240 STROKE VOL 11, No 3, MAY-JUNE 1980

artery occlusion in unanesthetized monkeys. Stroke 9: 143-149, in normotensive and spontaneously hypertensive rats. Expericn-
1978
5. Halsey J, Capra N, McFarland S: Use of hydrogen for
measurement of regional cerebral blood flow — the problem of
intercompartmental diffusion. Stroke 8: 351-357, 1977
6. Paulson O: The effect of hemodilution on cerebral blood flow
and blood gases in patients with polycythemia. A d a Neurol
Scand 60 (Suppl 72): 588-589, 1979
7. Halsey J, Capra N: The course of experimental cerebral infarc-
tion — the development of increased intracranial pressure.
Stroke 3 : 268-278, 1972
8. Halsey J, Capra N: Physiological modification of immediate
ischemia due to experimental middle cerebral artery occlusion
— its relevance to cerebral infarction. Stroke 2: 239-246, 1971
9. Fujishima M, Omae T: Upper limit of cerebral autoregulation
tia 32: 1019-1021, 1976
10. Fujishima M, Omae T: Carotid back pressure following
bilateral carotid occlusion in normotensive and spontaneously
hypertensive rats. Experientia 32: 1021-1022, 1976
11. Byrom F: The pathogenesis of hypertensive encephalopathy and
its relation to the malignant phase of hypertension. Experimen-
tal evidence from the hypertensive rat. Lancet 2:201-211, 1954
12. Rodda R, Denny-Brown D: The cerebral arterioles in ex-
perimental hypertension. I. The nature of arteriolar constric-
tion and effects on the collateral circulation. Am J Path 49:
53-76, 1966
13. Rodda R, Denny-Brown D: The cerebral arterioles in experi-
mental hypertension. II. The development of arteriolonccrosis.
Am J Path 49: 365-381, 1966

Physiological Mechanisms Controlling

Cerebral Blood Flow
GEORGE MCHEDLISHVILI, M.D.

S U M M A R Y The major conceptions of cerebral blood flow (CBF) control dereloped In the 19th and 20th
centuries are listed. The systems of CBF regulation are considered from the viewpoint of automatic control. In
the classification of CBF regulation mechanisms, 4 types are identified. The effectors of CBF regulation, i.e.
the specific arterial segments through which each type of regulation is accomplished, were found to be mainly
the major arteries of the brain and the small pial arteries rather than the intracerebral arterioles. Review of
controlling influences on these effectors of regulation, (myogenic, humoral and neurogenic), show that priority
should be given to neurogenic mechanisms. Several criteria governing efficiency of CBF regulation are
Downloaded from http://ahajournals.org by on March 21, 2021

proposed. Review of interactions of different types of CBF regulation shows that there may be both synergistic
and antagonistic relationships. Information about the processes is important for medical practice.
Stroke, Vol II, No 3, 1980

SEVERAL CONCEPTIONS of the physiological cerebral blood vessels in regulation of CBF.711

mechanisms controlling cerebral blood flow (CBF)
regulation were developed during the 19th and 20th
centuries. The earliest was the Monro-Kelly doc-
trine,1 which postulated that there are 3 incompres-
sible constituents inside the skull: cerebral tissue,
cerebrospinal fluid, and blood. Therefore, the amount
of blood and, hence, the CBF, should remain constant
under any physiological and pathological conditions.
The doctrine actually meant an absence of active con-
trol of CBF.
By the end of the 19th'century evidence had ac-
cumulated to show that CBF may, nevertheless,
change.1 According to this new concept, although the
diameter of cerebral blood vessels remained un-
changed, CBF could be altered and was thus con-
trolled by changes of the systemic arterial and/or
venous pressures.
The next concept concerning regulation of CBF was
developed in the 1930s when studies by Forbes and
associates2"9 showed that the pial arteries may actively
constrict and dilate. During the 1940s and 1950s
further evidence accumulated for an active role of the
From the Laboratory of Physiology and Pathology of the
Cerebral Circulation, I. Beritashvili Institute of Physiology,
Georgian Academy of Sciences, Tbilisi, USSR.
Investigators, being unaware of which blood vessels
were responsible for CBF regulation, speculated that
arterioles were responsible as arterioles were the
smallest precapillary arteries with one layer of smooth
muscle cells. The control of dilatation or constriction
of cerebral blood vessels was believed to be the direct
effect of metabolic agents, e.g. CO, and O2.
In the 1960s specific responses of particular por-
tions of cerebral arteries (i.e. of the major, pial and in-
tracerebral arteries) were found to be under different
control.10' u In this period experimental evidence ac-
cumulated on the important role of neurogenic control
of CBF. 12 "
The conceptions of the physiological mechanisms
regulating CBF mentioned above are schematically
summarized in the figure.
Regulation of CBF: Automatic Control
The physiological mechanisms for regulation of
CBF are triggered by disturbances such as a primary
decrease in cerebral blood flow or by increase in
cerebral blood volume. In response to such distur-
bances, a regulatory mechanism becomes active and
adjusts CBF to the new conditions within possible
limits. The mechanisms consist of 3 links: 1) afferent
information indicating the type of disturbances in
 PHYSIOLOGY OF CBF/Mchedlishvili 241

19th CKITURY:

CBP • constant

PRIOR TO 1930s:

Systeaic arterial
CRT
pressure

1940s > 1950a:

Systeaic arterial
pressure
FIGURE. Schematic presentation of essential
CB7
conceptions of CBF regulation of the 19th and
CerebroTaaoular resistance 20th centuries.
\ (arterloles),
fauBoral control only

1960s - 1970si

Systemic arterisl
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pressure
/ Hajor arteries,
car naurogenlc control
\ CerabroTMcular
resistaaoe

\ Saall plal arteries,

n euro genic control

regulation; 2) the controlling mechanism originating
in specific nervous centers and, 3) the effector
mechanisms of regulation. These links together
provide for a feed-back mechanism.
The afferent information may be of various kinds,
including the degree of stretch of vascular smooth
muscles resulting from changes of the intravascular
pressure, which may be caused by diffusion of vasoac-
tive metabolites accumulated in the tissue, or it may
be from specific nervous receptors located in the vessel
wall, or in the surrounding tissue such as baro- and
chemoreceptors.
In response to the afferent information, the con-
trolling effects occur. They may be either direct reac-
tions of the arterial smooth muscles to stretch
(myogenic mechanism), the direct effect of
metabolites or other active substances upon the vessel
walls (humoral mechanism), or efferent vasomotor
effects upon the particular blood vessels (neurogenic
mechanism). In the last, the controlling signals are
generated in specific neuron association centers whose
function is also concerned with the coordination of
changes in regulation with other processes, i.e. the
hemodynamics of the systemic circulation.
The effectors of regulation include the blood vessels
in the circulatory bed which respond to the controlling
signals and the hemodynamic events occurring in the
vascular bed as a result of regulation. These parts of
the regulatory mechanism make up control loops
which start from the subject of regulation, the arterial
tree, and terminate on it.
The efficiency of CBF regulation has gradually
developed during the processes of phylogeny and on-
togeny. The known basis for efficiency of CBF regula-
tion will be considered below.
Types of Cerebral Blood Flow Regulation
Review of investigations of CBF regulation9"11- "• "
shows that there are several types. The characteriza-
tion of types is based on differing circulatory and
metabolic disturbances which bring about the opera-
tion of respective regulatory mechanisms as well as
the central regulatory centers. Four types of CBF
 242 STROKE
regulation are recognized, each having particular
tasks:
Systemic Arterial Pressure
1. The regulation of CBF during changes of the
systemic arterial pressure is the first type. This
mechanism of maintenance provides a relatively con-
stant CBF in spite of changes in the perfusion pressure,
and is called "autoregulation." This is not exact since
all of the presently known types of CBF regulation
may be called autoregulatory to some extent. This
type of regulation was identified in the 1950s both
from animal experiments and studies on humans.26"19
Evidence has accumulated showing that CBF is com-
paratively independent of the systemic arterial
pressure level. Since changes of the arterial pressure
result in alterations of the perfusion pressure
(arteriovenous pressure difference) for the brain, the
comparative constancy of CBF indicates that it is
regulated by active changes of vessel lumina and, thus,
of resistance in the cerebral blood vessels.
Changes of O, and CO2
2. The regulation of CBF in response to changes of
O2 and COi content of arterial blood has been the sub-
ject of many experimental and clinical investigations
which showed that a decrease of arterial Po 2 , as well
as an increase of Pco 2 , results in a rise of cerebral
blood flow.17' S0"M but hyperoxia and a decrease of
arterial Pco, results in a decrease of CBF."- a 6
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Adequate Blood Supply
3. The assurance of an adequate blood supply to
brain tissue is the most important type of regulation.
Adequate in this case means a correspondence
between the actual rate of capillary blood flow and the
metabolic demands of the surrounding cerebral tissue.
Regulation provides an active change of CBF as soon
as this balance is disturbed because of a primary in-
crease in metabolic rate or a decrease in blood supply
to the tissue. The existence of this type of CBF regula-
tion was assumed as far back as the end of the 19th
century,** but only during the 1930s was it proved by
many investigators using different experimental
procedures.11- "• *>-"
Restriction of Blood Volume
4. The regulation of cerebral blood volume implies
elimination of superfluous accumulation by an active
restriction of blood inflow through the arteries. This
regulation of CBF, first demonstrated at the end of the
1950s, starts to operate under conditions of blood out-
flow restriction and/or following superfluous arterial
inflow.""40 Regulation consists of restriction of blood
inflow to the brain resulting in normalization of
cerebral blood volume.
Effectors of Cerebral Circulation Regulation
In the peripheral vascular bed, the effectors of blood
flow regulation are the resistance vessels, i.e. the
VOL 11, No 3, MAY-JUNE 1980
arteries. Though the precapillary arterioles have the
greatest resistance under resting conditions, regula-
tion is accomplished by means of those arterial
branches which are most strongly affected by con-
trolling influences and change their lumen and, hence,
resistance within wide limits.11 Thus, to elucidate
which of the cerebral arteries represent the actual
effectors for each type of CBF regulation, the func-
tional behavior of different portions of the cerebral
arterial system (the major arteries, pial arterial
ramifications and the intracerebral arteries and
arterioles) was studied.
Systemic and Pial Arterial Changes
With changes in the systemic arterial pressure, ac-
tive changes in the pial arterial diameter were
observed as early as the 1930s.2'4t * Further studies
showed that both constriction and dilatation of the
small pial arteries appeared with a considerable and
variable delay lasting from 25 seconds to 4 minutes.41
Thus, the diameter changes were proven not to be a
direct response of intraluminal pressure changes. The
diameter of the cortical arteries was also observed to
change insignificantly during hypo- and hyperten-
sion.42 As the result of these observations, small pial
and cortical arterioles are not believed to be concerned
primarily with regulation of a constant CBF during
changes in the systemic arterial pressure.
Resistance in the major arteries of the brain, both
the internal carotid and vertebrals, as judged from the
pressure gradient in them, increases with rising
systemic arterial pressure which results in an almost
constant pressure level at the circle of Willis. 43 '" It
has been recently shown that the larger pial arteries
(with a diameter more than 200 /*m) respond to an in-
crease in systemic arterial pressure.4" Thus, it may be
concluded that the principal effectors for CBF regula-
tion in response to blood pressure changes are the ma-
jor arteries of the brain and the large pial arteries. The
small pial arteries (diameter less than 200 ^m) play a
secondary role, since they act only when the response
of the larger arteries is insufficient, i.e. when the ade-
quate blood supply of cerebral tissue is disturbed (see
below).
Increased Cerebral Blood Volume
With increased cerebral blood volume, caused by
the simultaneous occlusion of the jugular veins or
rapid injection of blood into the venous sinuses of ex-
perimental animals, a drop in blood pressure in the
circle of Willis occurred while the systemic arterial
pressure remained unchanged. This proved that an in-
creased resistance in the major arteries of the brain
had occurred."- 4 " These vascular responses (along
with the collateral blood outflow from the skull) com-
pensate for the circulatory disturbances which reduce
blood outflow from the brain. In this situation, there
was no venous stagnation in the brain as the blood
pressure dropped in the pial arteries. The capillaries of
the cortex did not dilate, and the pressure in the
venous sinuses increased only for a short period and
insignificantly.
 PHYSIOLOGY OF CBF/Mchedlishvili
An analogous situation was observed when an in-
creased cerebral blood volume was caused by an in-
creased arterial inflow to the brain (e.g. following
recovery of CBF after 1-2 minutes stoppage). Under
these conditions a post-ischemic (reactive) hyperemia
simultaneously appeared with an increase in resistance
in the major arteries."
A similar constrictor response of the major arteries
of the brain was also observed during asphyxia47' **
when hyperemia appears in the whole brain because of
dilatation of the pial arteries8' 48 and following an
intra-arterial injection of strychnine causing seizures
and functional hyperemia throughout the cerebral
hemispheres.40
Consequently, with a superfluous increased cerebral
blood volume this disturbance is eliminated by a con-
strictor response of the major arteries to the brain (the
pial arteries may be either constricted or dilated under
these conditions depending upon the adequacy of
blood supply to cerebral tissue).
Changes in O, and CO2
During asphyxia O s decreases and CO 2 increases,
causing dilatation of the pial arteries. 8 ' 48 The major
arteries of the brain behave differently. Their reaction
was investigated by measuring both the pressure
gradient along them and the perfusion pressure in a
circulatory-isolated internal carotid artery in dogs.47"49
With asphyxia, these measurements showed evidence
of constriction. The intracortical arteries also behave
differently from the pial blood vessels, showing a
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pronounced tendency to constrict.48 Thus, the effectors
of CBF regulation which cause CBF to increase under
conditions of hypoxia and hypercapnia seem to be the
pial arteries which undergo considerable dilatation.
Neither the small cortical, nor the major cerebral
arteries take part in this regulation. The constrictor
responses in these vessels are a manifestation of
regulation of cerebral blood volume.
Regulation of Adequate CBF
There are several experimental models for the study
of the role of effectors in the regulation of adequate
CBF. These include deficient CBF caused either by a
primary decrease in blood supply to the cerebral tissue
(occlusion of respective arteries) or a considerable in-
crease in the metabolic demands of the brain (seizure
activity, etc.). Under these conditions47' M' " the pial
arteries regularly dilate,47' M' M especially the smallest
ramifications with a diameter of 30-100 ^m (in rab-
bits), and the specifically active microvessels, i.e. the
sphincters of their off-shoots, the precortical arteries
and the interarterial microanastomoses which control
blood supply to the smallest areas of the cerebral cor-
tex.42- " The functional behavior of the smallest cor-
tical arteries and arterioles under these experimental
conditions was distinctive in that their external
diameter never showed an increase but the internal
one, on the contrary, decreased regularly,41 though the
CBF in the same areas (measured by the "krypton or
hydrogen clearance method) showed a considerable
243
increase. Hence, the luminal contraction of the cor-
tical arterioles with a diameter up to 40 ^m did not in-
terfere with the acceleration of CBF in the respective
areas of the cerebral cortex. This may be explained, at
least partially, by an increase in blood fluidity as noted
by the Fahraeus-Lindqvist rheological phenomenon.
The experimental evidence seems to allow the conclu-
sion that the smallest pial arterial ramifications and
specific microvascular effectors located on the brain
surface are the principal vascular effectors of regula-
tion of adequate CBF.
Feedback Mechanisms Controlling CBF
Knowledge of the physiological feed-back
mechanisms regulating CBF was neither complete nor
conclusive for many years. A considerable advance in
understanding occurred during the last 2 decades and
was, at least partly, due to discovery of the effectors of
CBF regulation, i.e. of the specific function of the
cerebral arteries which are responsible for various
kinds of regulation.
In studies of CBF regulation it was shown that feed-
back was accomplished by: a) the myogenic
mechanism which occurs at the level of arteries, b) the
humoral mechanism which is believed to have direct
effect upon the vascular walls through humoral factors
either circulating in the blood (CO2 and O2) or ac-
cumulated in the tissue (acid metabolites, K + , etc); c)
the neurogenic mechanism which has materialized as a
true vasomotor reflex or a simplified variation like an
axon reflex. These feed-back mechanisms may operate
not only isolated from each other but also in various
combinations.
Myogenic Mechanism
The myogenic mechanism was believed to operate
by the well known Bayliss-effect which is an increase
in vascular tone in response to muscle stretch, and vice
versa. Theoretically, this mechanism may participate
in the regulation of CBF when it is to be maintained
constant under conditions of changes in systemic
arterial pressure. It is assumed that changes in the
stretch of the arterial walls cause changes in the level
of depolarization of muscle cell membranes and
result, in turn, in their constriction."-" It was also
believed that the myogenic mechanism is responsible
for vasodilatation during the development of
collateral blood flow and post-ischemic (reactive)
hyperemia, since the drop of the intravascular
pressure during ischemia is believed to cause a
decrease of vascular tone during the period of CBF
recovery."
The myogenic responses of vascular smooth
muscles have been experimentally observed.
Stretching the wall of caval vein results in an increase
in both spike and contractile activity of smooth mus-
cle cells." However, a problem remains as to whether
regulation of CBF can be achieved only by the
myogenic effects of cerebral arteries. It seems that
vascular responses dependent only on a myogenic
effect would never control CBF as well as it actually is
controlled during changes in the systemic arterial
 244 STROKE
pressure. There is an increasing accumulation of ex-
perimental evidence that the responses of the major
and pial arteries during changes of the systemic
arterial pressure are not myogenic. First, the arterial
smooth muscles respond only to a stretch having
specific characteristics" 1 "• " while CBF is maintained
virtually constant, independently of the rate and dura-
tion of the arterial pressure changes. Second, the
smaller pial arteries dilate earlier and more than the
larger arteries during arterial hypotension.41 The drop
in intravascular pressure, and, thus, decrease in
stretch of vascular muscles, should be more
pronounced in the larger vessels. Third, the com-
paratively long and considerable variations of latency
in dilatation and constriction of the pial-arteries dur-
ing changes in arterial pressure41 is a further argument
against a major myogenic mechanism. Thus, it might
be conjectured from these observations that the
myogenic responses of both the major and pial arteries
play a secondary role in CBF regulation during
changes of the systemic arterial pressure, but they
may favor the initial changes in vascular tone which
respond to quick changes in intravascular pressure.
Humoral Mechanism
The humoral mechanism may operate during the
following 2 types of regulation of CBF. It may operate
when changes are caused by primary alterations in the
content of blood gases and when adequate blood
supply to cerebral tissue is maintained. Under these
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conditions the sources of afferent input are changes in
the arterial Pco 2 and Po,, or changes in metabolic
content (e.g. acids, K + or other substances) actually
occurring in cerebral tissue. This humoral mechanism
for CBF regulation implies that the afferent informa-
tion directly reaches arterial walls without participa-
tion of neural structures but by diffusion of gases,
metabolites or other substances.
In the 1950s and early 1960s the most important
humoral factor was believed to be carbon dioxide.
This is the final product of metabolism and is believed
to be the most potent vasodilatating substance for
cerebral blood vessels. The speculation is that CO, ac-
cumulates in the cerebral tissue (e.g., during deficiency
of blood supply), diffuses to the arterial walls, and
causes vasodilatation.'- "• " Another hypothesis
suggests that vasodilatation is a result of the pH
changes which, in turn, are caused by accumulations
of CO 2 or other acid products (e.g. lactate) in the en-
vironment of vessel walls." 1 " Finally, as CBF in-
creases during hypoxia, it has been speculated that
vasodilatation may be caused by a decrease of Po, in
the environment of arterial walls.81- " Evidence has ac-
cumulated indicating the absence of a direct effect of
blood gases on cerebral blood vessels.*7' 41-S(M!1
Possible humoral factors which could trigger func-
tional vasodilatation in the cortex have been under ex-
tensive study in recent years. It has been shown that
an increase in the concentration of K + within
physiological limits causes dilatation of pial
arteries.*2"84 Estimation of K + and H + concentration
by selective microelectrodes within the cerebral cortex
VOL 11, No 3, MAY-JUNE 1980
have supported the hypothesis that functional
hyperemia may be triggered by K + increase and then
maintained by H+.85"87 Other possible humoral fac-
tors causing dilatation of the pial arteries included
adenosine. This is an activator of adenylcyclase,
producing cyclic AMP in the vascular smooth
muscle. 88 ' m These humoral factors affecting the
cerebral vessels may be interactive.84-70
There is evidence for a role of several humoral fac-
tors in the regulation of adequate blood supply to
the brain, but under some experimental conditions
there has been no correlation between the mentioned
metabolic factors and functional hyperemia,
which suggests that they could not be its immediate
cause.71-71
It is possible that humoral factors may be the
trigger of local vasomotor reflexes and may par-
ticipate in the neurogenic regulation of CBF. It could
be conjectured that when they are not an independent
controlling mechanism, changes of the chemical en-
vironment in vessel walls may contribute to those
other vascular regulators like the neurogenic ones.
If the humoral mechanisms have an independent
role in the control of vascular responses during regula-
tion of adequate blood supply to the brain, the
responses should be diffuse. If this is the case, it would
be difficult to explain the very localized reactions in
the microvascular effectors (sphincters of the offshoots
of the pial arteries, precortical arteries and pial
arterial microanastomoses) as these appear52 to be
responsible for distribution of blood among the in-
dividual radial arteries supplying the smallest areas of
the cerebral cortex.
Neurogenic Mechanisms
Neurogenic mechanisms of CBF regulation were
previously rejected by many research workers. Since
the 1960s, however, experimental evidence has
gradually led to general acceptance of the important
role of neurogenic control of CBF.12"16'18' 2O"24
The experimental evidence for neurogenic control
of CBF during changes of the systemic arterial
pressure is: First, the elimination of such regulation by
brain trauma, 73 - 74 hypercapnia76' " and hypoxia78- "• 7 8
may be used as evidence for a neurogenic, rather than
for a myogenic, mechanism as neural elements are
more easily damaged than vascular smooth muscle.
Second, complete deprivation of the internal carotid
arteries of neural innervation eliminates their active
reactions responsible for constant blood inflow to the
brain.44 Third, the role of the carotid sinus presso-
receptors for this type of CBF regulation has been
demonstrated experimentally.79 Fourth, the active
responses of the pial arteries to changes in the
systemic arterial pressure are eliminated following
blocking of cholinergic and adrenergic nerves.80"83
Changes in CBF which eliminate superfluous
cerebral blood volume are brought about by the con-
strictor responses of the major arteries to the brain,
and have been demonstrated to function reflexly
following distension of the cerebral venous system.48
Experimental evidence has gradually accumulated
 PHYSIOLOGY OF CBF/Mchedlishvili
indicating that the cerebral arterial responses to
changes of Po 2 and Pco 2 in the blood are in part
neurogenic because cholinergic blocking," removal of
vascular efferent nerves," and lesions of the respective
parts of the brainstem69 can eliminate or substantially
decrease the dilating effect of the blood gases on
cerebral blood vessels.
There is also evidence for a neurogenic vasodilatory
mechanism responsible for regulation of adequate
blood supply to the brain: a) microsurgical removal of
nerve fibers connecting the pial arteries with the
cerebral cortex stop vasodilatory responses during in-
crease in cortical activity.8* b) the vascular responses
with functional hyperemia in the cerebral cortex occur
with a very short latency.1'
Abundant efferent innervation in the walls of
cerebral blood vessels has been demonstrated by
histological, histochemical and electronmicroscopical
techniques which show both adrenergic and
cholinergic nerves in the walls of the major87 pial 8 8 "
and intracerebral arteries."1 M
When CBF is regulated by a neurogenic mechanism
the necessary afferent information originates from
specific nervous receptors located either in the walls of
cerebral vessels or in the brain tissue. The following
kinds of receptors are believed to be present: a)
mechanoreceptors in the vascular walls indicating the
intravascular pressure (baro-or pressoreceptors), 79 '"
b) mechanoreceptors of the cerebral veins and
meninges8*1" activated by an increase in cerebral
blood volume or brain volume changes; c)
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chemoreceptors in cerebral blood vessel walls and
probably in the cerebral tissue. These have not yet
been definitely identified. Little is known about the
afferent neural pathways carrying information to
respective central neurons in specific centers. There is
also little knowledge about the localization of specific
centers. It can be only conjectured that some are
localized in the hypothalamus and medulla
oblongata.69- "• •* It is possible that the neurogenic
mechanism responsible for reactions of the small pial
arteries during regulation of cerebral blood supply to
the cortex may be local. Afferent input may be from
nerve fibers which directly connect the cortex with the
pial arteries.*9' 10°
Efficiency Criteria of CBF Regulation
The regulatory system of blood flow to and in the
brain, gradually developed through evolution. The
criteria for efficiency depend on anatomical and
physiological peculiarities of the cerebrovascular
system.
One of the criteria depends mainly on blood vessel
structure and is the minimum energy lost by blood
when flowing through cerebral blood vessels. This is
especially important under unfavorable conditions for
blood supply to the brain, such as pronounced arterial
hypotension. Evidence for existence of this criterion
appears in the size of angles and the relation of radii in
arterial ramifications which should provide minimum
resistance.101 Studies of the geometry of pial arterial
ramifications show that the radii and angles of arterial
245
ramifications with a diameter more than 100 nm in
rabbits provides minimum resistance.102 For smaller
pial arteries the criteria for function efficiency seem to
be different (see below).
Other criteria for efficiency of CBF regulation are
related to the function of cerebral blood vessels, as
effectors of regulation. This function is the most
rapidly operating of the systems. This means that both
structure and function of the system should permit a
very rapid change in resistance and, hence, provide a
rapid redistribution of blood to various parts of the
brain. The rapid operation is provided for by the
following presently known peculiarities of the cerebral
vascular system. There are considerable windings
along the course of major arteries to the brain (both in
the internal carotid and vertebral arteries) where tur-
bulence can occur in blood flow.103 This should result
in a tangible change in resistance when luminal
changes occur even though they may be insignificant.10
In smaller pial arteries (under 100 jtm in rabbits) the
actual relation of angles and diameters of
ramifications causes considerable resistance under
normal conditions, but vasodilatation occurring after
a deficiency of blood supply to the cerebral cortex
results in the changes mentioned, a relationship that
provides a minimum resistance for blood transport
through the blood vessels.102
The third criterion for efficiency of the regulatory
system is the optimal selection of the possible effectors
of regulation. An increase or decrease of CBF may be
achieved in different ways, i.e. by a change in the per-
fusion pressure or in the resistance in some parts of the
cerebral arterial system: in the major, pial, or in-
tracerebral arteries. Regulation of CBF is achieved
usually in the most rational way. For instance, during
an increase in the metabolic demand of cerebral tissue,
an increase of its blood supply does not result from a
rise of the systemic arterial pressure, as this would en-
tail an increase of the perfusion pressure for the whole
brain and for all other organs of the body as well. Nor
does it occur by a decrease in resistance in the major
arteries of the brain as blood flow would become in-
adequate for the whole brain. Further, blood supply
does not result from dilatation of the cortical
arterioles as this would entail compression of the sur-
rounding tissue elements. What does occur is dilata-
tion of the respective small pial arteries which allows
an increase of blood flow only in those regions where
the metabolic demands are increased.
Maintenance of a constant CBF during changes in
systemic arterial pressure is achieved by changes in
resistance in the major arteries (internal carotid,
vertebral and larger pial arteries). Use of the small
pial arteries as effectors of regulation would interfere
with the simultaneous regulation of adequate blood
supply to the microvascular system.
Interaction of Different Types of CBF Regulation
Synergism and Antagonism
Different types of CBF regulation operate not in
isolation but in various combinations, and there is
 246 STROKE
evidence not only for synergism, but for antagonism
which may decrease the efficiency of the regulation of
cerebral blood supply.
An example of synergism between 2 types of regula-
tion is the maintenance of a constant CBF during
changes in systemic arterial pressure and the regula-
tion of an adequate blood supply to cerebral tissue. If
the changes in the perfusion become too great the
regulation accomplished by the major and large pial
arteries may become insufficient to maintain a con-
stant CBF which would inevitably cause a disturbance
in adequate blood supply to the brain. In this situa-
tion, the small pial arteries start to operate and ac-
complish the second stage of CBF regulation, tending
to keep an adequate blood supply to cerebral tissue."
An antagonistic relationship of CBF regulation
may occur following cerebral ischemia, asphyxia or a
considerable increase in neural activity throughout the
cerebral hemispheres. In this situation 2 types of
regulatory mechanisms having opposite tendencies
start to operate simultaneously. The rise in the
metabolic demand causes dilatation of the small pial
arteries which increases the blood supply to the brain
and the brain blood volume. The increased cerebral
blood volume must be controlled or reduced by
another regulatory mechanism, i.e. by constriction of
the major arteries of the brain."' "• ** These op-
positely directed vascular reactions, i.e. constriction of
the major and dilatation of the small pial arteries,
seem to be contradictory inherent functions of these
Downloaded from http://ahajournals.org by on March 21, 2021
vascular mechanisms. Under these conditions the
overall cerebrovascular resistance and, hence, the
CBF, would be determined by the algebraic sum of
these segmental resistances. The resistance may either
increase, resulting in a decreasing CBF, or decrease,
causing an increase of CBF. Under natural conditions
an optimal relation of these opposite tendencies for
change of CBF is determined by the operation of the
respective regulatory mechanisms.
References
1. Hill L: The Physiology and Pathology of the Cerebral Circula-
tion. London, Churchill, 1896
2. Forbes HS, Nason GL, Wortman RC: Cerebral circulation.
XLIV. Vasodilatation in the pia following stimulation of the
vagus, aortic and carotid sinus nerves. Arch Neurol Psychiatry
37: 334-350, 1937
3. Forbes HS, Cob SS: Vasomotor control of cerebral circula-
tion. Brain 61: 221-233, 1938
4. Fog M: Cerebral circulation. The reaction of the pial arteries
to a fall of blood pressure. Arch Neurol Psychiatry 37:
351-364, 1937
5. Fog M: Cerebral circulation. II. Reaction of pial arteries to in-
crease in blood pressure. Arch Neurol Psychiatry 41:260-268,
1939
6. Wolff HG: The cerebral circulation. Physiol Rev 16: 545-596,
1936
7. Schmidt CF: The Cerebral Circulation in Health and Disease.
Springfield, IL, Charles C Thomas, 1950
8. Klosovsky BN: Circulation of Blood in the Brain. Moscow,
Medgiz, 1951
9. Kety SS: The cerebral circulation. In McGoun HW (ed)
Handbook of Physiology, Section I: Neurophysiology vol. 3,
Baltimore, Williams and Wilkins, pp 1751-1760, 1960
10. Mchedlishvili GI: Functional Behaviour of Vascular
VOL 11, No 3, MAY-JUNE 1980
Mechanisms of the Brain. Leningrad, Nauka, 1968
11. Mchedlishvili GI: Vascular Mechanisms of the Brain. New
York-London, Plenum, 1972
12. Ingvar DH, Lassen NA: Regional Cerebral Blood Flow. An
International Symposium. Copenhagen, Munksgaard, 1965
13. Ingvar DH, Lassen NA, SjesjO BK, Skinhjjj E: Cerebral Blood
Flow and Cerebrospinal Fluid. Copenhagen, Petersen, 1968
14. Brock M, Fieschi C, Ingvar DH, Lassen NA, Schdrmann K:
Cerebral Blood Flow. Clinical and Experimental Results.
Berlin-Heidelberg-New York, Springer-Verlag, 1969
15. Mchedlishvili GI: Correlation of Blood Supply with
Metabolism and Function. Proceedings of an International
Symposium held in Tbilisi. Tbilisi, Metsniereba Publishers,
1969
16. Ross Russell RW: Brain and Blood Flow. London, Pitman,
1971
17. Purvcs M J: The Physiology of the Cerebral Circulation. Cam-
bridge University Press, 1972
18. Langfitt TW, McHenry LC, Reivich M, Wollman H: Cerebral
Circulation and Metabolism. New York-Heidelberg-Berlin,
Springer-Verlag, 1975
19. Moskalenko YE, Weinstein GB, Demchenko YT, Kisljakov
YY, Krivchenko AI: Intracranial Hemodynamics. Leningrad,
Nauka, 1975
20. Harper AM, Jennett B, Miller D, Rowan J: Blood Flow and
Metabolism in the Brain. Edinburgh-London-New York,
Churchill Livingstone, 1975
21. Mchedlishvili GI, Kovach AGB, Nyary I: Brain Blood
Supply. Proceedings of the 3rd Tbilisi Symposium. Budapest,
Akademiai Kiado, 1977
22. Ingvar DH, Lassen LA: Cerebral Function, Metabolism and
Circulation. Copenhagen, Munksgaard, 1977
23. Owman C, Edvinsson L: Neurogenic Control of Brain Cir-
culation. Oxford-New York-Toronto, etc., Pergamon 1977
24. Gotoh F, Nagai H, Tazaki Y: Cerebral Blood Flow and
Metabolism. Copenhagen, Munksgaard, 1979
25. Lassen NA: Cerebral blood flow and oxygen consumption in
man. Physiol Rev 39: 183-238, 1959
26. Carlyle A, Grayson J: Factors involved in the control of
cerebral blood flow. J Physiol, London, 133: 10-30, 1956
27. Green HD, Rapela CE, Conrad MC: Resistance (conduc-
tance) and capacitance phenomena in terminal vascular beds.
In Hamilton WF (ed). "Handbook of Physiology. Section II:
Circulation" 2: 935-960. Baltimore, Williams and Wilkins,
1963
28. Yoshida K, Meyer JS, Sakamoto K, Handa J: Autoregulation
of cerebral blood flow: electromagnetic flow measurement dur-
ing acute hypertension in the monkey. Circ Res 19: 726-738,
1966
29. Dickinson CJ: Neurogenic Hypertension. Oxford, Blackwell,
1965
30. Reivich M: Arterial Pco, and cerebral hemodynamics. Am J
Physiol 206: 25-35, 1964
31. Meyer JS, Gotoh F, Ebinhara S, Tomita A: Effects of anoxia
on cerebral metabolism and electrolytes in man. Neurology
(Minneap) 15: 892-903, 1965
32. Hirsch H, Schneider M: Durchblutung und Sauerstoffver-
brauch des Gehirns. In Olivecrone H und TOnnis W (eds)
Handbuch der Neurochirurgie. Bd I, Sect. 2,434-552, Berlin,
Springer-Verlag, 1968
33. Ldbbers DW: Physiologie des Gehirnkreislaufs. In GSnshirt
(cd) Der Gehirnkreislauf, pp 3214-260. Stuttgart, Georg
Thiemc Verlag, 1972
34. BergstrGm L, Johannsson H, Sjesjfl BK: The relationship
between arterial Po, and cerebral blood flow in hypoxic hypox-
ia. Acta Physiol Scand 93: 423^32, 1975
35. Bean JW, Lignell J, Caulson J: Regional cerebral blood flow,
O, and EEG in exposure to O, at high pressure. J Appl Physiol
31: 235-242, 1971
36. Roy CS, Sherrington CS: The regulation of the blood supply
of the brain. J Physiol (Lond) 11: 85-121, 1890
37. Bctz E: Cerebral blood flow: its measurement and regulation.
Physiol Rev 52: 595-630, 1972
38. Mchedlishvili GI: Role of internal carotid and vertebral
arteries in regulation of the cerebral circulation. Fiziol Zh
 PHYSIOLOGY OF CBF/ Mchedlishvili
SSSR 45: 1221-1228, 1959
39. Mchedlishvili GI: Changes in cerebral circulation during
resuscitation by intraartenal blood transfusion. Patol Fiziol i
Exper Terap 4: 14-20, 1960
40. Mchedlishvili GI, Ormotsadze LG, Mitagvaria NP, Antia
RV: Resistance in large and small cerebral arteries in
spasmodic activity. Bull Exper Biol i Med 75: No. 3: 27-29,
1973
41. MchedlisTivili GI, Nikolaishvili LS, Antia RV: Are the pial
arterial responses dependent on the direct effect of in-
travascular pressure and extravascular and intravascular Po,,
Pco, and pH? Microvasc Res 10: 298-311, 1976
42. Mchedlishvili GI, Baramidze DG: Nikolaishvili LS,
Mamisashvili VA' Vascular mechanisms responsible for
microcirculation of the cerebral cortex. Bioch Exper Biol 11:
113-129, 1974-1975
43. Mchedlishvili GI: The action of adrenalin in the regional
arteries of the brain. Bull Exper Biol i Med 49:, No. 5, 10-15,
1960
44. Mchedlishvili GI, Mitagvaria NP, Ormotsadze LG: Vascular
mechanisms controlling a constant blood supply to the brain
("autoregulation"). Stroke 4: 742-750, 1973
45. Kontos HA, Wei EP, Navari RM et al: Responses of cerebral
arteries and arterioles to acute hypotension and hypertension.
Am J Physiol 234: H37I-H383, 1978
46. Mchedlishvili GI, Ormotsadze LG: Investigation of the reflex
effects from the venous sinuses on the regional arteries of the
brain. Bull Exper Biol I Med 53: No. 2: 9-13, 1962
47. Mchedlishvili GI: On the independent nature of mechanisms
regulating the lumen of regional cerebral arteries (internal
carotid and vertebral) and pial arteries. Bull Exper Biol i Med
49: No. 6: 21-25, I960
48. Mchedlishvili GI, Ormotsadze LG, Nikolaishvili LS,
Baramidze DG: Reaction of different parts of the cerebral
vascular system to asphyxia. Exp Neurol 18: 239-252, 1967
49. Mchedlishvili GI: "Chest-head" preparation for investigation
of cerebral circulation. Bull Exper Biol i Med 53: No. 2:
Downloaded from http://ahajournals.org by on March 21, 2021
123-125, 1962
50. Ingvar DH. Extraneuronal influence upon the electrical ac-
tivity of isolated cortex following stimulation of the reticular
formation. Acta Physiol Scand 33: 161-193, 1955
51. Mchedlishvili GI, Baramidze DG, Nikolaishvili LS: Func-
tional behaviour of the pial and cortical arteries in conditions
of increased metabolic demands from the cerebral cortex.
Nature (Lond) 213: 506-507, 1967
52. Baramidze DG, Mchedlishvili GI: Functional behaviour of
microvascular mechanisms in the pial, precortical and cortical
arteries under experimental conditions. In Mchedlishvili GI,
Kovach AGB, Nyary Y (eds). Brain Blood Supply, pp 55-68.
Budapest, Akademiai Kiado, 1977
53. Somlyo AP, Somlyo AV: Vascular smooth muscle. Normal
structure, pathology, biochemistry and biophysics. Pharmacol
Rev 20: 197-272, 1968
54. Orlov RS, Azin AL: Studies of the electromechanical coupling
in smooth muscle cells of cerebral arteries. Fiziol Zh SSSR
60: 1439-1445, 1974
55. Gannushkina IV: Collateral Circulation in the Brain.
Moscow, Meditsina, 1973
56. Johansson B, Melander S: Static and dynamic components in
the vascular myogenic response to passive changes in length as
revealed by electrical and mechanical recordings from the rat
portal vein. Circ Res 36: 76-83, 1974
57. Sigurdsson SB, Johansson B, Melander S: Rate-dependent
myogenic response of vascular smooth muscle during imposed
changes in length and force. Acta Physiol Scand 99: 183-189,
1977
58. Sokoloff L, Kety SS: Regulation of cerebral circulation.
Physiol Rev 40, Suppl. 4: 38-49, 1960
59. Shalit MN, Reinmuth OM, Shimojyo S, Scheinberg F: Car-
bon dioxide and cerebral circulatory control. Arch Neurol 17:
337-341,342-353, 1967
60. Pittman RN, Duling BR: Oxygen sensitivity of vascular
smooth muscle. Microvasc Res 6: 202-211, 1973
61. Kontos HA, Rapcr AJ, Patterson JL: Analysis of vasoactivity
of local pH, Pco. and bicarbonate on pial vessels. Stroke 8:
247
358-360, 1977
62. Kuschinsky W, Wahl M, Bosse O, Thurau K: Perivascular
potassium and pH as determinants of local pial arterial
diameter in cats. Circ Res 31: 240-247, 1972
63. Moskalenko YE: Regional cerebral blood flow and its control
at rest and during increased functional activity. In Ingvar DH,
Lassen NA (eds) Brain Work, pp 343-352. Copenhagen,
Munksgaard, 1975
64. Kuschinsky W, Wahl M: Interaction between perivascular
norepinephrine and potassium or osmolarity on pial arteries of
cats. Microvasc Res 14: 173-180, 1977
65. Urbanics R, Leniger-Follert E, Ldbbers DW: Extracellular
H + and K + activities of the brain cortex during and after direct
electrical stimulation. Arzneim-Forsch/Drug Res 27:
1510-1519, 1977
66. Silver TA: Cellular microenvironment in reaction to local
blood flow. In Purves MJ (ed) Cerebral Vascular Smooth
Muscle and its Control, pp 49-67, Amsterdam, Elsevicr, 1978
67. Heuser D: The significance of cortical extracellular H + , K+
and Ca + + activities for regulation of local cerebral blood flow
under conditions of enhanced neuronal activity. In Purves MJ
(ed) Cerebral Vascular Smooth Muscle and its Control, pp
339-349. Amsterdam, Elscvier, 1978
68 Wahl M, Kuschinsky W: The dilatatory action of adenosine
on pial arteries of cats and its inhibition by theophylline.
Pflugers Arch 362: 55-59, 1976
69. Wahl M, Schrader J, Kuschinsky W: Increase of adenosine
content in cerebral cortex of the cat during bicuculline induced
seizure. PflOgers Arch 273: R26, 1978
70. Wahl M, Kuschinsky W: Influence of H* and K+ on
adenosine induced dilatation of pial arteries in cats. Blood
Vessels 14: 285-293, 1977
71. Astrup J, Norberg K: rCBF increase in hypoglycemia but no
brain acidosis and normal extracellular K+. In Cervbs-
Navarro J, Betz E, Matakas F, Wullenweber R (eds). Cerebral
Vessel Wall, pp 157-163. New York, Raven Press, 1976
72. Astrup J, Heuser D, Lassen NA et al: Evidence against H +
and K+ as main factors for the control of cerebral blood flow:
a microelectrode study. In Purves MJ (ed). Cerebral Vascular
Smooth Muscle and its Control, pp 313-332. Amsterdam,
Elsevier, 1978
73. Filatov YM, Shakhnovitch AR, Bczhanov VT et al: Con-
tinuous control of local blood flow and metabolism of the
brain following surgical operations of arteriovenous
aneurisms. Vopr Neirokhir No. 3: 23-27, 1971
74. Reivich M, Marshall WJS, Kassel N: Loss of autorcgulation
produced by cerebral trauma. In Brock M, Fieschi C, Ingvar
DH, Lassen NA, Schdrmann K (eds). Cerebral Blood Flow,
pp 205-208. Berlin-Heidelberg-New York, Springer-Verlag,
1969
75. Waltz AG, Sundt TM: Influence of systemic blood pressure on
blood flow and microcirculation of ischemic cerebral cortex: a
failure of autoregulation. Progr Brain Res 30: 107-112, 1968
76. Reichel K, Kanzow E: Der Einfluss von Barbiturat-Narkose
und CO, auf die Autoregulation der Hirnrindendurchblutung.
PflOgers Arch ges Physiol 279: R14, 1964
77. HSggendal E, Johansson B: Effects of arterial carbon dioxide
tension and oxygen saturation on cerebral blood flow
autoregulation in dogs. Acta Physiol Scand 66, Suppl 258:
27-53, 1965
78. Freeman J, Ingvar DH: Elimination by hypoxia of cerebral
blood flow autoregulation and EEG relationship. Exp Brain
Res 5: 61-71, 1968
79 Ponte J, Purves MJ: The role of the carotid body chemorecep-
tors and carotid sinus baroreccptors in the control of cerebral
blood vessels. J Physiol (Lond) 237: 315-340, 1974
80. Mchedlishvili GI, Nikolaishvili LS: Evidence of a cholinergic
nervous mechanism mediating the autoregulatory dilatation of
the cerebral blood vessels. PflOgers Arch ges Physiol 315:
27-37, 1970
81. Meyer JS, Okamoto S, Sari A et al: Effects of beta-adrenergic
blockade on cerebral autorcgulation and chemical vasomotor
control in patients with stroke. Stroke 5: 167-179, 1974
82. Kawamura Y, Meyer JS, Hiromoto H, Aoyagi M, Haehi K:
Neurogenic control of cerebral blood flow in the baboon.
 248
Effects of alpha adrenergic blockade with phenoxybenzamine
on cerebral autoregulation and vasomotor reactivity to
changes of Paco 2 . Stroke 5: 747-758, 1974
83. Fitch W, MacKenzie ET, Harper AM: Effects of decreasing
arterial pressure on cerebral blood flow in the baboon. Circ
Res 37: 550-557, 1975
84. Meyer JS, Ott EO, Aoyagi M et al: Double cholinergic and
adrenergic functional control of cerebral blood flow. In
Mchedlishvili GI, Kovach AGB, Nyary I (eds). Brain Blood
Supply, pp 119-135. Budapest, Akademiai Kiado, 1977
85. Stone HL, Raichle ME: The effect of sympathetic denervation
on cerebral CO 2 sensitivity. Stroke 5: 13-18, 1975
86. Mchedlishvili GI, Nikolaishvili LS: Zum nervSsen
Mechanismus der functionellen Dilatation der Piaarterien.
Pfliigers Arch ges Physiol 296: 14-20, 1967
87. Borodulya AV, Pletchkova EK: Distribution of cholinergic
and adrenergic nerves in the internal carotid artery. Acta Anat
86: 410-425, 1974
88. Falck B, Mchedlishvili GI, Owman C: Histochemical
demonstration of adrenergic nerves in cortex-pia of rabbit.
Acta Pharmacol et Toxicol 23: 133-142, 1965
89. Lavrentieva NB, Mchedlishvili GI, Pletchkova EK: Distribu-
tion and activity of cholinesterase in nervous structures of pial
arteries. Bull Exper Biol i Med 66, No II: 110-113, 1968
90. Iwoyama T, Furness JB, Burnstock G: Dual adrenergic and
cholinergic innervation of the cerebral arteries of the rat. An
ultrastructural study. Circ Res 26: 635-646, 1970
91. Edvinsson L, Nielsen KC, Owman C, Sporrong B: Cholinergic
mechanisms in pial vessels. Histochemistry, electron
microscopy and pharmacology. Z Zellforsch 134: 311-325,
1972
92. Cervos-Navarro J: The structural basis of an innervation
system of brain vessels. In Owman C, Edvinsson L (eds)
Neurogenic Control of Cerebral Circulation, pp 75-89. Ox-
ford, New York, Pergamon, 1977
Downloaded from http://ahajournals.org by on March 21, 2021
STROKE VOL 11, No 3, MAY-JUNE 1980
93. Pletchkova EK, Mchedlishvili GI, Lavrentieva NB,
Nikolaishvili LS: On the cholinergic mechanism responsible
for the functional dilatation of the arteries supplying the
cerebral cortex. In Mchedlishvili GI (ed) Correlation of Blood
Supply with Metabolism and Function, pp 172-184. Tbilisi,
Metsniereba Publishers, 1969
94. Hartman BK, Zide D, Udenfriend S: The use of dopamine
B-hydroxylase as a marker for the central adrenergic nervous
system in rat brain. Proc Nat Acad Sci 69: 2722-2726, 1972
95. Sousa Pereira JMM: de Circulacao Colateral do Cerebro.
Oporto, Inova-Artes Graficas, 1974
96. Lazorthes G: Vascularisation et circulation c6rebrale. Paris,
Masson et Cie, 1961
97. Kuprianov VV, Zhitsa VT: Neural Apparatus of Cerebral
Blood Vessels. Kishinev, Stiintia Publishers, 1975
98. Sutchkov VV: Possible mechanisms and some reasons of the
violation of haemocirculator influence of the hypothalamus
and reticular formation. In Mchedlishvili GI, Kovach AGB,
Nyary I (eds), Brain Blood Supply, pp 177-187. Budapest,
Akademiai Kiado, 1977
99. Owman C, Falck B, Mchedlishvili GI: Adrenergic structures
of pial arteries and their connection with the cerebral cortex.
Bull Exper Biol i Med 59, No. 6: 98-101, 1965
100. Edvinsson L, Lindwall M, Nielsen KC, Owman C: Are brain
vessels innervated also by central (non-sympathetic)
adrenergic neurones? Brain Res 63: 496-499, 1973
101. Rosen R: Optimality Principles in Biology. London,
Butterworth, 1967
102. Mamisashvili VA, Babunashvili MK, Mchedlishvili GI: The
optimality criteria of functional behaviour of larger and
smaller pial arteries in regulation of the brain blood supply.
Fiziol Zh SSSR 61: 1501-1506, 1975
103. Stehbens WE: Discussion on vascular flow and turbulence.
Neurology (Minneap) 11, part 2: 66-67, 1961