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Control of cerebral blood vessels Present state of the art.

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EDITORIAL
Control of Cerebral Blood
Vessels: Present State of the Art
M. J. Purves
The cerebral circulation differs in a number of important respects from other peripheral vascular beds.
Brain tissue has only small stores of oxygen and substrate, and its capacity for anaerobic respiration is
limited. The margin for error, therefore, between
supply and usage is tiny, and it is not surprising that the
vascular response to an increase in cerebral metabolism is both precise and prompt. The functioning of
brain cells is readily affected by changes in temperature and the immediate chemical environment, and
there is every reason to believe that keeping these
variables constant is critically dependent upon the
level of cerebral blood flow. A further unusual feature
of the regulation of cerebral circulation is the constraint imposed by a rigid skull, which means that an
increase in blood volume, for example in the pial
circulation, may well affect, through an increase in
intracranial pressure, the resistance to blood flow offered by the delicate, thin-walled pial veins. The situation is made yet more complex by the fact that the
brain is manifestly not one homogeneous organ but a
series of subsystems, each with its own metabolic requirements. We would predict that perfusion is also
far from homogeneous, and this is in fact so. This
poses a technical dilemma: if total cerebral blood flow
is measured, local changes are likely to be overlooked, but if local blood flow is measured, it is
likely to be atypical of the whole.
It is therefore unrealistic to ask, “How are cerebral
blood vessels regulated?” The question can only be
answered by breaking it down into the typical elements
of some form of homeostatic control system. We
should first determine what is being regulated: the
supply of oxygen and substrate? extracellular fluid
p H ? temperature? the pressure drop across the intracerebral vascular bed? Next, which are the important
disturbances to the system? Three groups might be
proposed: those that threaten the oxygen and substrate supply, such as hypoxia, hypoglycemia, and
hypotension; those that tend to alter the chemical
environment of brain tissue, such as hypocapnia and
hypercapnia; and those that arise from local or general
changes in cerebral metabolism. Then we should inquire how these disturbances are detected and how
the vascular responses are brought about. Is there a
common signal which in turn activates a unique agent
responsible for adjusting the level of perfusion to
metabolic demand? Or does each type of disturbance,
systemic or local, generate its own signal, so that coupling perfusion and metabolism involves many factors? Almost certainly the latter, I think. We can assume that since the metabolic rate varies so widely in
different parts of the brain, the degree of compensatory adjustment varies similarly, implying that the factor or factors adjusting blood flow are relatively local.
But this also implies that the disturbance has to be
registered in the tissue in question before the factor
adjusting blood flow is activated. This could take
time, and in the meantime, the tissue becomes vulnerable. We should therefore suspect a second, possibly more general, activating system which starts to
operate before the tissue is affected.
The problem facing the student of cerebral circulation is thus partly conceptual and partly technical. He
has to assume a particular type of control system and
then verify it, or identify particular regulating elements and build these up into a credible control system. Either way, the unique features of the cerebral
circulation make it imprudent simply to apply principles derived from other vascular beds. Further, the
study of cerebral circulation will continue to require
technical skill and ingenuity. There are no shortcuts to
understanding how the cerebral blood vessels are regulated, yet such an understanding is essential before
other problems, such as how the cerebral circulation is
affected in disease states, can be tackled.
From the Department of Physiology, School of Veterinary Sciences, Bristol, England.
Address reprint requests to Dr Purves, Department of Physiology,
School of Veterinary Sciences, Park Row, Bristol, England BS1
5LS.
Systemic Disturbances
We consider three systemic disturbances: hypoxia,
hypercapnia, and hypotension.
Hypoxia could be detected by specific receptors in
the aortic and carotid areas that act upon cerebral
blood vessels reflexly through an arc that includes the
depressor and sinus nerves, neurons in the nucleus of
0364-5134/78/0003-0501$01.00@ 1978 by M. J. Purves 377
the solitary tract in the medulla, and vasodilator fibers
which originate in the reticular formation. The evidence for such a reflex action is conflicting. Physiological evidence indicates that if the depressor or sinus
nerves are stimulated electrically [2 11, pial vessels
dilate, and if the carotid body chemoreceptors are
stimulated with blood of altered composition, an increase in regional cerebral blood flow follows, as
measured by the clearance of xenon 133 in the baboon
[45]. As will be discussed later, increasing evidence
suggests that specific and highly discrete lesions in the
mesencephalic reticular formation can markedly affect the cerebrovascular response to chemical or physical stimulation. If the seventh cranial and greater
superficial petrosal nerves, which are thought
uniquely to carry cerebral dilator fibers [ l l ] , are
stimulated, pial vessels dilate [ 11, 121 and blood flow
increases [31, 511. It is thought that these changes are
mediated by an acetylcholinesterase (AChE)-staining
cholinergic plexus accompanying the principal afferent and pial arteries [lo, 151. Fibers of this plexus
terminate on cerebrovascular smooth muscle adjacent
to adrenergic terminals [15, 291 and probably affect
the vascular smooth muscle by two separate mechanisms. Their main action is to cause dilation through
muscarinic receptors on the cerebral vessels, an action
blocked by atropine [35]. They also make axoaxonal
contacts with adjacent adrenergic terminals, and in
vitro evidence indicates that activation of cholinergic
fibers inhibits the release of the adrenergic transmitter
through nicotinic receptors [ 141. If this occurs in vivo,
the tonic action of adrenergic nerves could be markedly affected.
Considerable doubt is cast upon the involvement of
peripheral chemoreceptors and the adrenergic and
cholinergic pathways in the vascular response to
hypoxia or hypercapnia, however, by the observations
that (1) when another method of measuring blood
flow and another species have been used (injection of
microspheres and dog, respectively), stimulation of
the chemoreceptors is without effect [27], and (2)
when the afferent nerves from the chemoreceptors
are cut, the cerebrovascular response to hypoxia is
preserved [2,27]. At present it is difficult to reconcile
these discrepancies; there may well be flaws in or
limitations to the methods used, as well as speciesrelated differences, that will emerge only if similar
methods are used in different species and different
methods in similar species.
These discrepant results, however, emphasize that
there may be alternative methods of activating the
proposed cholinergic dilator pathway to cerebral vessels, and indeed, alternative dilator mechanisms. In
this regard, it has recently been shown that bilateral
section of the petrosal nerves is not followed by any
significant degeneration of the AChE-staining plexus
378 Annals of Neurology Vol 3 No 5 May 1978
on cerebral blood vessels [611such as occurs when the
adrenergic constrictor pathway is interrupted [29].
This suggests that the main dilator pathway is carried
by nerves other than the seventh cranial and petrosal.
Also, strong evidence now suggests that stimulation of
other pathways such as the intracerebral adrenergic
system originating in the locus ceruleus may induce
capillary dilation [47], a view consistent with the observation that intracerebral capillaries are innervated
[49]. The presence of actin and myosin in capillary
pericytes [43] suggests that cerebral capillaries may
be capable of independent vasomotor responses,
Another candidate for inducing vasodilation is the
recently observed dilator system involving vasoactive
intestinal polypeptide (VIP) terminals on pial and intracerebral vessels [36]. The possibility remains, of
course, that hypoxia acts directly upon cerebrovascular smooth muscle, as it is known to do in other vascular beds, or less directly, by inducing tissue lactic
acidosis, which in turn could cause dilation. This last
mechanism is not likely to be of great importance
because lactic acid is first detected many seconds after
cerebral blood flow has increased [9]. Finally, we must
accept that several of these mechanisms could be involved. We can easily conceive that a neural or other
rapidly acting system is responsible for the early pial
dilation and increase in blood flow, and that lactic acid
or some other local factor is responsible for the
slower, fine regulation of local blood flow. But much
more work is required to establish these points.
Systemic hypercapnia also causes pial dilation and a
rise in blood flow. Here, we may assume that the
vascular changes are compensatory, not in the sense
that the oxygen supply is threatened, but because
without dilation the p H of extracellular fluid would
fall unacceptably. Outside the physiological laboratory, of course, pure hypercapnia is rare and generally
accompanies hypoxia. Its dilating action could therefore be viewed as enhancing that of hypoxia, but in a
nonspecific way; this may have its drawbacks. Thus it
has been shown that in normoxic rats, a 50% reduction in cerebral perfusion pressure, sufficient to reduce cerebrovenous PO, to 30 mm Hg, causes a disturbance of brain tissue energy state as indicated by
the tissue content of adenylates [16, 171. But if a
similar reduction in perfusion pressure is accompanied by hypercapnia, the disturbance in the energy
state begins at acerebrovenous PO, of 50 mm H g 1181.
In other words, hypercapnia impairs the ability of
cerebral tissue to withstand ischemia with hypoxia;
this may be because carbon dioxide, by dilating all
capillaries, obliterates the small but crucial adjustments of blood flow in different parts of the brain.
An increase in Pq-, is detected by the peripheral
arterial chemoreceptors. If these are the principal or
unique receptors, then a reflex pathway'similar to that
proposed for mediating the effects of hypoxia would
be predicted. In support of such a pathway is evidence
from experiments which have shown that (1) cortical blood flow increases when the carotid body
chemoreceptors are stimulated with blood having a
high P c q [30],a response abolished by section of the
sinus nerves; (2) the cerebrovascular response to inhaled carbon dioxide is reduced after section of afferent fibers from vasosensory receptors [45];( 3 ) discrete electrolytic lesions in the tegmentum of the
reticular formation reduce or abolish the response to
carbon dioxide [ 5 2 ] ;and ( 4 )the vascular response to
carbon dioxide is reduced after section of the seventh
cranial nerves [31]. O n the other hand, as with the
responses to hypoxia, others have found that the response to carbon dioxide is not significantly altered
after the vasosensory afferent nerves have been cut
[2, 271.
Other hydrogen ionlcarbon dioxide sensors cannot
be ruled out. Pessacq [44]has described a widespread
system of dendrovascular glomera throughout the
cerebrovascular system, and it is also worth recalling
that neurons in the brain [33]and spinal cord [58]have
been shown to be sensitive to changes in CO,/H+.
More specifically, it has been shown that stimulation
of the COz/Hf-sensitive respiratory area located superficially in the ventrolateral surface of the medulla
with mock cerebrospinal fluid of altered p H results in
activation of cervical sympathetic nerves and the
branch from the stellate ganglion destined for vertebral arteries [GO]. Both carbon dioxide and H+ can act
directly upon vascular smooth muscle [54,621. Since
carbon dioxide diffuses so easily, it could very likely
bring about its effects at a number of sites and by a
number of mechanisms. Nonetheless, the evidence of
Scremin et al[52]that the cerebrovascular response to
carbon dioxide can be markedly altered by lesions in
the reticular formation in an area which is known to
relay dilator pathways to other vascular beds is provocative.
Changes in cerebral perfasion pressure may be caused
by changes in arterial, venous, or CSF pressure, and
they have in common that if pressure falls, pial and
possibly intracerebral blood vessels dilate; if perfusion
pressure rises, pial vessels constrict. In dynamic terms,
if pressure is suddenly raised, blood flow at first rises
briefly, and presumably passively, and then falls more
slowly to control levels [64].These adjustments mean
that under steady-state conditions over the normal
range of arterial pressure, as well as a distance above
and below it, blood flow is independent of perfusion
pressure. The use of the term autoregulation to describe this phenomenon implies that the compensatory mechanism is intrinsic to the vascular bed, and a
myogenic mechanism proposed by Bayliss [3] and
amplified by Folkow [20]has been invoked to account
for it. In this view, and within limits, vascular smooth
muscle reacts actively to oppose changes in perfusion
or transmural pressure; if perfusion pressure falls
below a level of approximately half control, however,
blood flow falls, and if it rises 30 to 40 mm Hg above
control, blood flow progressively rises.
Although intrinsic mechanisms may be important,
clear evidence indicates that interruption or stimulation of neural pathways affects this pattern of autoregulatory response. Thus if sympathetic fibers are
cut during hypotension, blood flow is higher than in
the hypotensive intact animal [ 191, implying the removal of a constrictor mechanism. Again, stimulation
of the sympathetic nerves at high blood pressure substantially raises the upper limit of autoregulation [8].
Such stimulation can reduce the lesions that ordinarily
accompany breaching of the blood-brain barrier at
high arterial pressure [39]. Even more striking
changes in the relation between cerebral blood flow
and arterial pressure can be obtained when specific
areas in the brain are stimulated. Thus, stimulation of
the fastigial nucleus completely abolishes the characteristic flow/pressure relationship and produces a large
increase in blood flow [39].By contrast, stimulation of
the vasopressor area in the dorsal tegmentum of the
medulla raises the upper limit of autoregulation, and
if this stimulation is repeated after section of sympathetic nerves in the neck, the flow/pressure relation becomes linear [40].Based on what is known
from other sources about the function of these areas,
it is probable that the fastigial nucleus forms part
of a dilator pathway, the efferent or motor limb of
which is unknown; it is not in the spinal cord or
sympathetic pathway [39]. Stimulation of the medullary tegmentum is likely to activate dilator and
constrictor pathways, and if the constrictor pathway is interrupted, the dilation is unopposed.
The involvement of baroreceptors in regulating the
cerebral circulation is controversial. Rapela et a1 [48]
found that if the carotid baroreceptors were denervated, the flowlpressure curve was shifted but autoregulation was preserved. Similarly, Heistad et a1
[26] found that stimulation of the baroreceptors is
without effect upon cerebral blood flow as measured
with microspheres in the dog. O n the other hand,
Ponte and Purves [45]showed that the flow/pressure
curve in the baboon became linear after denervation
of the baroreceptors, a result confirmed in the dog
[301.
As with the discrepant results obtained with respect
to hypoxia and hypercapnia, these different results
from baroreceptor stimulation raise the question of
technique and species differences. But they also raise
the question whether cerebral blood vessels respond
homogeneously to such factors as nerve stimulation,
changes in perfusion pressure, and so on. Harper et al
Editorial: Purves: Regulating Cerebral Circulation
379
[241 and Bill and finder [81 suggested that these
stimuli may affect primarily extracerebral blood vessels, i.e., pial vessels and the major afferent vessels.
Constriction or dilation of these vessels alters the
perfusion pressure at the origin of the intracerebral
vessels, and conceivably the smooth muscle of intracerebral vessels responds to this pressure rather than
to that which is commonly measured in the aorta. If so,
a sympathetically induced constriction of pial vessels
would be associated with dilation of intracerebral vessels, and in consequence, intracerebral blood flow
would remain constant. Such mechanisms might explain why those who have used a microsphere injection method [27] or the venous drainage method [481
(both of which reflect mainly changes in intracerebral
blood flow) have been unable to demonstrate any
changes with sympathetic stimulation, while those
who have used the 13”e clearance method [24, 311
(the fast component ofwhich is affected by changes in
the pial circulation) have shown such changes. It is also
possible that if intracerebral vessels are already dilated, e.g., in response to hypercapnia, their ability to
respond to changes in pial vessel tone will be compromised. This would explain the observation that the
effect of stimulating sympathetic nerves is more obvious at high carbon dioxide levels [24, 311. O n the
other hand, a small amount of evidence suggests that
stimulating sympathetic nerves does cause a fall in
blood flow in intracerebral vessels [13, 531, and this
would be consistent with the morphological observation that intracerebral blood vessels receive a major
but variable sympathetic innervation [ 531.
These results suggest that it will be increasingly
important to distinguish between the responses of
extracerebral and intracerebral blood vessels. It is
possible, in this connection, that the extension of an
approach developed by Shapiro et al[55] and Stromberg and Fox [59] would be of particular value. These
workers considered the cerebral circulation as comprising three segments in series-the large arteries,
the pial vessels, and the intracerebral vessels.
By measuring the pressure drop across these segments, they showed that the percentage contribution
to the total vascular resistance between aorta and
cerebral veins was in the proportion 3912 1/40. With
an increase in arterial pressure, these proportions
changed to 33/15/52. This finding indicates that the
main pressure stepdown occurred distal to the pial
vessels, though the exact site remains uncertain. It
could have been at the arterial “cushions” [25], which
are known to be innervated [42], and may correspond
to precapillary sphincters in other vascular beds. The
increase in resistance might also have been postcapillary. For example, small venules could be susceptible
to changes in intracranial pressure.
380
Annals of Neurology Vol 3 No 5 May 1978
It would be of the greatest interest and importance
if the effects of all the stimuli outlined in this
section-both neural and chemical-could be systematically measured using a similar technique.
Disturbances d u e to Changes
i n Metabolism
The second group of perturbations which may affect
cerebral blood flow arise from general changes (for
example, those induced by barbiturates o r analeptic
drugs) or local changes (for example, those induced
by changes in neuronal activity) in metabolism. Ever
since cerebral metabolic activity could be measured
quantitatively [32], the general view has been that it
remains rather constant despite such diverse stimuli as
hypoxia, hypercapnia, and mental arithmetic. The
suspicion that this apparent constancy of overall cerebral metabolism might conceal regional or local
changes could not be confirmed until recently, when
Sokoloff [57] developed satisfactory methods of measuring such changes.
The carbon 14 deoxyglucose method introduced by
Sokoloff 1571 measures the rate of glucose uptake
in a wide variety of brain structures with quantitative
autoradiography. The results reveal that metabolic
rate varies considerably between different structures
and that the metabolic rate of such discrete structures
as the olfactory bulb 1561or the striate cortex [281 can
increase markedly if the appropriate afferent pathways are stimulated. Furthermore, if the distribution
of blood flow in similar structures is measured concurrently with 14Ciodoantipyrine, metabolic and perfusion rates correlate closely ( r = 0.974), indicating tight
coupling between these variables. A disadvantage of
the method is that only single measurements can be
made, and those only under steady-state conditions.
However, it is clear from methods involving the clearance of hydrogen [371 or heat [53] that electrical or
pharmacological activation of structures in the brain
which presumably raise metabolic rate is accompanied
by very rapid increases in local blood flow [37]. In
addition, local tissue Po, measured with an oxygen
microelectrode rises equally rapidly in rough proportion to the duration of the stimulus [37], despite an
increase in metabolic rate. There is thus evidently a
mechanism which ensures that the oxygen and substrate requirements of the cells metabolizing at a
greater rate are rapidly and efficiently met. The
simplest view of this mechanism is that a substance is
formed and diffuses into extracellular fluid in proportion and at the same speed as the changes in metabolism, and that this substance affects blood vessels
locally, causing a change in blood flow proportional to
metabolism. A variant of this view is that a local reflex
pathway is involved or that the coupling factor is phys-
ical. For example, a rise in metabolism is accompanied
by a rise in temperature which could affect blood
vessels, or an increase in neuronal activity could alter
the geometry of glial cells interposed between
neurons and capillaries and so alter the capillary resistance. Evidence for and against the chemical coupling
factors that have been proposed can be briefly reviewed.
Hydrogen Ion
Carbon dioxide is a product of oxidative phosphorylation in cells. It is generally inhibitory to excitable
tissue, causing hyperpolarization and reduction of
spontaneous activity in smooth muscle [23] and in
cells in the cerebral cortex [33] and spinal cord [581.
There is some evidence that carbon dioxide causes
dilation of cerebrovascular smooth muscle, presumably by a similar direct action [54].Its action on intracerebral capillaries is not known. Hydrogen ion has a
similar but much weaker action upon membrane potential. It also causes pial vessels to dilate, though their
sensitivity to hydrogen ion has not yet been quantified. Similarly, its action on intracerebral vessels is
not known.
The hypothesis that H+ is an important, if not
unique, metabolic-perfusion coupling agent has been
widely held for some years, but recent evidence obtained by the use of p H microelectrodes gives little
support to such a theory. Thus the p H of extracellular
fluid in the cerebral cortex does not alter greatly with
bicuculline seizures, amphetamine intoxication, hypoglycemia, or acute hypoxia, though in each case,
local blood flow increases [ 13. Similarly, although
cerebral blood flow rises after a latent period of 10
seconds when rats inhale 5% oxygen in nitrogen, no
increase in lactic acid in tissue can be detected by
10 seconds, and even after 60 seconds, when the full
blood flow response has occurred, the lactic acid concentration of 1.5 pmoUgm would have been unlikely
to cause a significant change in extracellular fluid pH,
especially since P C O had
~ fallen. These results suggest
that if H+ is an important coupling agent, it acts not
directly upon blood vessels but as an adjuvant in some
other reaction, e.g., involving Ca++. Or, of course, it
may not act at all.
Potassium
Depolarization of excitable tissue is associated with
extrusion of K+ from the cell, and if the scale of
depolarization is large enough, as in a cortical seizure,
extracellular [K+] rises rapidly and by large amounts
despite the presence in glia of a potassium sink [46].
The close application of K+ in a concentration of 10 to
20 mmoUL causes dilation of pial vessels [7, 341.
However, the use of potassium microelectrodes has
shown, as with H+, that with amphetamine intoxication and hypoglycemia, cerebral blood flow increases
without detectable change in extracellular [K+]. With
hypoxia and the onset of seizures, the rise in extracellular [K+] to 7 mmoUL is unlikely to explain the very
substantial increases in blood flow [l].
Calcitlm and Interactions
with H + and K+
Though both €and
-I+
K+ cause pial dilation, it is probable that they act in different ways, since if pial vessels
are perfused with Ca++-free mock CSF, a fall in p H
will cause yet further dilation, whereas the dilator
action of K+ is lost [6].It may be that H+ affects the
membrane permeability to Ca++ while changes in K+
affect membrane potential by a change in the activity
of the electrogenic sodium pump. Changes in intracellular [H+]brought about by changes in Pco~, and to a
lesser degree by extracellular [H+],are also likely to
affect intracellular [Ca++] by altering the level of intracellular binding. These findings indicate a number
of possible sites of interaction between H+ and Ca++.
Adenosine
The extracellular concentration of adenosine in brain
is increased with electrical stimulation, hypoxia, and
hypotension [50], and the substance is known to cause
dilation of pial vessels in concentrations of between
and
moVL. This action is reversibly
blocked by theophylline [5,631. Adenosine probably
acts in this way on smooth muscle by blocking Ca++
uptake [4].
It would be possible to add to this list of putative
coupling agents. Adenosine triphosphate, for example, is known to diffuse through cell membranes, to
accumulate in venous blood (and therefore presumably in the extracellular space), and to be a powerful
dilator agent [22].But with this and the other agents
outlined, we are still some distance from proving that
they couple metabolism to perfusion, either separately or together. For this it would be necessary to
show, as for putative neurotransmitters, (1) that the
agent is secreted as a result of increased functional
activity; ( 2 ) that the presumed action of the agent on
local blood flow can be mimicked by local application,
i.e., by microiontophoresis; ( 3 ) that accumulation of
the agent in the extracellular space lies within the
range of sensitivity determined by (2); ( 4 ) that the
time course of secretion and diffusion accounts for the
observed changes in blood flow; and ( 5 ) that, preferably, the action is appropriately blocked. Although this
is a formidable list, the introduction of ion-selective
microelectrodes and methods for measuring local
blood flow hold great promise; already such methods
Editorial: Purves: Regulating Cerebral Circulation
381
have been able to dispose of one or two cherished
hypotheses.
Conclusion
The cerebral vessels are regulated by a variety of
factors. Some of these are fairly well understood, most
are uncertain o r controversial, some are hinted at, and
some-possibly
the most important-remain
unknown. In the search for these factors it may be useful
to make two speculations. First, it may be sensible to
regard the large extracerebral vessels and possibly the
pial vessels as the prime regulators of cerebral blood
flow and not simply, as in most other vascular beds, as
conducting vessels. Intracerebral vessels respond to
an immediate stimulus, which is.unknown but which
may be pressure changes at their origin, by mechanisms which are also unknown. The overall function of
such a system may be to maintain a constant pressure
difference across the intracerebral vascular bed. If this
view is correct, it becomes imperative to determine
what the dense network of adrenergic and cholinergic
nerves is doing and, in this connection, to reconcile
the methods currently in use for the measurement of
cerebral blood flow. It should be recognized that
species differences could be very significant in the
regulation of cerebral vessels, since it is in the arrangement of the large vessels (for example, in having
a rete mirabile or a circle of Willis) that species differ
most obviously.
The second speculation that may be worth making is
that two quite different regulating systems exist.
One is concerned with initiating rapid responses, particularly to systemic disturbances such as hypoxia,
hypercapnia, and hypotension which threaten the
supply of oxygen and substrate and the immediate
chemical environment of neurons. The second system
could be considered a fine tuner which makes local
adjustment of perfusion to the metabolic rate. This
may or may not be the same system as that invoked
when metabolism is altered generally or locally. It
could involve factors very different from those known
to affect pial or extracellular vessels, such as K+,
H+, adenosine, and others. These factors could be
unique to the cerebral circulation or they could be
similar to those responsible for functional hyperemia
in the skeletal muscle during exercise or in a gland
during active secretion; as indicated previously, they
need not be chemical. There is no doubt that clarifying
the nature of these coupling factors constitutes one of
the great challenges in vascular physiology.
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Editorial: Purves: Regulating Cerebral Circulation
383
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