5. Regulation of blood flow

Question 1

What happens when blood flow to the brain is reduced by more than 50%? What happens if blood flow is stopped?

Answer 1

Insufficient oxygen delivery
Function becomes impaired
If the total cerebral blood flow is interrupted for as little as 4 seconds, you will become unconscious
After a few minutes, irreversible damage will occur to the brain

Question 2

What is syncope and what causes it?

Answer 2

• Syncope (= fainting) is a common manifestation of reduced blood supply to the brain.
• Has many causes including low blood pressure, postural changes which would cause fluctuations in BP and blood flow, vaso-vagal attack (such as shock or a phobia), sudden pain, emotional shock etc.
All result in a temporary interruption or reduction of blood flow to the brain

Question 3

Why is a glucose supply essential to the brain?

Answer 3

• A supply of glucose is really important because the brain can’t synthesise or utilise any other source of energy. The brain also can’t store glucose so a constant supply is needed
  
  • Ketones can be metabolised if there is a shortage of glucose but glucose is the main nutrient

Question 4

What would happen if the brain was hypoglycaemic? Where hypoglycaemia often seen?

Answer 4

• Hypoglycaemia can lead to a loss of brain function and individuals appear disoriented, have slurred speech and an impaired motor function
  
  • This is often seen in people that have insulin dependent diabetes upon administration of too much insulin
  • If the blood glucose concentration falls below 2 mM it can result in unconsciousness, coma and DEATH

Question 5

What are the two types of mechanisms that control cerebral blood flow?

Answer 5

Mechanisms affecting total cerebral blood flow

Mechanisms that relate activity to requirement in specific brain regions by altered localised blood flow - you need a system that can divert blood to the parts of the brain that really need it at the time

Question 6

How does autoregulation allow cerebral blood flow to remain constant?

Answer 6

MYOGENIC response to stretch:
The smooth muscle lining the arteries can stretch in response to blood flow
An increase in pressure on the vessel wall will result in a myogenic response that leads to contraction of the smooth muscle - this decreases cerebral blood flow
This myogenic response occurs when there is a change in blood pressure in the body
So stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP.

Question 7

What is the autoregulatory pressure range?

Answer 7

Autoregulation occurs within a relatively wide breadth of the arterial blood pressure from 60 - 160 mm Hg.

Question 8

What happens if blood pressure is above or below the regulatory pressure range?

Answer 8

Below the autoregulatory pressure range, insufficient supply leads to compromised brain function
Above this autoregulatory pressure range, increased flow can lead to increased pressure in the blood vessels, pushing fluid out of vessels and causing swelling of brain tissue. This is not accommodated by the “closed” cranium, therefore intracranial pressure increases – dangerous.

Question 9

Why is local autoregulation required?

Answer 9

The local delivery of oxygen to brain tissue is related to the needs of that tissue by local autoregulation. The local brain activity determines the local O2 and glucose demands, therefore local changes in the blood supply required

Question 10

By what mechanisms can local autoregulation occur?

Answer 10

Neural control or chemical control

Question 11

Outline the structure of the vascularisation that supplies blood to the brain

Answer 11

• Blood supply to brain tissue comes from the surface
  
  • Arteries enter the CNS tissue as branches of the surface pial vessels. These branches penetrate into the brain parenchyma, branching to form capillaries which drain into venules and veins which drain into surface pial veins.
  • So the vessels come in from the surface into the brain where they will supply it then drain back up to the surface again

Question 12

What are the different ways that neural control of blood flow to the brain is achieved?

Answer 12

• Sympathetic Nerve Stimulation
○ Sympathetic innervation of the main cerebral arteries can cause vasoconstriction - this only happens when the arterial blood pressure is HIGH
• Parasympathetic (facial nerve) Stimulation
○ We don’t normally associate the parasympathetic nervous system with vasculature
○ However, facial nerve fibres are innervated by parasympathetic fibres - this causes a slight vasodilation
• Central Cortical Neurones
○ The neurones within the brain itself can release neurotransmitters such as catecholamines that cause vasoconstriction
• Dopaminergic Neurones
○ Produce vasoconstriction
○ They are important in regulating differential blood flow to areas of the brain that are more active

Question 13

How do dopaminergic neurones have a local effect?

Answer 13

• NOTE: Capillaries in the brain have PERICYTES around them, which are contractile
○ Pericytes are a type of brain macrophage
○ They have a variety of functions e.g. immune function, transport properties, contractile
• Dopaminergic neurones innervate the smooth muscle surrounding arterioles and the pericytes around the capillaries
• When the dopaminergic neurones are active, they can cause the contraction of pericytes to decrease the blood flow to a particular area thus diverting blood to other, more active areas of the brain
• Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors

Question 14

Outline 6 different chemicals/chemical changes that can act as vasodilators

Answer 14

CO2, ph, nitric oxide, K+, adenosine, anoxia (no O2 being delivered), and others (kinins, prostaglandins, histamine etc)

Question 15

How does a change in pH occur and cause vasodilation?

Answer 15

When cells are active they will produce lactic acid - the H+ ions in the lactic acid will cause a drop in pH and cause vasodilation in that area

Question 16

How does CO2 cause vasodilation? Why is this physiologically useful?

Answer 16

• H+ ions DO NOT cross the BBB
  
  • However, CO2 is generated within the brain (on the other side of the BBB) from higher metabolic activity elsewhere in the brain. This reacts with water and forms carbonate and H+ ions, of which the H+ can enter the smooth muscle. So they are not crossing the blood brain barrier but entering from the other side
  • CO2 from the blood (due to high metabolic activity that the local blood may have had) can diffuse across the BBB as it is hydrophobic
  • When it gets into the smooth muscle it again combines with water in the presence of carbonic anhydrase to form carbonate and H+ ions
  • These H+ act as a vasodilator of the vessels . So elevated H+ = lower pH = relaxation of the smooth muscle = vessel dilation = greater flow
  • So when there is a lot of activity in the brain a lot of CO2 is produced indirectly leads to a high pH in the area, causing local vessels to dilate, creating an increased flow rate

Question 17

How does nitric acid cause vasodilation?

Answer 17

• NO stimulates guanylyl cyclase which converts GTP to cGMP which then causes vasodilation

Question 18

How can blood flow be used to assess neuronal activity?

Answer 18

An increased blood flow locally is due to a higher metabolic activity which is a consequence of a higher neuronal activity
PET scans and functional MRIs can be done to see where neuronal activity is the most prominent

Question 19

What are the different types of fluid found in the brain and where exactly are they found ?

Answer 19

Intracellular fluid is the fluid within cells, tissue fluid is found between the cells of the brain and CSF is found around the outside of the brain and also in the ventricles

Question 20

Outline the structure of the ventricular system of the brain

Answer 20

The brain has a pair of lateral ventricles, a single midline third ventricle and an inferior fourth ventricle. They are lined by aqueducts. These are all lined with ependymal cells (a type of glial cell and they are often ciliated)

Question 21

What is the choroid plexus?

Answer 21

• In some regions of the brain ependymal cells are modified to form branched villus structures: the choroid plexus.
• The plexus is surrounded by ciliated ependymal cells
• It is here that the CSF is formed

Question 22

What is the role of ependymal cells in the choroid plexus?

Answer 22

• Capillaries are leaky but surrounded by ependymal cells which have tight junctions so the layer is impermeable. This allows control of the production of CSF
• Ependymal cells secrete molecules into the ventricles to make the CSF - this is why the CSF is different to blood

Question 23

Outline the path of CSF flow

Answer 23

○ Lateral Ventricles
○ 3rd Ventricle (via interventricular foramina)
○ Cerebral Aqueduct
○ 4th Ventricle
○ Subarachnoid Space (via medial and lateral apertures)

Question 24

How much CSF do we have in circulation? How much is formed each day?

Answer 24

Volume of CSF = 80 - 150 mL

Volume of CSF formed per day = 450 mL/day

Question 25

What is the function of CSF?

Answer 25

Protection (chemical and physical)
Nutrition of neurones
Transport of molecules

Question 26

What is the difference between plasma and CSF? Why is this clinically important?

Answer 26

CSF has very little protein in it but plasma has a lot. This is important clinically as when you take some CSF from the body due to a suspected bleed/ injury/ infection then any findings of protein would be abnormal

Question 27

What is the function of the blood brain barrier?

Answer 27

• The BBB is needed because the activity of neurones is highly sensitive to the composition of local environment, and the CNS must be protected from the fluctuations in the composition of the blood. Homeostasis is key for the brain.
  
  • Protects the brain tissue from certain toxins and circulating transmitters like catecholamines
  • It also protects the brain from wide variations in ion concentrations

Question 28

Explain how capillary structure changes as they enter the brain and how the blood brain barrier is formed

Answer 28

• The endothelial cells that line the capillaries in the brain, unlike in the rest of the body, have VERY TIGHT JUNCTIONS - the capillaries are non-fenestrated
  
  • In the BBB, the capillaries come from pial vessels and penetrate into the brain. As they penetrate, they change in phenotype so that they form much tighter barriers and as they go deeper into the brain they go from having fenestrations and being permeable to becoming completely impermeable. This is due to the tight junctions
  • These tight junctions mean that molecules can’t pass readily through the BBB
  • In addition, these capillaries are surrounded by pericytes (which are sparse in normal capillaries) that have end-feet that run along the capillary wall. The feet are projections coming from astrocytes but cover the pericytes
  • When the pericytes contract, they make it more likely for molecules to escape the capillary
  • So it is mainly the tight junctions between endothelial cells that form the BBB but the pericytes are also involved

Question 29

Give examples of solutes that can’t cross the BBB

Answer 29

Hydrophilic solutes such as glucose, amino acids, many antibiotics, some toxins

Question 30

Which molecules can cross the BBB and how?

Answer 30

• The BBB controlS the exchange of these substances using specific membrane transporters to transport into and out of the CNS. (influx and efflux transporters)
• Some molecules - lipophilic molecules - cross the BBB relatively easily (e.g. alcohol and anaesthetics)
• Only certain hydrophilic substances are allowed through the BBB by means of specific transport mechanisms including:
○ Water via aquaporin channels
○ Glucose via GLUT1 proteins
○ Amino acids via 3 different transporters
○ Electrolytes via specific transporter systems

Question 31

What are circumventricular organs?

Answer 31

Circumventricular organs have fenestrated capillaries and therefore they lie outside the BBB

Question 32

How does exchange occur in circumventricular organs between blood and the CSF? How does their structure support this?

Answer 32

In CVOs, molecules can readily pass from the blood to the CSF which is important for their function. However, the ventricular ependymal lining close to these areas can be much tighter than in other areas, limiting the exchange between them and the CSF. This allows the exchange between the CSF and the CVOs to be controlled by the endothelial cells instead of the BBB

Question 33

Where are CVOs found and give examples of some CVOs

Answer 33

• Circumventricular organs are found close to the ventricles and include:
○ Median eminence region of the hypothalamus
○ Subfornical organ (SFO)
○ Organum vasculosum of the lamina terminalis (OVLT)
• These regions of the brain are generally involved in secreting into the circulation, or need to sample the plasma

Question 34

What is the clinical importance of the BBB?

Answer 34

• The BBB breaks down in many pathological states: inflammation, infection, trauma, stroke, which obviously can have profound effects on CNS function.
• A major issue is in relation to pharmacology:
  
  • Do you want a particular drug to get into the brain, or not?
• Many therapeutic drugs cannot access the brain.
• Others may access the brain too readily causing adverse effects.

Question 35

How have histamines changed over the years and why? How do current histamines differ?

Answer 35

• In the treatment of allergy, the “old-fashioned” H1 blockers are hydrophobic and could cross the BBB by diffusion. Since histamine is important in wakefulness and alertness, these antihistamines made people drowsy. Used as sedatives (often over-the-counter).
• Second-generation antihistamines are polar (i.e. have hydrophilic attachment), therefore do not readily cross the BBB, so do not cause drowsiness.

Question 36

Outline a therapy used in Parkinson’s disease

Answer 36

A key therapy in Parkinson’s disease is pharmacologically raising the levels of dopamine in the brain.

Question 37

How does dopamine therapy in Parkinson’s disease work? What other drug must be administered?

Answer 37

• Peripheral administration of dopamine not the answer, as dopamine cannot cross the BBB.
• L-DOPA (a precursor to dopamine) can cross the BBB via an amino acid transporter, and is converted to dopamine in the brain.
• However, most of the L-DOPA gets converted into dopamine outside the brain by DOPA decarboxylase before it can even get into the brain so there is a lot less dopamine available to the brain
• This conversion therefore must be inhibited
• Co-administration with the DOPA decarboxylase inhibitor, Carbidopa, does the job. Carbidopa cannot cross the BBB, so does not affect conversion of L-DOPA in the brain.

Question 38

End

Answer 38

End