Cerebral Blood Flow Regulation and The Blood Brain Barrier

Question 1

Quantify the avg. blood flow to the brain, and its oxygen consumption

Answer 1

Blood: 55 ml/100g tissue/min

Oxygen: 3 ml/100g tissue/min

Question 2

Define and give causes of syncope, and state when irreversible brain damage may occur

Answer 2

If total CBF is interrupted for as little as 4 seconds, unconsciousness will result => fainting (=syncope)
- low blood pressure, postural changes, vaso-vagal attack, sudden pain, emotional shock etc.

After a few minutes irreversible damage occurs

Question 3

Blood glucose below what value will lead to loss of consciousness, coma and death?

Answer 3

2mM

Normal fasting levels 4-6 mM

Question 4

Cerebral blood flow is regulated by two kinds of mechanisms. What are they?

Answer 4

1. Mechanisms affecting total cerebral blood flow

2. Mechanisms which relate activity to the requirement in specific brain regions by altered localised blood flow

Question 5

Between what range in mean arterial blood pressure can autoregulation maintain a constant cerebral blood flow?

Answer 5

60-160 mmHg

Question 6

Describe myogenic mechanism of cerebral blood flow auto-regulation

Answer 6

Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP - compensates for altered local blood flow

Question 7

State what occurs above and below the autoregulatory pressure range

Answer 7

Below: compromised brain function

Above: increased flow => swelling of brain tissue => intracranial pressure increases

Question 8

In mechanism 2, what are the two subtypes of control?

Answer 8

Neural and chemical

Question 9

Describe the pattern of vascularisation in the CNS tissues

Answer 9

Arteries branch off surface Pial vessels and penetrate brain parenchyma. They form capillaries which drain into venules and veins which drain into surface Pial vein - no neurone is more than 100µm from a capillary

Question 10

What are the four types of neural control of cerebral blood flow?

Answer 10

1. SNS activity to main cerebral arteries => vasoconstriction
2. PNS activity (facial nerve) => slight vasodilation
3. Central cortical neurone => vasoconstrictor neurotransmitter release (NA, A)
4. Dopaminergic neurones => localised vasoconstriction high activity areas

Question 11

What are pericyte cells? Give other examples of their activities.

Answer 11

Contractile cells that wrap around capillaries in the brain.

Other activities e.g. immune function, transport properties

Question 12

How do dopaminergic neurones bring about vasoconstriction?

Answer 12

They innervate arteriole smooth muscle and pericytes; Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors

Question 13

Name some chemical factors that increase localised blood flow

Answer 13

(VASODILATORS)

Carbon dioxide 
NO 
pH 
Anoxia 
Adenosine 
K+ 
Other (e.g. kinins, prostaglandins, histamine, endothelins)

Question 14

Describe how carbon dioxide indirectly causes cerebral artery vasodilation and hence increased blood flow

Answer 14

• CO2 from the blood/local metabolic activity generates H+ which can’t cross the BBB (CO2 + H2O <=> HCO3- + H+) catalysed by carbonic anhydrase in surrounding neural tissue and contractile smooth muscle cells.
• Increased H+ = decreased pH = relaxation of contractile cells (mediated by NO)

Question 15

What is the clinical significance of the brains ability for local changes to cerebral blood flow?

Answer 15

Allows imaging and mapping of brain activity using PET scan and fMRI

Question 16

Where is CSF produced?

Answer 16

Choroid plexus – these are specific cells lining the ventricles (in particular the lateral ventricles)
* Capillaries are leaky, but local ependymal cells have extensive tight junctions

Question 17

What is the volume of CSF in a normal person?

Answer 17

80-150 mL

Question 18

What is the volume of CSF formed per day?

Answer 18

450 mL/day

Question 19

State three functions of the CSF

Answer 19

• Protection (chemical and physical)
• Nutrient provision to neurons
• Transport of molecules

Question 20

Describe the passage of CSF through the ventricular system

Answer 20

• CSF from the lateral ventricles goes through the foramen of Monro to the 3rd ventricle and flows down the cerebral aqueduct to the 4th ventricle
• From the 4th ventricle it enters the subarachnoid space (via medial and lateral apertures) and eventually drains back into the venous system via arachnoid granulation
• Also flows down into the central canal

Question 21

Describe the structure of the blood-brain barrier. Which cells are involved?

Answer 21

• BBB capillaries have extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across the capillary wall
• Pericytes have important functions in maintaining capillary integrity and function; BBB capillaries have dense pericyte coverage compared to peripheral vessels
• BBB capillaries are covered with “end-feet” from astrocytes - important for maintaining BBB properties

Question 22

What type of molecule can cross the blood-brain barrier easily?

Answer 22

Lipophilic molecules

Question 23

How do solutes such as water, glucose, amino acids, and many antibiotics cross the blood-brain barrier?

Answer 23

Using influx and efflux transporters

e.g. aquaporin for water, and GLUT 1 transporters for glucose

Question 24

What are Circumventricular organs?

Answer 24

Areas of the brain in which their capillaries lack BBB properties (i.e. leaky, fenestrated); these areas are found close to the ventricles

Question 25

Name two circumventricular organs giving reasons why

Answer 25

1. Posterior pituitary and median eminence secrete hormones into the circulation
2. Area postrema samples the plasma for toxins and will induce vomiting

Note: others are involved in sensing electrolytes and regulate water intake

Question 26

State four components that have a lower concentration in the CSF than the plasma.

Answer 26

K+
Calcium
Amino acids
Bicarbonate

Question 27

State two components that have a higher concentration in the CSF than the plasma.

Answer 27

Magnesium

Chloride

Question 28

How is the osmolarity different between the CSF and the plasma?

Answer 28

The same

Question 29

How is the pH different in the CSF compared to the plasma?

Answer 29

CSF is slightly more acidic

Question 30

In the treatment of allergy, why do ‘old-fashioned’ antihistamines cause drowsiness, and how are second generation antihistamines different?

Answer 30

“Old-fashioned” H1 blockers are hydrophobic and can cross the BBB by diffusion; Since histamine is important in wakefulness and alertness, these antihistamines made people drowsy (sleep aid e.g. Nytol)

2nd gen. antihistamines are polar (i.e. have hydrophilic attachment) therefore do not readily cross the BBB

Question 31

A key therapy in Parkinson’s disease is pharmacologically raising the levels of which substance in the brain?

Answer 31

Dopamine

Question 32

How can DOPA be increased in the brain pharmacologically?

Answer 32

• Dopamine CANNOT cross the BBB so peripheral administration of dopamine won’t work
• L-DOPA however CAN cross the BBB via an amino acid transporter, and is converted to dopamine in the brain
• Co-administration of L-DOPA with the DOPA decarboxylase inhibitor (e.g. Carbidopa) is required since most of the circulating L-DOPA is converted to dopamine peripherally
• Carbidopa cannot cross BBB, so does not affect the conversion in the brain.