23

Describe structure of blood brain barrier

Answer 23

• BBB is a result of the continuous tight junctions in the cerebral circulation. This makes it difficult for substances to move across into the interstitial areas of the brain and keeps them in the lumen of the vessel.
• There is also very little vesicle transport so it is not a viable way of getting things into the brain.
• Lipophillic substances can move across like CO2, O2 and anaesthetics so these can easily go out.
• Things that aren’t lipophilic but are important for the brain e.g. glucose, amino acids must have carrier-mediated transport mechanisms to get them across. This is done by facilitated diffusion.

Question 24

What are the functions of the BBB?

Answer 24

• The BBB keeps substances out of the brain. This is important because in our blood we have circulating neuro-active chemicals that would interfere with neuronal signalling e.g. catecholamines like adrenaline. We don’t want these getting into the brain interstituim from the blood as it will alter how the brain is working.
• The BBB keeps substances in the brain. Namely neurotransmitters, otherwise if they could easily move out they would be continuously washed out of the brain due to high blood flow.
• However, the BBB is defective and breaks down at special sites, this is to allow access of circulating signalling molecules.

Question 25

Name and explain some areas where the BBB is broken down

Answer 25

• The area postrema of brainstem (chemoreceptive trigger zone). This is so it receives inputs from blood borne drugs (emetic molecules) or hormones and communicates with the vomiting centre. Angiotensin II can also move into the brain at the area postrema and stimulate Ang II receptors to stimulate the sympathetic system. In this way the RAAS system is communicating with the brain.
• Sub-fornicular organ of the hypothalamus. Angiotensin II can diffuse into the brain stem and cause thirst sensation.
• Periventricular osmoreceptors (in the hypothalamus). Here plasma osmolarity can be measured by osmoreceptors as the BBB is leaky, this can lead to ADH secretion if required
• These areas allow the brain to sense what is going on in the circulation.

Question 26

List the 4 special problems in the cerebral circulation

Answer 26

1. Postural hypotension.
2. Cerebral artery vasospasm.
3. Cerebrovascular accidents or strokes.
4. 4. Encasement in a rigid cranium, cerebral tumours or haemorrhage causes Space-Occupying-Lesions (SOL) raising intracranial pressure. This causes Cushing’s reflex (increased BP and a reflex bradycardia).

Question 27

What is postural hypotension?

Answer 27

• When laying down (supine), there is much more linear distribution of venous blood and blood pressure as the effect of gravity is not impacting on the distribution. When supine there is high central blood volume, high cardiac filling pressure and thus a nice large stroke volume (we know this from Starling’s law).
• When a person stands up, gravity is going to pull down on the venous blood and as veins are compliant, blood will pool in the lower limb veins. This is called venous pooling and the veins will distend and pressure will increase as the blood pushes against the walls. This results in much less blood going back to the heart, there is reduced CVP and so reduced filling and lower SV. This leads to a drop in blood pressure.

Question 28

Describe postural hypotension on cerebral vessels and the symptoms a individual may get

Answer 28

Drop in CVP -> Will decrease right stroke volume -> Will decrease left ventricular filling pressure (as less flowing back into heart)-> Decreased left stroke volume -> Decreased arterial pressure (due to decrease CO) -> Decreased cerebral blood flow.
The decreased cerebral blood flow will lead to a decreased O2 supply to the brain, the individual may get dizziness, visual fade and may syncope.

Question 29

What can make postural hypotension worse?

Answer 29

Postural hypotension is made worse if warm (as causes venodilatation), bed rest (linear for long periods of time changes baroreceptors, so when stand up don’t kick in properly initially), zero gravity.

Question 30

Describe how our body changes to combat postural hypotension

Answer 30

1. If you stand up, there will be a decrease in CVP and BP, hence baroreceptor afferents coming from the carotid sinus and aorta will switch off.
2. This means NTS will not be receiving input from these afferents, therefore it will stop firing excitatory signals to the CVLM.
3. The CVLM has inhibitory neurones that usually when excited will release inhibitory NTs that turn down RVLM.
4. BUT, because the CVLM is no longer being stimulated, the inhibitory mechanism is switched off and the RVLM activity will increase.
5. RVLM increased activity will increase stimulation of sympathetic nerves (at intermediolateral point of spinal cord).
6. This will lead to arteriole constriction (increased TPR), increased venoconstriction (increase CVP), increase pacemaker/tachycardia (increased HR, also due to decreased vagal drive) and increased contractility of myocardium (increased SV).
   - All of this will increase BP!

Question 31

What is cerebral artery vasospasm?

Answer 31

• Vasospasm of extracerebral arteries is triggered by subarachnoid haemorrhage (a type of extracerebral haemorrhage), due to the body trying to prevent blood loss.
• It is an arterial spasm leading to vasoconstriction. Vasospasm is quite a serious issue, as it can have the same effect as a blockage and cause ischaemia. Vasospasm will reduce blood flow significantly and this can cause a stroke (cerebral infarct).

Question 32

What local constrictor agents are responsible for vasospasm?

Answer 32

• 5-HT from perivascular nerves.
• Neuropeptide Y from perivascular nerves.
• Endothelin-1 released from the vascular endothelium.
• K+ ions may be released from damaged cells. If they go up extremely high (higher than for regional hyperaemia) , then there will be vasoconstriction as it depolarises VSMCs, this will activate vgCa2+.

Question 33

What can reduce vasospasms?

Answer 33

• vgCa2+ blockers (e.g. amlodipine, acting on VSM)

- ETA receptor blockers e.g. bosentan.

Question 34

Describe Ischaemic/Obstruction stroke

Answer 34

• Caused by a cerebral artery thrombosis or embolism.
• Due to atheroma (often).
• Transient ischaemic attacks may be caused by small arterial emboli being shed from an atheromatous carotid/vertebral artery. TIAs resolve in hours between episodes.

Question 35

Describe Haemorrhagic stroke

Answer 35

• Intracerebral.
• Common cause is rupture of a microaneurysm.
  Neurological damage is due in part to the triggered vasospasm, not just loss of blood.

Question 36

Describe space occupying lesions and cushing’s reflex

Answer 36

• The brain is held within a rigid cranium. If there is a tumour expanding in the brain, the brain will move and expand due to increased intracranial pressure. Potentially it can move downwards through the foramen magnum, the increased pressure can push down and compress the RVLM in the medulla.
• In response to this compression there will be increased activity of the RVLM, so this means there will be increased sympathetic vasoconstrictor activity, which will increase TPR (arterioles) and HR + SV (heart).
• This will increase BP! This is because the brain wants to try get maintain blood flow into the brain despite the increased intracranial pressure.
• Higher BP will activate the baroreflex, this will increase vagal activity (switches on vagus nerve) to the heart causing the HR to decrease. This is reflex bradycardia.
• This forms Cushing’s reflex which where an individual would present with high blood pressure (acute hypertension) but reduced heart rate.