Regulation of Blood Flow; Blood Brain Barrier Flashcards
Glucose levels below what concentration will cause unconsciousness?
2mM
causes unconsciousness->coma-> death
How is total cerebral blood flow regulated?
autoregulated between MABP 60-160mmHg (above/below- CBF cannot be maintained)
Stretch-sensitive cerebral vascular SM contracts at higher BPs and relaxes at lower BPs.
If the BP is too high, the increased flow can lead to swelling of the brain tissue (closed cranium leads to pressure problems.
How is CBF regulated locally?
Local brain activity determines the local O2 and glucose demands, therefore local changes in blood supply are required –Local Autoregulation (i.e. more flow required when giving a speech etc.)
Local regulation is mediated by:
- Neural control
- Chemical control
The local changes to blood flow can then me imaged on PET scans and fMRIs (functional MRIs)
What are the neural factors in local CBF regulation?
Sympathetic nerve innervation –vasoconstricts when MABP is high.
PNS facial nerve innervation –slight vasodilation.
Central cortical neurones –release vasoconstrictor NTs such as catecholamines.
Dopaminergicneurones –local vasoconstrictive effects.
- These innervate penetrating arterioles and pericytes (brain macrophages) around capillaries.
- These may participate in diversion of cerebral blood to areas of high activity.
- Act by causing contraction of pericytes via aminergic and serotoninergic receptors.
What are pericytes?
cells that wrap around capillaries - have diverse activities e.g immune function, transport properties, contractile
What are the chemical factors that affect local CBF regulation?
CO2(Indirect,) Vasodilator
pH (i.e. H+, lactic acid, etc) - Vasodilator
NO - Vasodilator
K+ - Vasodilator
Adenosine - Vasodilator
Anoxia - Vasodilator
Other (i.e. kinins, prostaglandins, histamine, etc.) - Vasodilator
How does an increase in CO2 cause cerebral arterial vasodilation?
The increase in H+ decreases the pH inside the VSMCs which causes the cell to constrict resulting in vasoconstriction.
The H+ can be derived from the (higher) CO2 in the blood (NOT directly from H+ in the blood) or from increased neural metabolic activity (directly).
Describe the flow and function of CSF.
CSF is produced by the choroid plexus (modified ependymal cells that ordinarily line the ventricles).
The capillaries are leaky but adjacent ependymal cells have extensive tight junctions.
CSF is secreted into the lateral ventricles and then follows the course -> 3rd ventricle (via interventricular foramina) -> 4th ventricle (via cerebral aqueduct) -> subarachnoid space via medial and lateral apertures.
Volume = 80-150mls.
Functions –protective, nutritionaland transport
Compare the composition of CSF and plasma
Similar pH and osmolarity but importantly very low protein levels (allows a CSF sample to diagnose bacterial infection).
K+ (lower), Mg2+ (higher) , Ca2+ (lower), aa (much lower)–very different concentrations compared to plasma
What are some differences between peripheral and BBB capillaries?
BBB
extensive tight junctions at endothelial cell-cell contact zone -> reduces leakage
pericytes closely adherent to capillaries in brain -> maintain capillary function and integrity
BBB capillaries covered in “end-feet” from astrocytes which help maintain BBB properites
What is the consequence of having such tight junctions?
BBB can control exchange of many large or hydrophilic solutes such as glucose, amino acids, antibiotics etc. (so it uses specific transporters to transport these across the BBB).
This means blood-borne infectious agents are generally prevented from entry into the CNS tissue – infections more commonly affect he meninges whose vessels are not BBB.
Transporters: Water - Aquaporin channels Glucose - GLUT1 proteins Amino acids - 3 transporters Electrolytes - Specific mechanisms
Lipophilic molecules CAN cross the BBB.
What are CVOs?
Circumventricular Organs
In some places in the brain, it is necessary for capillaries to lack BBB properties – i.e. pituitary gland.
These capillaries are often fenestrated and are present as the CVOs often need to sample blood or secrete into the blood itself.
E.G. Posterior pituitary secretes, Area Postrema samples blood.
What is the clinical importance of the BBB?
Many therapeutic drugs cannot access the brain whereas many access the brain too readily and can cause adverse effects so it must be monitored.
In treatment of allergies, “old-fashioned” H1-channel blockers are hydrophobic and so would cross the BBB and cause drowsiness (as histamine is a drug that keeps you alert).
Second-generation antihistamines are now polar and so do not cross the BBB so no drowsiness.
How does the BBB affect the treatment of Parkinson’s Disease?
Raising dopamine levels in the brain is important in treating Parkinson’s disease but it cannot cross the BBB and so cannot be given peripherally.
L-DOPA can cross the BBB (converted to dopamine by DOPA decarboxylase) but circulating L-DOPA is broken down in the body peripherally so co-administration of DOPA-decarboxylase inhibitor (Carbidopa) is necessary so L-DOPA can cross the BBB (Carbidopa does NOT cross the BBB).
