Cerebral Blood Flow Regulation and the Blood Brain Barrier Flashcards
04.10.2019
How much of the CO goes to the brain?
15%
How much of the body weight does the brain make up?
2%
What percentage of the oxygen does the brain consume?
20%
What happens whenever blood flow is reduced by more than 50%?
- insufficient oxygen delivery
- function becomes significantly impaired
What happens when cerebral blood flow is interrupted?
- for as little as 4 seconds, unconsciousness will result
- After a few minutes irreversible damage occurs to brain
Syncope
- common manifestation of reduced blood supply to the brain.
- Causes: low BP, postural changes, vaso-vagal attack, sudden pain, emotional shock etc.
- > All result in a temporary interruption or reduction of blood flow to the brain
How much of the body’s glucose does the brain utilise?
estimated 50-60%
What does the brain utilise an=s an energy source?
Supply of glucose vital because the brain cannot store, synthesize or utilise any other source of energy (although, in starvation, ketones can be metabolised to a limited extent – adaptation possible in chronic undernutrition?)
Hypoglycemia signs
An individual appears disoriented, slurred speech, impaired motor function.
If the glucose concentration falls below 2mM it can result in unconsciousness, coma and ultimately death. (Normal fasting levels 4-6 mM)
In what 2 ways is cerebral blood flow controlled?
- mechanisms affecting total cerebral blood flow
- mechanisms which relate activity to the requirement in specific brain regions by altered localised blood flow
How is total cerebral blood flow regulated?
Autoregulation -> between MABP of 60 -160 mmHg
- the 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 range: insufficient blood supply
above range: can lead to swelling of the brain tissue -> (dangerous) increase in intracranial pressure)
Why is local cerebral blood flow auto regulated?
The local brain activity determines the local O2 and glucose demands
In what 2 ways is local blood flow regulated?
- neural control
- chemical control
Pattern of vascularisation of the CNS tissues
- arteries enter as branches of the surface pial vessles
- these penetrate into the brain parenchyma branching to form capillaries
- the capillaries drain into venules and veins which drain into surface pial veins
Is the CNS densely vascularised?
Yes it is. No neurone more than 100µm from a capillary.
Neural factors controlling CBF
a) sympathetic nerve stimulation
b) parasympathetic (facial nerve) stimulation
c) central cortical neurones
d) dopaminergic neurones
The neural control on global brain blood flow is not well defined, and its importance is uncertain.
Sympathetic nerve stimulation as a neural factor controlling CBF
sympathetic nerve stimulation to main cerebral arteries, producing vasoconstriction; probably only operates when arterial blood pressure is high
Parasympathetic nerve stimulation as a neural factor controlling CBF
facial nerve producing slight vasodilation
central cortical neurones as a neural factor controlling CBF
releasing a variety of vasoconstrictor neurotransmitters, such as catecholamines (e.g. A, NA)
dopaminergic neurones as a neural factor controlling CBF
producing vasoconstriction (localized effect related to increased brain activity) to redirect BF to areas of higher brain activity.
- Innervate penetrating arterioles and pericytes around capillaries
- may participate in the diversion of cerebral blood to areas of high activity
- Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors
Pericytes
cells that wrap around capillaries; have diverse activities (e.g. immune function, transport properties, contractile)
- They have important functions in maintaining capillary integrity and function.
Chemical factors that regulate CBF
a) CO2 (indirect) vasodilator
b) pH (i.e. H+, lactic acid, etc.) vasodilator
c) nitric oxide vasodilator
d) K+ vasodilator
e) adenosine vasodilator
f) anoxia vasodilator
g) other (e.g. kinins, prostaglandins, histamine endothelins)
how does pCO2 affect CBF?
an increase in CO2 leads to an increase in CBF (S shaped curve)
How does CO2 increase BF?
- CO2 generates H+ through carbonic anhydrase
- this occurs in surrounding neural tissue and the smooth muscle cells
- more H+ -> decreased pH -> relaxation of SMC -> dilatation of BV -> increased BF
How can local changes in CBF be used in brain imaging?
- in the CNS, increased BF means increased neuronal activity
- allows imaging and mapping of brain activity using techniques such as PET scanning and functional MRI (fMRI).
What do ependymal cells line?
The ventricles, aqueducts and canals of the brain
In some regions of the ventricles, this lining is modified to form branched villus structures: the choroid plexus.
Formation of CSF
- formed by choroid plexus
- 500 ml per day (300 of that produced in the choroid plexus)
- circulated from there through ventricles and into subarachnoid space
- Function: Protection (physical an chemical), nutrition of neurones, molecule transport
- total volume ~ 150 mL
- has very little protein
Why is there a need for the Blood Brain Barrier?
- The activity of neurones is highly sensitive to the composition of local environment
- The CNS must be protected from the fluctuations in the composition of the blood
- Homeostasis is key for the brain.
At what level is the BBB?
The BBB is at the level of CNS capillaries.
What fraction of vasculature do capillaries form?
~ 80%
How are capillaries in the BBB special?
- have extensive tight junctions at the endothelial cell-cell contacts massively reducing solute and fluid leak across the capillary wall.
- continuous type, little transcellular vesicular transport
-
How does pericyte coverage differ in peripheral and BBB vessles?
- Peripheral vessels have sparse pericyte coverage, while BBB capillaries have dense pericyte coverage.
- in addition BBB vessels are covered with the end feet of astrocytes
Which substances can pass peripheral capillaries but not BBB?
Hydrophilic solutes such as:
- glucose
- amino acids
- many antibiotics
- some toxins
- many others
-> BBB can control the exchange of these substances using specific membrane transporters (influx and efflux transporters)
Can blood borne pathogens enter the CNS?
- may have reduced entry into CNS tissue
- CNS infections more commonly affect the meninges, whose vessels are not BBB
-(Some evidence that loss of BBB can help with clearing some infections by allowing immune cells access.)
What substances can easily cross the BBB?
Lipophilic molecules
- O2
- CO2
- alcohol
- anaesthetics?
-> Direct diffusion across concentration gradient
How do some hydrophilic substances enter the brain?
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
What areas of the brain require more leaky vessles?
In some areas of the brain it is necessary to lack the BBB properties (this is near the ventricles in the CVOs).
- these capillaries are fenestrated
- the ventricular ependymal lining close to these areas can be much tighter than in other areas -> limits exchange between them and the CSF.
What are CVOs generally involved in?
- secreting into the circulation
OR - need to sample the plasma
- posterior pituitary and median eminence secrete hormones
- area postrema samples the plasma for toxins and will induce vomiting
- others are involved in sensing electrolytes and regulate water intake.
-> need leaky and fenestrated vessels to carry out these functions
In what circumstances does the BBB and what are the consequences?
inflammation, infection, trauma, stroke
-> obviously can have profound effects on CNS function
What is the disadvantage of H1 blockers?
- H1 blockers are hydrophobic and can cross the BBB
- histamine is important in alertness and wakefullness
- these antihistamines will make people feel drowsy
- used in sleep aids today e.g. otc Nytol
What is the advantage of second generation antihistamines?
- are polar (i.e. have hydrophilic attachment)
- do not readily cross the BBB -> don’t cause drowsiness
PD: how is dopamine administered?
- dopamine cannot cross the BBB (-> no peripheral admin)
- L-DOPA can cross BBB via AA transporter and is converted to Dopamine in the brain
- BUT: most of circulating L-DOPA is converted to dopamine peripherally -> less accesses the brain
-> Co-admin of L-DOPA with the DOPA decarboxylase inhibitor “carbidopa”. Carbidopa does not cross the BBB.
What are normal fasting blood glucose levels?
4-6 mM
In what range is total cerebral BF regulated? how?
- auto regulated between the mean arterial BP (MABP) which is 60 - 160 mmHg
- arteries and arterioles dilate or contract to maintain BF
- stretch sensitive cerebral vascular SM contracts at high BP and relaxes at lower BP
Why is there such good auto regulation of CBF? What happens if the pressures are too low or too high?
- low: insufficient BF leads to compromised brain function
- high: can lead to swelling of Brian tissue (which is not accommodated. by the closed cranium) therefore ICO increases which is dangerous!!
Chemical control of CBF - are there more vasodilators or vasoconstrictors?
vasodilators (e.g. CO2 (indirect), pH, NO, K+, adenosine, anoxia, kinins, prostaglandins, histamine, endothelins)
What are the foramina of Luschka and Magendie?
Foramen of Luschka: lateral aperture.
Foramen of Magendie: Median aperture;
CSF travels from 4th ventricle to subarachnoid space via the two -> circulates
How did scientists discover that there is a BBB?
they realised that dyes accumulate inn. different organs but not in the CNS (brain, also no accumulation in retina)
-> experiments in mice.
At what level is the BBB?
at the level of CNS capillaries
Are the vessles of the meninges BBB?
no
Name some regions of the brain where there is lack of BBB
- organum vasculosum lamina terminalis
- Neurohypophysis
- area postrema
- pineal body
- subcomissural organ
- subfornical organ
- median eminence
=> generally involved in secreting into the circulation or sampling the plasma (e.g. toxins or sensing electrolytes and regulate water intake)
What does the area postrema do?
samples plasma for toxins and will induce vomiting
What is histamine important for in the brain?
wakefulness and alertness
effects of CO2 on vessles in the brain
- increased CO2 in surrounding neural tissue and smooth muscle cells causes increased conversion via CA
- this increases H+ and decreases pH
- this causes relaxation of VSMC
- increases BF (and also O2?)
-> indirect effects of CO2
