Regulation of blood blow; blood brain barrier

Question 1

Describe the blood flow to the brain

Answer 1

• High at approximately 55ml/100g tissue/min
• 15% of Cardiac output
• 2% of body weight
• 20% oxygen consumption

Question 2

Describe what happens whenever blood flow to the brain is reduced by more than 50%

Answer 2

• 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 3

What is syncope and what causes it?

Answer 3

Syncope (=fainting) is a common manifestation of reduced blood supply to the brain.

Caused by:

• low blood pressure
• postural changes
• vaso-vagal attack
• sudden pain
• emotional shock

All result in a temporary interruption or reduction of blood flow to the brain

Question 4

Describe the glucose supply to the brain. What happens when there is reduced glucose delivery to the brain.

Answer 4

• Normally a VAST SURPLUS of glucose to the brain via the blood
• A supply of glucose is really important because the brain can’t synthesise or utilise any other source of energy
• Ketones can be metabolised during starvation
• Hypoglycaemia can lead to a loss of brain function
• If the blood glucose concentration falls below 2 mM it can result in unconsciousness, coma and DEATH

Question 5

Why must cerebral blood flow be maintained?

How is that achieved?

Answer 5

Because of the constant need by the brain for oxygen and glucose.

Achieved by having an efficient regulatory system.

Question 6

What is cerebral blood flow regulated by?

How is TOTAL cerebral blood flow regulated? (draw graph)

Answer 6

• mechanisms affecting tol cerebral blood flow
• mechanisms which relate activity to the requirement in specific brain regions by altered localised blood

Total cerebral blood flow is autoregulated, between MAP of aprox 60 and 160 mmHg.

Question 7

How is autoregulation of total cerebral blood flow achieved?

Answer 7

MYOGENIC (response to stretch)

Arteries and arterioles dilate or contract to maintain blood flow. Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP.

• Below this autoregulatory pressure range, insufficient suply leads to compromised brain function.
• Above this autoregulatory pressure range, increased flow can lead to swelling of brain tissue, intracranial pressure increases.

Note: the local delivery of oxygen to brain tissue is related to the needs of that tissue by local autoregulation

Question 8

How does local regulation of cerebral blood flow achieved?

Answer 8

1. neural control
2. chemical control

Question 9

Describe the 4 neural factors involved in local regulation of cerebral blood flow.

Answer 9

1. Sympathetic Nerve Stimulation: to the main cerebral arteries producing vasoconstriction when the arterial blood pressure is HIGH
2. Parasympathetic (facial nerve) Stimulation: producing slight vasodilation to increase blood supply
3. Central Cortical Neurones: release neurotransmitters such as catecholamines that cause vasoconstriction
4. Dopaminergic Neurones: produce vasoconstriction (localised effect related to increased brain activity)

NOTE: neural control on global brain blood flow is not well defined, and its important is uncertain

Question 10

Describe the pattern of vascularisation in the CNS tissues

Answer 10

Arteries enter the CNS tissue from as branched of the surface pial vessesls (from meninges). These branches penetrate into the brain parenchyma branching to form capillaries which drain into venules and veins drain into surface pial veins.

Question 11

Describe the function of dopaminergic neurones.

Answer 11

• Innervate penetrating arterioles and pericytesaround capillaries Pericytesare cells that wrap around capillaries; have diverse activities (e.g. immune function, transport properties, contractile)
• may participate in the diversion of cerebral blood to areas of high activity
• Dopamine may cause contraction of pericytesvia aminergicand serotoninergic receptors

Question 12

Describe the chemical factos (generally localised) involved in the regulation of cerebral blood flow.

Answer 12

• CO2 (indirect)
• pH (i.e. H+,; lactic acid, etc.)
• nitric oxide
• K+ (released during action potentials)
• adenosine
• anoxia
• other (e.g. kinins, prostaglandins, histamine endothelins)

-> ALL ARE VASODILATORS THUS INCREASE BLOOF FLOW

Question 13

Describe the effect of pCO2 on Cerebral Blood Flow

Answer 13

increasing pCO2 even slightly, causes a large increase in blood flow

Question 14

How does CO2 cause cerebral arterial vasodilation?

Answer 14

CO2 from the blood or from local metabolic activity generates H+using carbonic anhydrase in surrounding neural tissue and in the smooth muscle cells.

Elevated H+ means decreased pH. This causes relaxation of the contractile smooth muscle cells, dilation of vessels, resulting in increased blood flow.

(high Co2, high H+, low pH, high blood flow)

Question 15

Describe the structure of fluid compartments in the brain

Answer 15

The brain is “floating” in cerebrospinal fluid produced by regions of choroid plexus in the cerebral ventricles.

This is an important protective mechanism.

Question 16

How is CSF formed?

Describe its functions.

Answer 16

• The ventricles, aqueducts and canals of the brain are lined with ependymal cells (epithelial-like glial cells, often ciliated).
• In some regions of the ventricles, this lining is modified to form branched villus structures: the choroid plexus.

CSF formed by choroid plexus:

• Capillaries leaky, but local ependymal cells have extensive tight junctions.
• Secrete CSF into ventricles (lateral ventricles, 3rd ventricle via interventricular foramina, down cerebral aqueduct into 4thventricle and into subarachnoid space via medial and lateral apertures) – circulates.
• Volume: 80-150ml.
• Functions: protection (physical and chemical), nutrition of neurones, transport of molecules.

Question 17

Give the differences between plasma and CSF composition.

Answer 17

Csf has little protein -> high protein would indicate infection or damage

Question 18

Describe the Blood Brain Barrier (bbb)

Answer 18

• BBB was at the level of the CNS capillaries.
• Because of the “tightness” of the BBB capillaries, hydrophilic solutes (egglucose, amino acids, many antibiotics, some toxins) that can exchange across peripheral capillaries cannot cross the BBB.
• This allows the BBB to control the exchange of these substances using specific membrane transporters to transport into and out of the CNS. (influx and efflux transporters)
• Blood-borne infectious agents may have reduced entry into CNS tissue. (CNS infections more commonly affect the meninges, whose vessels are not BBB).
• Many hydrophilic substances to enter the CSF and brain ECF by means of specific transport mechanisms, examples being:

a) water, via aquaporin (AQP1, AQP4) channels
b) glucose, via GLUT1 transporter proteins
c) amino acids, via 3 different transporters
d) electrolytes, via specific transporter systems

Question 19

What are the functions of the BBB?

Answer 19

• Protects the brain tissue from certain toxins and circulating transmitters like catecholamines
• It also protects the brain from wide variations in ion concentrations

Question 20

Describe the structure of the BBB

Answer 20

• 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
• These tight junctions mean that a lot of molecules can’t pass readily through the BBB
• In addition, these capillaries are surrounded by pericytes that have end-feet that run along the capillary wall
• 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 21

Describe the differences between BBB and plasma capillaries.

Answer 21

• BBB capillaries have extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across the capillary wall.
• Peripheral vessels have sparse pericyte coverage, while BBB capillaries have dense pericyte coverage. (Pericytes are cells closely apposed to capillaries. They have important functions in maintaining capillary integrity and function)
• BBB capillaries are covered with “end-feet” from astrocytes. These associations are important for maintaining BBB properties.

Question 22

What are CVO’s? Give examples.

Answer 22

CVOs = Circumventricular organs

Certain areas, found close to ventricles, that their capillaries lack BBB properties.

Capilaries are instead fenestrated and hence leaky. The ventricular ependymal lining close to these areas can be much tighter than in other areas, limiting the exchange between them and the CSF.

Examples:

• the posterior pituitary and median eminence secrete hormones
• the area postrema samples the plasma for toxins and will induce vomiting
• others are involved in sensing electrolytes and regulate water intake.

CVOs need leaky, fenestrated vessels to carry out these functions.

Question 24

Clinical importance of BBB: how does it affect the treatment for Parkinson’s disease

Answer 24

• Dopamine cannot cross the BBB.
• L-Dopa can cross the BBB via an amino acid transporter and is converted to dopamine in the brain.
• Most of the L-Dopa is converted to dopamine outside the CNS, so less is available to access the brain.
• To inhibit this conversion outside the brain, co-administration with the DOPA decarboxylase inhibitor, Carbidopa, does the job. Carbidopa cannot cross the BBB, so does not affect the conversion of L-DOPA in the brain.