Physiology of Autoregulation of cerebral blood flow for neurology and Neurosurgery residents

1. AUTOREGULATION OF CEREBRAL
BLOOD FLOW
Dr SAMEEP KOSHTI

2. • CBF = CPP/CVR
– CVR = Cerebral vascular resistance
• Under normal physiologic conditions,
– blood flow is regulated in the brain through changes in vascular
resistance.
– n = Blood viscosity
– L= vessel length
– r= radius of vessel
• CVR
– subject to dynamic changes in the contractile state of vascular
smooth muscle (VSM),
– most at the principal cerebral resistance vessels
• those that arise perpendicularly from the pial arteries on the brain surface
before penetrating the parenchyma.
• However, up to 50% of total CVR arises from smaller pial arteries (150 to
200 μm in diameter) and arteries of the circle of Willis.

3. Viscosity
• critical to cerebral perfusion in pathologic states of low blood flow.
• low blood flow may be due to
– is a decrease in arterial perfusion pressure or
– an increase in vascular resistance,
• Low blood flow  decrease in shear stress  causes an elevation in
the hematocrit.  increased viscosity  further retardation in blood
flow,  vicious circle.

4. CBF AND ICP RELATIONS
• CBF and ICP are
– related by the Monro-Kellie doctrine, states that
• “Because the intracranial space is fixed and its principal
components,
• The brain parenchyma, blood, and CSF, are nearly incompressible,
• any change in the volume of one component must lead to a
reciprocal change in volume of the other components or ICP must
rise.”
– Cerebral blood volume (CBV) takes up a significant
proportion of intracranial volume.
• At any point in time, changes in CBV
– are determined by changes in arterial inflow relative to venous drainage
and are therefore reliant on CBF.
– So CBF has important role in management of ICP

5. REGULATION OF CBF
• On entering the brain parenchyma, cerebral arteries lose this ganglionic nerve
supply and instead acquire “intrinsic” innervation from parenchymal neurons.
– The best characterized intrinsic neural pathways that project to cortical blood vessels are those
from
• the nucleus basalis, locus caeruleus, and raphe nucleus.
– With electrical or chemical stimulation of these areas, increase or decrease in cortical CBF occur.
• There are three principal components in the regulation of CBF.
1. AUTOREGULATION
– changes in perfusion pressure are capable of producing marked changes in
CVR.
2. cerebral blood vessels changes in caliber in response to
– variations within certain ranges of partial pressure of carbon dioxide (PCO2)
and, to a lesser extent, partial pressure of oxygen (PO2).
3. Flow-metabolism coupling,
– the activity of the brain is linked to blood flow
– wherein changes in cerebral metabolism resulting from neural stimulation are
tied or “coupled” to corresponding changes in CBF.

6. VASOMEDIATORS
• NO
– Vasodilator
• EICOSANOIDS
– vasoconstrictors such as
• prostaglandin F2α and
• thromboxane A2,
– vasodilators such as:
• prostaglandin I2 (prostacyclin) and prostaglandin E2.
• ENDOTHELIUM DERIVED HYPER-POLARIZING FACTOR (EDHF)
– Complement NO in vasodilation
• ENDOTHELIN
• ADENOSINE
– Vasodilatation
– Neuroprotective in ischemia
• K+ Ions
– Perivasular conc. 3 to 15 mmol/L  vasodilation
– >15 mmol/L  vasoconstrictor
• H+ Ions
– vasodilatation

7. AUTO-REGULATION

8. • Def:
– The brain maintains its regional and total blood flow (and therefore perfusion) at a fairly constant rate
over a wide range of systemic blood pressure by a vasomotor phenomenon known as cerebral
autoregulation.
• In normal individuals, CPP varies directly with MAP because ICP is constant.
• the brain is
– protected from fluctuations in perfusion over a MAP range of 60 to 150 mm Hg
– Beyond this limit CPP passively follows MAP.
• It is important to note that the limits of autoregulation
– are by no means invariable.
• For example,
– they may be right-shifted in
• chronic hypertension (associated with increased sympathetic tone) and in
– Left shifted in
• increased renin release; conversely, a left shift may be observed in sleep,
• “physiologic hypotension” in athletes,
• “pathologic hypotension” associated with hemorrhage, and the presence of angiotensin-converting enzyme
inhibitors,
• prolonged hypoxemia, or
• hypercapnia.
– disturbed in
• acute, severe hypotension or hypertension and
– Profoundly impaired or even abolished in
• severe cerebral ischemia,
• Arteriovenous malformation beds, or
• brain injury and
• after aneurysmal subarachnoid hemorrhage.
• The changes induced by autoregulation
– pial arteries indicate a time course ranging from 5 to 10 seconds.

9. • The precise mechanism not known.
• Proposed mechanisms include:
1. Intrinsic changes in VSM tone (myogenic hypothesis),
2. The release of a variety of vasoactive substances from the
endothelium (endothelial hypothesis) or
3. Periadventitial nerves (neurogenic hypothesis) in response to
changes in transmural pressure, and
4. the effect of circulating or local metabolites (metabolic
hypothesis).
• argues against a significant involvement of “metabolic”
– First : microdialysis measurements of the metabolites, normally do not change
in response to alteration in CPP.
– Second: the time course of autoregulation may be too rapid to
depend on the generation of metabolic products.
– Third : the autoregulatory response has been observed in isolated,
perfused vessels in vitro (i.e., not subject to the influences of neuroglial
metabolism).

10. MYOGENIC HYPOTHESIS
• Denotes key role to the inherent response of VSM to mechanical
stimulation.
– an increase in intraluminal pressure leads to increased
contraction,
– whereas a decrease in pressure leads to decreased contraction.
• VSM integrins
– serves as mechanotransducers through their physical associations
with the extracellular matrix, cytoskeleton,
– These peptides containing integrin-specific amino acid signaling
regulates VSM [Ca2+]i, the primary trigger for contraction, by
altering L-type Ca2+ current.

11. ENDOTHELIAL HYPOTHESIS
• An increase in flow rate and shear stress without
an increase in transmural pressure can induce
vasodilation
– most likely through the endothelial release of NO.
• It has been said that endothelium-dependent
arteriolar contractions can be demonstrated in
response to
– increased transmural pressure.
• Due to depression of EDRF release or an
• increase in EDCF release (or both).

12. NEUROGENIC HYPOTHESIS
• Denotes the resistance of cerebral blood vessels
– to release of neurotransmitters from perivascular nerve
fibers.
• The sources of cerebrovascular innervation may be
either
– extrinsic (i.e., from remote neurons) or
– intrinsic (i.e., involving local neurons)
• Nerve stimulation studies have demonstrated a
– functional correlation between electrical stimulation of
isolated arteries (even those subject to mechanical de-
endothelialization) and altered vasomotor tone.

14. REGULATION OF CBF BY GASES
• 1. CO2
• Most important for physiological chemoregulation.
• PaCO2
– exerts profound effects on CBF,
– particularly across the physiologic range of 30 to 50 mm Hg
• hypercapnia (increased PaCO2) is found to cause
– cerebral vasodilation,
• whereas hypocapnia causes
– Cerebral vasoconstriction
• In fact, inhalation of 5% to 7% CO2 is associated with an
– almost exponential increase in CBF of 50% to 100%,
– thus rendering CO2 one of the most potent vasodilatory influences on the
cerebral circulation.
• When alterations in PCO2 have been sustained for 3 to 5 hours,
– there is an adaptive return of CBF toward baseline levels.

16. • It is most likely that extracellular acidosis is the major
determinant of hypercapnic hyperemia.
– rather than intracellular acidosis or molecular CO2 itself.
• When PaCO2 increases  molecular CO2 diffuses across the BBB 
Perivascular PCO2 rises  astrocytes convert the CO2 to HCO3− and
H+ via carbonic anhydrase  increasing the extracellular or
perivascular concentration of H+ (i.e., there is a fall in local pH).
• There is no consensus on the mechanism or mechanisms linking
changes in extracellular pH to cerebral VSM tone
– Suggested explanations for the inconsistent data in adults are that NO may
have a permissive role in facilitating the action of other mediators
– or that multiple redundant pathways may interact in CO2 induced
vasodilation.

17. PaO2
• Important determinant of CVR and hence CBF.
• Increased Pao2 elicit CVR  decrease CBF.
• Conversely, a fall in PaO2  vasodilation increased CBF.
• Response of CBF to PaO2 is a threshold phenomenon that is evident only
– when PaO2 falls below the normal physiologic range
• Hypoxia inhibits sarcoplasmic Ca2+ uptake  stimulates the
production of EDRF (over EDCF)  increases VSM relaxation
• Hypoxia also causes :
– alterations in cellular metabolism that lead to increased generation and
release of the vasoactive tissue factors K+, H+, and adenosine.
• Hypoxia-
– induces stimulation of oxygen-sensing neurons in the rostral
ventrolateral medulla may increase CBF via neurogenic vasodilation.
• Hypoxia
– If severe (PaO2 < 35 mmHg)
• Induces NO signaling and causes vasodilatation.

19. CEREBRAL NEUROVASCULAR COUPLING
• Through research,
– Found that astrocytic end feet serving as individual vasoregulatory
units through neurotransmitter-evoked Ca2+-dependent signaling events.
• It has been demonstrated that arteriolar vasodilation occurs in a
time frame similar to the rise in astrocytic [Ca2+]i.
• Low PaO2
– astrocyte [Ca2+]i is elevated  astrocyte glycolysis is maximized 
extracellular accumulation of lactate and adenosine decreases
uptake of the vasorelaxant PGE2 from the ECS and block
astrocyte-mediated constriction,both of which facilitate
vasodilation.
• An additional hypothesis is that Ca2+ currents in astrocytic end-feet,
termed “transients” and not present in the soma of the cell, are
responsible for some aspects of neurovascular coupling.

20. THANK YOU