483
Brief Review
Autoregulation of Blood Flow
Paul C. Johnson
A UTOREGULATION of blood flow, the tenden-
/ \ cy for blood flow to remain constant despite
A. \ . changes in arterial perfusion pressure, is a
ubiquitous and much studied phenomenon. Autoregu-
lation was first described in the kidney in 1931,1 but it
had been anticipated by Bayliss 30 years earlier2 based
on changes in hind limb volume during alterations in
arterial pressure. Bayliss noted a secondary decrease
of organ volume with arterial pressure elevation and
suggested that "the peripheral powers of reaction pos-
sessed by the arteries is of such a nature as to provide
so far as possible for the maintenance of a constant
flow of blood through the tissues supplied by them,
whatever may be the height of the blood pressure,
except so far as they are directly overruled by impulses
from the central nervous system." The widespread oc-
currence of autoregulation in various organs of the
body began to be recognized in the 1950's as part of an
intensified interest in local mechanisms of blood flow
regulation. In 1963 a symposium on this topic,3 pro-
vided a detailed view of the field at that time.
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Since the 1963 symposium, autoregulation has been
a topic of continuing interest. New experimental tech-
niques for studies in whole organs and in the micro-
circulation have provided a means for analyzing and
quantifying behavior of vessels responsible for auto-
regulation. Also, new biochemical methods have
become available to study purported vasodilators. Fi-
nally, the importance of autoregulation in clinical
medicine has been explored. The purpose of this re-
view is to examine the principal developments since
that time.
In 1963 four mechanisms of autoregulation — myo-
genic, metabolic, tissue pressure, and tubulo-glomeru-
lar feedback — were recognized as potentially impor-
tant while a fifth possible mechanism — local neural
control — was noted but given little credence. The
experimental evidence relevant to each of these four
theories will now be reviewed.
Metabolic Hypothesis
According to this hypothesis blood flow and tissue
metabolism are tightly coupled in such a way that any
reduction in arterial inflow causes a buildup of vasodi-
lator metabolites in the tissue. This buildup could be
due to a reduced rate of washout of aerobic vasodilator
From the Department of Physiology, University of Arizona
Health Sciences Center, Tucson, Arizona.
Address for reprints: Paul C. Johnson, Ph.D., Department of
Physiology, University of Arizona Health Sciences Center, Tuc-
son, AZ 85724.
Received July 8, 1985; accepted July 16, 1986.
metabolites such as CO2 or increased production of
vasodilator substances due to hypoxia or to both. Evi-
dence to be presented subsequently indicates that
washout is probably not a significant factor. There is
substantial evidence that the dependence of tissue oxy-
gen on blood flow is responsible for autoregulation in
organs with high oxygen consumption.
Both myocardium and brain exhibit a high degree of
autoregulation, and in both organs blood flow is highly
dependent on tissue oxygen consumption.45 The latter
observation suggests a tight coupling between blood
flow and tissue PO2 or vasodilator metabolite produc-
tion. In myocardium the hypothesis has been suggest-
ed6 that blood flow is regulated to maintain a constant
tissue PO2. Laird et al7 examined this hypothesis using
venous PO2 as an overall indicator of tissue PO2. The
relation between vascular resistance and venous PO2
was identical under conditions of functional hyperemia
and autoregulation, suggesting that the same mecha-
nism may be operating in both circumstances.
Consistent with this concept is the observation that
in some tissues elevated oxygen consumption greatly
enhances autoregulation. This was shown in skeletal
muscle by Stainsby,8 in stomach by Holm-Rutili et al9
and in intestine by Norris et al.10 The key factor in the
enhancement of autoregulation may be a lowering of
tissue oxygen levels as oxygen consumption in-
creases." Venous O2 levels in resting skeletal muscle
are relatively high (70% saturated), reflecting a high
tissue PO2. An increase in metabolism in skeletal mus-
cle leads first to increased O2 extraction and lowered
venous O2 content with modest increase in flow.12 This
increased extraction is apparently aided by a more
widespread perfusion of the capillary bed to include
vessels previously without flow.13'1* Granger et al11
have suggested that the terminal arterioles are more
sensitive than the larger arterioles to reduction in tissue
oxygen tension. This response would allow perfusion
of more capillaries and greater oxygen extraction with-
out substantially altering overall vascular resistance.
Klitzman et al have suggested that relatively small
changes in tone of the distal arterioles may have a
disproportionate effect on capillary perfusion. When
the capillary network is well perfused and O2 extrac-
tion is maximized, a drop in arterial pressure and flow
would lower tissue PO2 and lead to relaxation of the
larger arterioles and restoration of blood flow. Avail-
able evidence suggests that low tissue PO2, whether
due to elevated metabolism or low blood flow, appar-
ently favors autoregulation. Jones and Berne found in
skeletal muscle that autoregulation was much better in
preparations with high vascular tone and low venous
 484
oxygen levels. Granger et al" found in a variety of
circumstances that lowering tissue PO2 increased the
autoregulatory flow response of a skeletal muscle vas-
cular bed.
Tissue PO2 levels have not been examined exten-
sively during autoregulation. However, in myocardi-
um Schubert et al16 found a number of hypoxic sites
(<5 mm Hg PO2) at normal perfusion pressure in prep-
arations that showed good flow autoregulation. The
number of such sites increased as arterial pressure was
reduced even though mean tissue PO2 was maintained.
This study suggests that localized reduction in tissue
PO2 may be responsible, at least in part, for flow auto-
regulation.
An argument against tissue PO2 as a determinant of
autoregulation in the brain is that infusion of vasodila-
tor substances that increase cerebral blood flow does
not weaken blood flow autoregulation.17 This finding
is surprising since it would be expected that the in-
creased blood flow would elevate tissue PO2 and lower
tissue metabolite concentration. It is also interesting
that sustained reduction in cerebral blood flow can
occur without affecting autoregulation. After a period
of spreading cortical depression, cortical blood flow
and vascular responsiveness to CO2 are reduced18 but
the efficacy of autoregulation is not altered. In this
case it is possible that flow is reduced in proportion to a
fall in O2 consumption, maintaining a normal tissue
PO2. In support of latter possibility, a normal tissue pH
is seen in spreading depression. Also, when cerebral
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O2 consumption is reduced by 50% in pentobarbital
coma, cerebral blood flow also falls by 50% and auto-
regulation is not impaired.19 Similarly, in the heart,
reduction in cardiac function leads to a fall in myocar-
dial blood flow but the degree of autoregulation is not
impaired.20
More direct evidence for a role of oxygen in blood
flow autoregulation has involved suffusion of an oxy-
gen-rich solution over a microcirculatory preparation.
Elevating the O2 level typically causes vasoconstric-
tion of arterioles and reduced flow. In such studies
Kontos et al21 found that the dilation of pial arterioles,
which normally was quite prominent following arterial
pressure reduction, was entirely abolished when an
oxygen-rich solution was suffused over the tissue.
Similar results were obtained by Sullivan and John-
son22 in the cat sartorius muscle microcirculation,
while Morff and Granger23 found autoregulatory dila-
tion in rat cremaster arterioles was diminished but not
abolished. Since the autoregulatory dilation in two of
these tissues was completely abolished with elevated
oxygen, it appears that in those tissues production rath-
er than washout of vasodilator metabolites is important
in blood flow autoregulation. If washout were impor-
tant, there should have been some residual autoregula-
tion despite the fact that oxygen was supplied from an
external source. The firmness of this conclusion, how-
ever, is tempered by the fact that washout of vasodila-
tor substances from tissue near the surface may be
quite different from that in deeper areas. The absence
of any apparent role of washout in these studies does
Circulation Research Vol 59, No 5, November 1986
not prove it is unimportant in thicker tissue. The pres-
ence of residual dilation in Morff and Granger's stud-
ies23 could indicate a role for washout in their prepara-
tion, but other evidence from those studies favored a
myogenic mechanism asresponsiblefor the remaining
dilation.
Since O2 causes arteriolar constriction, it is also
possible that the abolition of autoregulation is due to a
nonspecific vasoconstrictor effect of oxygen. Klitz-
man et al14 showed that norepinephrine suppressed the
normal vasodilator response to stimulation of skeletal
muscle fibers in the cremaster muscle. A nonspecific
effect does not appear to be involved in the inhibitory
effect of oxygen on autoregulation since autoregula-
tion is enhanced rather than inhibited in preparations
with elevated vascular tone.1113
If tissue PO2 is the sole determining factor in blood
flow autoregulation, it would seem logical that there be
a detectable fall in flow as arterial pressure is reduced,
in order to reduce O2 delivery and tissue PO2. Howev-
er, in some vascular beds such as brain and myocardi-
um, there is a substantial change in precapillary resis-
tance in the absence of a measurable change in blood
flow. Mosher et al20 reported instances of no measur-
able change in myocardial blood flow in the dog in the
arterial pressure range 80-120 mm Hg. Also, cerebral
blood flow in man does not change significantly as
arterial pressure is lowered from 130 to 60 mm Hg.24
The latterfindingrequiresthat total vascular resistance
in this bed falls by half as arterial pressure is reduced.
Since capillary and venous vessels do not participate in
the response, precapillary resistance must fall by more
than half. Tissue PO2 must change appreciably in order
to alter vascular resistance to this degree. It is not
immediately obvious how tissue PO2 could change ap-
preciably in the absence of a change in blood flow.
One possible explanation of this finding that would fit
the tissue oxygen hypothesis is that there is continuous
countercurrent exchange of oxygen from arterial to
venous vessels.23 Such exchange would be greater at
reduced arterial pressure when the arterioles are dilated
and flow velocity is decreased. In these circumstances
capillary PO2 would fall even though blood flow is
maintained constant. This phenomenon would decou-
ple flow from tissue O2 levels and flow might actually
increase as arterial pressure is reduced. Such "super-
regulation" is seen in individual microcirculatory ves-
sels in skeletal muscle23 and mesentery26 and has been
reported in measurements of total blood flow in the
intestine10 during absorption of foodstuffs.
The studies by Schubert et al16 suggest that an in-
crease in the number of hypoxic sites leads to produc-
tion of anaerobic vasodilator metabolites as arterial
pressure is reduced. One problem with this hypothesis
is that the oxygen threshold for production of such
vasodilators is thought to be very low. The critical PO2
for cytochrome oxidase in isolated mitochondria is
known to be less than 1 mm Hg.27 However, if the
intracellular diffusion coefficient is low, as suggested
by studies in cardiac myocytes,2829 the critical extra-
cellular PO2 may be considerably higher (=6 mm Hg).
 Johnson Autoregulation of Blood Flow
This factor, coupled with heterogeneous O2 distribu-
tion in the tissue30 could lead to localized regions
where oxygen supply is inadequate for normal oxida-
tive metabolism. In addition, there is a variety of en-
zyme systems that have a considerably higher k,,, for
oxygen.31 If the latter play a role in blood flow regula-
tion they could sense changes at the hypoxic sites or in
mean tissue PO 2 , which is about 11 mm Hg in hamster
cheek pouch32 and 19 mm Hg in rat cremaster muscle.33
In this connection, it may be significant that as suffus-
ing solution PO 2 is elevated over these preparations,
the arterioles constrict and maintain a constant mean
tissue PO2. Oxygen causes generalized vasoconstric-
tion in all orders of arterioles in the cat sartorius
muscle.34
In examining the tissue oxygen hypothesis of blood
flow autoregulation, primary credence has been given
to an indirect effect of oxygen on the arterioles, i.e.,
via an alteration of tissue metabolism and production
of vasodilator metabolites. Relatively little work has
been done to identify possible chemical mediators of
this vasodilation. Morff and Granger35 found that theo-
phylline reduced but did not abolish autoregulatory
dilation of arterioles in rat cremaster muscle following
arterial pressure reduction, suggesting a role for aden-
osine in autoregulation. Schrader et al36 found that
coronary venous levels of adenosine and inosine in the
saline-perfused guinea pig heart increased at reduced
arterial pressures. On the other hand, Dole et al37 found
that adenosine deaminase infused into the blood-per-
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fused dog myocardium moderately reduced the magni-
tude of reactive hyperemia but did not significantly
affect autoregulation. Hanley et al38 also found that
adenosine deaminase did not attenuate autoregulation
the blood-perfused dog heart. Winn and co-workers39
found adenosine levels in the rat brain increased as
systemic arterial pressure was reduced, but the in-
crease was statistically significant only at pressures
below the autoregulatory range.
It is conceivable that changes in tissue PO 2 could
bring about an autoregulatory response by a direct ef-
fect on the resistance vessels. Studies on larger ves-
sels4041 revealed a direct effect of oxygen on vascular
tone. The importance of this observation for regulation
of resistance vessels has been disputed since the larger
vessels may have an anoxic core in the wall due to a
larger diffusion distance from the vessel surface. The
latter would not be a consideration in the arterioles.42
Moreover, local changes in periarteriolar PO2 did not
alter arteriolar diameter.43 However, evidence for a
direct effect of oxygen on arterioles has been provided
recently by Jackson and Duling,44 who reported oxy-
gen-induced constriction of isolated arterioles and
arterioles in a network dissected free from surrounding
parenchyma. To date this effect has been demonstrated
only when arteriolar PO 2 is substantially elevated.
Whether this effect is operative at normal or reduced
arteriolar PO2 has not been determined.
If oxygen has a direct effect on arterioles, intralu-
minal PO2 in these vessels as well as tissue PO2 would
be a factor in regulation. Since there is a longitudinal
485
gradient of intraluminal oxygen along the arteriolar
network to the capillaries,45 a reduction in flow would
reduce arteriolar PO 2 . The degree of PO2 reduction in
any arteriole with a fall in flow would depend on the
location of the arteriole in the network and various
other factors including the magnitude of flow reduc-
tion, the O 2 -Hb dissociation curve and any associated
change in tissue O2 consumption.
Since it appears that oxygen may act directly on the
arteriole, the possibility that it inhibits autoregulation
by suppressing another mechanism such as a myogenic
response must also be considered. However, as noted
in the following section (myogenic hypothesis), eleva-
tion of tissue PO2 does not inhibit the myogenic
response.
There is an additional possible mechanism of auto-
regulation that involves flow but does not depend on
metabolism per se. The endothelium of arteries is
known to produce prostaglandins with vasodilator
properties that tend to reduce basal tension.46 While
blockage of prostaglandin production does not abolish
autoregulation,47 it is possible that a steady rate of
production of such a substance by the endothelium
would enhance the degree of autoregulation, assuming
that reduced flow would reduce the rate of washout by
the bloodstream. Alternatively, if the plasma contains
a vasoconstrictor substance, as suggested by studies of
Bohr and Johansson,48 a reduction in flow would re-
duce the rate of delivery of the substance to the arteri-
oles. Under these circumstances vasodilation might
occur in the arterioles with flow reduction.
Myogenic Hypothesis
According to this hypothesis the arterioles respond
to intravascular pressure as a stimulus, with pressure
elevation causing constriction. The response may be of
a transient or sustained nature. Mellander and co-
workers49 have extensively studied the transient activa-
tion of resistance vessels and portal vein strips by dy-
namic stretch. It appears that transient stretch caused
by the arterial pulse pressure induces an especially
pronounced response in the distal arterioles of skeletal
muscle50 and may be particularly important in deter-
mining the basal vascular tone in those vessels. If
arterial pressure to skeletal muscle is reduced, the
metabolic mechanism apparently is quite effective in
attenuating the arteriolar response to the arterial
pulse.51
The resistance vessels of certain vascular beds also
respond in a sustained fashion to maintained pressure
elevation. The sustained response is of special interest,
as it would lead to autoregulation of blood flow, and
will therefore be considered in detail in this section.
The evidence for a role of the sustained myogenic
response in autoregulation comes about directly and
also through exclusion of other possibilities. For ex-
ample, in some vascular beds autoregulation persists
under conditions of elevated oxygen. In rat cremaster
muscle the autoregulatory dilation of arterioles was
reduced but not abolished by elevated tissue Oj. 23 Con-
striction of arterioles in hamster cheek pouch to elevat-
 486
ed transmural pressure was enhanced by elevated oxy-
gen52 although oxygen also caused these vessels
initially to constrict."
Several techniques have been employed to test the
hypothesis that arterioles constrict in response to ele-
vated intravascular pressure. Venous pressure eleva-
tion (which increases arteriolar transmural pressure but
reduces the arterio-venous pressure gradient) increases
vascular resistance in some vascular beds (small and
large intestine and liver)54"56 and causes arteriolar con-
striction in the rat mesoappendix,37 rat cremaster,23 and
cat mesentery.58 In the rat mesoappendix and rat cre-
master the constriction to venous pressure elevation is
greatest in the terminal region of the arteriolar network
where the pressure rise would presumably also be
greatest. Studies on cat mesentery, however, indicate
that the magnitude of the response is equal in arterioles
that experienced a large pressure increase and those
that underwent little or no rise in local intraluminal
pressure when venous pressure was elevated by a fixed
amount. This observation would suggest that the
mechanism of constriction of these vessels was not a
myogenic response to local pressure rise. Alternative-
ly, a myogenic constriction may have been propagated
from arterioles that did experience a pressure rise.
Propagated constriction is seen in the arteriolar net-
work of the hamster skin flap during periodic vasomo-
tion. Vasomotion in the hamster skin flap originates
at vessel bifurcations, is propagated in a decremental
fashion, and as a consequence, affects the vessels in
the immediate vicinity most strongly.
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In some vascular beds the arteriolar constriction to
venous pressure elevation may be neurogenic in ori-
gin. A local venous-arteriolar reflex has been de-
scribed in skin60 and skeletal muscle.61 However, the
reflex response is abolished by increasing the level of
sodium pentobarbital anesthesia.62 The possibility that
a neural reflex is responsible for the precapillary con-
striction in intestine with venous pressure elevation is
minimized by the fact that the experiments were done
under pentobarbital anesthesia and also that sympa-
thetic blocking agents and local anesthetics did not
abolish the constrictor response.5463 In rat cremaster
muscle, venous pressure elevation also causes arterio-
lar constriction, which is more pronounced in the pres-
ence of elevated ambient oxygen.23
Other studies have also shown a sensitivity of arte-
rioles to altered transmural pressure. Bouskela and
Wiederhielm64 raised arterial and venous pressure si-
multaneously in the bat wing by placing the animal's
body in a sealed chamber with the wing extended out-
side. Under these circumstances pressure elevation in
the chamber caused arteriolar and precapillary sphinc-
ter constriction. The constriction is not likely to be due
to a venous-arteriolar reflex such as seen in human
skin since the terminal arterioles have inconsistent
sympathetic innervation.65 In a somewhat similar type
of experiment, lowering ambient pressure around the
hamster cheek pouch preparation caused constriction
of the arterioles.52
Baez66 stopped flow in the rat mesoappendix and
Circulation Research Vol 59, No 5, November 1986
then elevated static intravascular pressure in the prep-
aration. He found, under conditions of no flow, that
pressure elevation caused arteriolar constriction. John-
son and Intaglietta26 also reported that static pressure
elevation in cat mesentery caused arteriolar constric-
tion. In addition, they found that arterioles in cat
mesentery dilated moderately when flow was reduced
or stopped by a microneedle applied to an arteriole at a
point downstream to the site of observation, indicating
that mesenteric arterioles possess a degree of flow sen-
sitivity. However, after flow was stopped completely
by microocclusion, the arteriole still dilated substan-
tially when arterial pressure to the mesentery was
reduced.
Isolated small arteries from brain show a myogenic
type of constriction to intravascular pressure elevation.
Vessel diameter tends to be maintained or decrease
slightly as intravascular pressure is elevated in the
range 55—110 mm Hg.67 This can best be explained as
due to a stimulatory effect of the intravascular pres-
sure. This response would aid the autoregulatory re-
sponse of the brain circulation, but would appear to be
too weak to account for the maintenance of constant
flow seen in that organ.
The mechanism by which vascular smooth muscle
senses the elevated intravascular pressure is an unre-
solved question. Bulbring68 observed that stretch of the
taenia coli muscle of the guinea pig led to depolariza-
tion and increased spontaneous spike activity of the
muscle. However, Bulbring found depolarization of
the muscle cell to be better correlated with tension than
with muscle length. This observation led several work-
ers to suggest that circumferential tension may be the
controlled variable in the myogenic response of arte-
rioles.66469"71 When intravascular pressure is elevated,
the myogenic response leads to a sustained shortening
of the vascular smooth muscle. The sustained shorten-
ing may reflect the special geometry of smooth muscle
in the arterioles and the dependence of circumferential
tension on both the vessel radius and transmural pres-
sure T = Pr (Law of Laplace). According to the La-
place relationship an increased tension occasioned by
elevated internal pressure would be counteracted by
arteriolar constriction, which would reduce vessel
radius.
Several studies lend support to this hypothesis.
Bouskela and Wiederhielm64 found that the constric-
tion of arterioles and precapillary sphincters in the bat
wing tended to maintain calculated wall tension con-
stant during simultaneous elevation of arterial and ve-
nous pressures. Burrows and Johnson72 found that as
arterial pressure to the cat mesentery was reduced,
arteriolar dilation tended to maintain wall tension. As
noted by the latter authors, if the dilation were too
pronounced with pressure reduction, wall tension
would rise, which would not support the wall tension
hypothesis. A rise in wall tension was rarely seen with
arterial pressure reduction, and the results were con-
sidered consistent with the hypothesis. It would be
expected that the degree of constriction of an arteriole
would be proportional to the local rise in pressure in
 Johnson Autoregulation of Blood Flow
that vessel. However, with a single step elevation of
arterial pressure (or venous pressure as noted earlier)
the magnitude of constriction in individual arterioles
was not proportional to the local pressure change.
Thus, wall tension did not appear to be well regulated
when arterioles were compared with each other. As
noted above, if the myogenic mechanism causes a
spreading vasoconstriction, there may not be a close
correlation between local pressure change and the
myogenic response. However, the lack of correlation
may also indicate that a variable other than wall ten-
sion is regulated.
A more critical examination of the wall tension
hypothesis requires consideration of a possible trans-
ducing mechanism that would sense wall tension and
stimulate the vascular smooth muscle cell to contract.
Two sites on the smooth muscle plasma membrane
have been proposed: 1) the myoendothelial junction
and 2) the dense area on the plasma membrane where
the actinomyosin filaments attach to the cell wall.73 In
respect to the myoendothelial junction, the internal
elastic lamina in many arterioles is fenestrated and
allows direct contact between endothelium and vascu-
lar smooth muscle cells. It has been proposed that
actual fusion of the two plasma membranes takes place
in certain circumstances.74 As intravascular pressure
rises, it is thought that the endothelial cell contents are
extruded through the IEL fenestration, deforming and
stretching the myoendothelial junction. This would
possibly lead to a rise in membrane conductance for
calcium and activation of the contractile machinery of
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the smooth muscle cell or alternatively to a change in
conductance of other ions that influence transmem-
brane potential. The ensuing contraction of the vascu-
lar smooth muscle cell would tend to oppose the trans-
location of the endothelial cell across the internal
elastic lamina and thus provide a negative feedback.
However, it is not clear how such a mechanism would
provide a well-modulated control system in which a
rise in intravascular pressure would cause the vascular
smooth muscle cell to shorten to less than its initial
length. Despite this possible shortcoming, it is of inter-
est that club-shaped protrusions of endothelial cells
into vascular smooth muscle cells are common in arte-
rioles of mesentery and interlobular arteries and af-
ferent renal arterioles where experimental studies fa-
vor a myogenic mechanism. However, such an
arrangement is more scarce in the efferent renal arteri-
oles where a myogenic response is apparently absent.
This mechanism cannot explain the stretch-induced
tone in rabbit ear arteries that is not affected by remov-
al of the endothelium.76
The second proposed cellular site of transduction
(the region of the plasma membrane near the dense
bodies) has been suggested73 because this region is in-
series with the contractile machinery and, hence, the
cell membrane in this vicinity should be deformed to a
degree which depends on the circumferential wall ten-
sion. However, this deformation would depend on to-
tal wall tension only as a first approximation because
other passive elements in the wall also are load bear-
487
ing. Moreover, as the vascular smooth muscle cell
contracts it would tend to unload these parallel elastic
elements, and thus, the wall tension borne by the mus-
cle would not fall as much as total wall tension when
the muscle contracts. A further complicating factor is
that the orientation of the contractile elements on the
luminal side of the cell apparently becomes relatively
more radial rather than tangential as the smooth muscle
cell shortens and, therefore, relatively ineffective in
load-bearing.77 This would suggest that those contrac-
tile filaments on the abluminal side and the associated
dense bodies carry proportionately more of the load
borne by the vascular smooth muscle cell. The effect
of such a shift of load bearing in the cell on stretch of
the cell membrane cannot be easily predicted.
Whatever the site of transduction of the myogenic
response may be, there is evidence that intravascular
pressure alters vascular smooth muscle transmembrane
potential. Harder78 found that pressure elevation in iso-
lated cerebral arteries caused membrane depolarization
of 1.45 mV/10 mm Hg in vascular smooth muscle
cells. The slope of this relation was directly dependent
on external calcium concentration, suggesting the lat-
ter cation may play a role in membrane depolarization.
Under some circumstances these vessels also showed
spontaneous spike activity that increased with pressure
elevation. In respect to a possible role of calcium in the
myogenic response. Baker et al79 and Cohen and Fray80
found that calcium was important in renal autoregula-
tion under conditions where only the myogenic mecha-
nism appeared to be involved. Addition of calcium
channel blocking agents nifedipine or verapamil abol-
ished autoregulation. Also, raising Ca in the perfu-
sate from 0 to 1.8 mM did not alter vascular resistance
at an arterial pressure of 50 mm Hg but did increase
resistance at 100 and 150 mm Hg. Haws and Heistad
showed that a calcium blocker, nimodipine, virtually
abolished the autoregulatory response in pial arterioles
to elevated arterial pressure.
Guharay and Sachs82 recently demonstrated single
ionic channels in skeletal muscle that are activated by
stretch. The channels are apparently not specific for
calcium but provide a possible mechanism by which
force applied to vascular smooth muscle might alter
transmembrane ion fluxes and transmembrane
potential.
In respect to the role of a myogenic mechanism in
autoregulation of blood flow, a question remains as to
how flow could be regulated effectively by a tension-
or pressure-sensitive mechanism. If the arteriolar net-
work is regarded as a single resistance element which
acts as a unit to constrict when internal pressure is
elevated, a reasonable degree of autoregulation can be
expected, provided that there is only a moderate range
of variability of control system gain.2683 However, if
the system gain is high, an inverse relation between
flow and arterial pressure would be expected and might
lead to a vicious cycle, where constriction generally in
the peripheral vasculature would lead to a further rise
in arterial pressure which would beget further constric-
tion, etc., as suggested by Hall. It is true that a rise in
 488
total vascular resistance would tend to increase sys-
temic arterial pressure. But a true vicious cycle could
be induced only if the rise in total vascular resistance
were greater than the rise in systemic arterial pressure.
The possibility of this occuring is unlikely because
baroreceptor reflexes would come into play. Also the
autoregulatory mechanism has an upper limit (general-
ly around 160 mm Hg) above which resistance declines
with further pressure increase. In addition, some vas-
cular beds autoregulate poorly and would attenuate the
total resistance rise.
The degree of over-regulation in individual organs is
limited by the fact that part of the total resistance of the
peripheral vascular bed is relatively fixed (i.e., in cap-
illaries, venous vessels, and perhaps large arteries). As
a consequence, moderate changes of the gain in the
arteriolar portion of the network would not cause a
radical shift in the pressure-flow curve as described in
earlier studies.73 This type of unitary myogenic con-
troller could however explain the occasional report of
increased flow in individual organs or microcircula-
tory vessels with reduced arterial pressure (super-regu-
lation) cited above.
An alternative myogenic control system that pro-
vides for a higher degree of precision in flow autoregu-
lation is the series-coupled independent effector sys-
tem.73 In this model the individual arteriolar branches
operate independently of each other and respond to
internal pressure elevation by contracting. It is not
required that the individual vessels sense tension. The
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behavior of this system can be illustrated by consider-
ing the response when arterial pressure is reduced
modestly. Pressure in the larger arterioles will be af-
fected more than distal vessels and the large vessels
will dilate, reducing the pressure drop through them
and tending to restore pressure in the mid-sized arte-
rioles downstream. If the larger arterioles dilate suffi-
ciently to restore normal pressure in the mid-sized ar-
terioles to normal, the latter vessels will not dilate.
However, if dilation of the larger arterioles is inad-
equate, pressure in the mid-sized arterioles will be
reduced and they will also dilate to bring pressure in
the more distal arterioles back to normal levels. Down-
stream from the point in the arteriolar network where
pressure is restored to normal by dilation, the pressure
profile and dimensions of the network will be identical
to the control state. If this is the case, it follows that
flow will also be returned exactly to control levels. If
arterial pressure is reduced further the vasodilation will
extend further downstream. When the vasodilation ex-
tends to the most distal branches of the arteriolar net-
work the autoregulatory capability of the network wih
be exhausted and any further reduction in arterial pres-
sure will lead to a decrease of flow. The detailed char-
acteristics of such a model have been examined in
respect to the interlobular arteries and afferent arte-
rioles and good flow autoregulation is predicted by the
model.
A noteworthy feature of this model is that blood
flow can be perfectly regulated although flow itself is
not sensed. Flow regulation is secondary to regulation
Circulation Research Vol 59, No 5, November 1986
of intravascular pressure in the myogenically active
vessels. It also follows that pressure in the capillary
network will be autoregulated so long as flow is held
constant.
The fact that individual arteries arid arterioles in
vitro contract in response to pressure67'86 suggests that a
network composed of independent myogenic effectors
is not an unreasonable model. However, in vivo, peri-
odic vasomotion seems to spread over localized re-
gions of the arteriolar network.59 Moreover, this vaso-
motion is pressure dependent, i.e., the frequency of
vasomotion increases when pressure is elevated.72
Thus, it is quite possible that the myogenic response of
individual vessels to pressure elevation spreads to ad-
jacent vessels and the response of each vessel to local
pressure changes is enhanced by vasoconstrictor input
from adjacent vessels. In this way the constriction of
an individual arteriole to pressure elevation in the net-
work may be more pronounced than would be seen in
the same vessel in isolation. This may serve to increase
the overall gain of the system. Speden87 has noted that
the contractile response of the isolated rabbit ear artery
to pressure elevation is less pronounced than reported
for individual arterioles in a network. He suggested
that the presence of the vessel in the network may
enhance the response. While this may be the case,
studies of vasomotion suggest that the spread is decre-
mental and would not make the entire arteriolar net-
work behave as a single unit.39
Tubuloglomerular Feedback (TGF) Hypothesis
Autoregulation was first described in the kidney1
and that organ regulates blood flow extremely well in
the arterial pressure range 70-140 mm Hg in the dog88
and 105 to 165 mm Hg in the rat.89 The main candi-
dates for autoregulatory control in the kidney are the
myogenic response and the tubuloglomerular feedback
mechanism. According to the TGF hypothesis, an in-
crease in arterial pressure leads first to increased glo-
merular filtration. According to Navar et al90 the in-
crease in glomerular filtration rate would increase the
solute and electrolyte concentration in the tubular fluid
at the macula densa. Specialized cells in the macula
densa are thought to sense changes in the tubular fluid.
The sensed variable has been suggested to be solute or
sodium chloride concentration.9192 The nature of the
constrictor stimulus from the macula densa to the
smooth muscle cells of afferent arteriole is not known
but appears not to be mediated by the renin-angioten-
sin system. Studies by Hall provide several lines of
evidence which discount this mechanism as of impor-
tance in regulation of afferent arteriolar tone.
If a rise in solute and/or electrolyte concentration
acts as a stimulus to the macula densa, the system
should behave as a proportional controller. It might
appear that perfect regulation of renal blood flow and
hence glomerular filtration rate would require that the
macula densa be exquisitely sensitive to the change in
tubular fluid solute or electrolyte concentration. This
need not be the case, however, since a small but sig-
 Johnson Autoregulation of Blood Flow
nificant fall in volume reabsorption was seen in hydro-
penic animals when arterial pressure was elevated.93
This effect, whatever its cause, would provide a resid-
ual offset or error signal even in the face of perfect flow
autoregulation. However, perfect flow autoregulation
by this mechanism would require that the sensitivity of
the macula densa receptor system and the fall in vol-
ume reabsorption be quantitatively matched so as to
provide adequate arteriolar constriction with arterial
pressure elevation. Otherwise the system would likely
over- or under-compensate and renal blood flow would
not be held constant in response to changes in arterial
pressure.
There is evidence that the tubuloglomerular feed-
back mechanism does not act alone in regulating renal
blood flow. Knox et al94 found that autoregulation of
the glomerular filtration rate persisted in superficial
nephrons after flow to the distal tubule was arrested.
Also, blood flow autoregulation is weakened but not
abolished in nonfiltering kidneys. 9596 Moreover, affer-
ent arterioles in renal tissue transplants in the hamster
cheek pouch constrict when vascular transmural pres-
sure is elevated.97 A myogenic mechanism could be
activated secondarily to constriction of the distal affer-
ent arteriole by the TGF mechanism since such con-
striction would tend to elevate pressure in the arteriolar
network immediately upstream and therefore lead to
myogenic constriction in those vessels. TGF alone
may be unable to regulate flow since the control is
located at the distal end of the arteriole and therefore
could not influence the total arteriolar network unless
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there is an ascending vasoconstriction of myogenic or
other origin.
Tissue Pressure Hypothesis
If tissue pressure is to play a role in autoregulation it
must vary with arterial pressure and be high enough in
the initial state to be an appreciable fraction of arterial
pressure. The best evidence for a role of tissue pressure
was obtained by Hinshaw in the isolated, pump-per-
fused kidney.98 The importance of this mechanism has
been questioned99 because pump-perfusion may have
rendered the kidney preparation edematous and, there-
fore, tissue pressure may have been elevated above
normal levels. However, such conditions may obtain
in tissue injury, at least in encapsulated organs. In
addition to the kidney, the brain would appear to be a
likely organ for such autoregulation during tissue in-
jury. In the case of head injury, autoregulation of cere-
bral blood flow is seen in areas of cortex where injury
is more severe while it is absent in areas less severely
injured. This observation led Enevoldsen and Jen-
sen100'101 to suggest that head injury causes a general
depression of vascular responsiveness, leading to au-
toregulatory loss in most areas. However, autoregula-
tion due to changes in tissue pressure (as a result of
capillary leakage), which the authors characterized as
"false autoregulation," may occur in the most severely
injured tissues. Decompression of the affected area
abolishes this type of autoregulation.
489
Maintenance of Capillary Pressure
When blood flow is held constant by the autoregula-
tory response, it is to be expected that there will be a
constant capillary pressure as well. From the relation
P c = P v + F R V , where P c = capillary pressure, P v =
venous pressure, F = blood flow, and R v = venous re-
sistance, it can be seen that capillary pressure can be
expressed in terms of flow rather than in terms of
arterial pressure. If arterial pressure changes and auto-
regulatory mechanisms are strong enough to maintain
a constant flow, capillary pressure should be unaltered
and independent of arterial pressure. There is evidence
for this behavior, for example, in the kidney, where
autoregulation maintains a constant glomerular capil-
lary hydrostatic pressure by adjustment of afferent ar-
teriolar resistance.69 Since efferent arteriolar resistance
is also substantial, constant glomerular filtration de-
pends on the latter remaining constant.
In other vascular beds (hind limb, intestine) capil-
lary hydrostatic pressure as measured by the iso-
gravimetric or isovolumetric method102"104 seems to be
nearly independent of arterial pressure in the autoregu-
latory range. Microcirculatory pressure measure-
ments, however, do not provide unequivocal support
for this concept. Gore105 found instances in which cap-
illary pressure in mesentery measured directly by the
servo-null technique was not maintained as arterial
pressure fell. Also, in capillaries where hydrostatic
pressure was maintained it appeared that flow redis-
tribution at the precapillary level was responsible. Re-
distribution could explain pressure maintenance in in-
dividual capillaries but would not seem to account for
general maintenance of pressure in the capillary bed as
reported in whole organ studies. The degree to which
capillary pressure is autoregulated in a given vascular
bed depends on the degree of flow autoregulation and
also on whether postcapillary resistance remains con-
stant or varies with changes in arterial pressure. These
factors have not been examined in microcirculatory
studies to the same extent as in whole organ studies.
It is likely that capillary pressure would be autoregu-
lated to a different degree than flow if there were
simultaneous changes in venous resistance. In skeletal
muscle and intestine it has been shown that venous
resistance rises as arterial pressure is reduced, espe-
cially below the range in which flow is regulated.1*4106
In intestine a local arterio-venous reflex may be in-
volved.107 In muscle, there is evidence that suggests
that blood viscous resistance in the venules increases
as blood shear rate decreases. The number of venules
with flow or the diameter of the venules in skeletal
muscle does not change significantly as arterial pres-
sure is reduced.108 But direct measurements in small
(4th order) venules show that pressure in these vessels
is well maintained as flow falls.109
Localization of Autoregulatory Adjustments
It has been shown that arterioles participate strongly
in the autoregulatory response in brain,110 skeletal mus-
cle,22 and cat mesentery. 1 " Studies in which pressure
 490
was directly measured in small arteries and determined
in the capillary bed by the isogravimetric method indi-
cate that the larger arteries do not contribute to auto-
regulatory response in intestine.103 By contrast, in the
kidney it appears that interlobular arteries and afferent
arterioles but not efferent arterioles participate in the
autoregulatory response."2113 In the brain there is a
substantial pressure drop in the large and small arteries
and these vessels may contribute appreciably to the
autoregulatory response.110
Interaction Among Control Systems
In the brain there is evidence that the arteries are
under myogenic control84 while the pial and smaller
arterioles imbedded in the tissue are principally under
metabolic control.21 This is an example of a series
arrangement of myogenic and metabolic control. As
noted above, constriction of the distal afferent arterio-
lar segment in the kidney by the TGF system may tend
to raise upstream pressure and therefore cause further
myogenic constriction. This would represent a series
arrangement, in this case of myogenic and TGF control
mechanisms. The myogenic and metabolic systems
may also be present in parallel in some tissues. In the
rat cremaster muscle it appears that both metabolic and
myogenic mechanisms are present in the arterioles
since elevation of PO2 with a suffusing solution re-
duced but did not abolish arteriolar responses to arteri-
al pressure changes. In cat mesentery the arterioles
are sensitive to changes in both pressure and flow. In
this instance it appears that the two mechanisms act
somewhat independently since the arterioles dilate
substantially with arterial pressure reduction even after
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flow is stopped locally by micro-occlusion.
In the presence of other types of vasomotor input,
i.e., humoral and nervous vasoconstrictor stimuli, the
myogenic and metabolic mechanisms may still be ef-
fective in producing autoregulation. In the brain, stim-
ulation of the sympathetic fibers apparently causes
only constriction of the large arteries and a transient
fall in flow. The flow rapidly returns to normal as the
autoregulatory adjustment occurs in the downstream
vessels.114 The brain may be somewhat unusual in this
respect as it lacks sympathetic innervation of the arte-
rioles. In skeletal muscle there is histological evidence
that sympathetic nerves extend to the smallest arte-
rioles"3 and induce constriction of those vessels when
stimulated.116 However, there is also evidence that
sympathetic innervation is not continuous in the termi-
nal arterioles of the bat wing. Thus, it might be ex-
pected that this tissue would behave similarly to brain,
with sympathetic stimulation lowering blood flow only
transiently. This sympathetic escape phenomenon has
been linked to autoregulation although it is not clear
that the mechanism would be identical in all cases.
In skeletal muscle, sympathetic stimulation elicits
constriction in both large and small arterioles as well as
in large arteries but the constriction is not maintained
in the smaller arterioles.116 The escape of the small
arterioles is in the face of continuing sympathetic exci-
tation and apparently represents an instance where lo-
Circulation Research Vol 59, No 5, November 1986
cal mechanisms dominate when there is direct opposi-
tion between central and local mechanisms. In the
larger vessels in skeletal muscle apparently there is
similar opposition but central mechanisms prevail.
The degree of autoregulation that occurs in various
organs during systemic arterial pressure reduction will
depend on the interplay of central and local mecha-
nisms. When systemic blood pressure is reduced there
is an increase in sympathetic outflow and circulating
plasma levels of Angiotensin H1'7 and ADH"8 which
would cause vasoconstriction. At the same time the
autoregulatory mechanisms should counteract the for-
mer. The net result in skeletal muscle arterioles is
constriction in larger arterioles and dilation of the more
distal arterioles."9 The latter can be prevented in thin
muscle by elevating the O1202 level over the muscle sur-
face. Sympathetic nerve stimulation does not inhibit
autoregulation in the brain but does alter the autoregu-
latory range. Under these circumstances the arteries
are constricted and the small resistance vessels are
believed to be already dilated to a degree to maintain
constant blood flow at normal arterial pressure. As a
consequence, the lower limit of autoregulation in brain
is reached at a higher than normal arterial pressure. But
the upper limit is also elevated. Based on the consider-
ations discussed above in respect to sympathetic es-
cape, it is possible that vascular beds with innervation
throughout all levels of the arteriolar network would
also show an alteration of the autoregulatory range. It
is believed that alteration of the autoregulatory range is
of particular importance in the brain because the
sympathetic constriction acts in concert with autoregu-
lation to protect the capillary network against the dis-
ruptive effects of elevated capillary pressure.
Long-Term Autoregulation and
Structural Changes
Most studies of blood flow autoregulation involve
very short term pressure adjustments, sometimes of
only a few minutes duration. Guyton and coworkers122
have pointed out that the vascular adjustments to sus-
tained alteration in arterial pressure may differ in
mechanism from acute changes. In the areflexic ani-
mal, autoregulatory responses are more pronounced
over a period of hours than over a few minutes. Guyton
suggests that the more slowly developing autoregula-
tion is more important than the acute response since the
latter is quite weak, at least in the areflexic animal.
Moreover, when systemic arterial pressure is chron-
ically elevated over a longer time period (i.e., days or
weeks), structural changes take place in the walls of
arteries and arterioles that elevate vascular resistance.
Folkow and co-workers" favor the view that this
structural type of autoregulation is due to a thickening
of the arteriolar wall with consequent narrowing of the
arteriolar lumen. Microcirculatory studies have shown
that in spontaneous hypertension there is a decrease in
arteriolar density that could also serve to elevate
resting vascular resistance. Whatever the nature of the
structural change, arteriolar resistance increases and
this tends to maintain a constant blood flow. If capil-
 Johnson Autoregulation of Blood Flow
lary and venous circuits are not structurally altered,
one would expect that capillary pressure would also be
maintained at near normal levels. Studies by Mein-
inger et al!28 indicate that in some types of hypertension
the elevated pressure is dissipated in the arteriolar net-
work, leading to normal or near normal pressures in
the capillary network.
Chronic reduction of pressure and flow by ligation
of a feeding artery leads to a change opposite to that
described above, that is, a reduction in structural vas-
cular resistance in the downstream vascular bed. Mi-
crocirculatory studies after arterial ligation have
shown a proliferation of arterioles and return of total
blood flow in the cremaster muscle to normal levels.129
The stimulus for proliferation of arterioles in this cir-
cumstance is not known, although it is generally recog-
nized that vasculogenesis is promoted under condi-
tions where tissue PO2 is below normal levels, perhaps
in part through stimulation of macrophages.130131 It is
also possible that elevated PO2 promotes the vascular
regression and reduction of arteriolar density noted in
certain types of hypertension.
Abolition of Autoregulation
Autoregulation is easily impaired, as those who
have attempted to study it experimentally can testify. It
is often abolished under experimental conditions that
involve extensive perfusion circuitry.132 Surgical prep-
aration of the tissue may also render arterioles unre-
sponsive to arterial pressure reduction.133 There is also
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evidence in brain injury, as noted above, that autoregu-
lation is impaired or abolished.100 Arterial hypoxia to
less than 60% saturation abolished cerebral blood flow
autoregulation in man according to one study,134 while
in another study autoregulation was maintained with a
comparable degree of hypoxia.17 By contrast, Granger
et al11 found that arterial hypoxia (exact level undeter-
mined) enhanced autoregulation in skeletal muscle due
to a reduction of tissue PO2.
Anesthetics are known to adversely affect autoregu-
lation although the results are variable depending on
the depth of anesthesia and type of anesthetic. Smith et
al133 found cerebral autoregulation was well main-
tained under light nitrous oxide anesthesia. With deep
cyclopropane anesthesia cerebral autoregulation was
maintained when arterial pressure was elevated above
normal levels but not when pressure was reduced
below normal levels, apparently because the resistance
vessels were already nearly maximally dilated. Mile-
tich et al136 also found that cerebral autoregulation was
weakened as evidenced by a higher pressure threshold
for autoregulation with enflurane and halothane under
moderate anesthesia (0.5 MAC) but that as the anes-
thetic level with halothane was elevated (1.0 MAC)
autoregulation was lost. Perhaps the anesthetic used is
important since, as noted earlier, Donegan et al found
cerebral autoregulation was maintained in sheep dur-
ing pentobarbital coma. In the isolated kidney halo-
thane (0.9%) did not abolish autoregulation, but
when systemic pressure was altered by varying anes-
thetic depth, renal blood flow was not autoregulated,
491
perhaps due to activation of baroceptor reflexes.138 Au-
toregulatory dilation of arterioles in cat mesentery was
substantially weakened when a supplemental dose of
Na pentobarbital was given." Given the clinical and
experimental importance of the anesthetic effects, it is
surprising that this area is not better understood.
Significance of Short-Term Autoregulation
When systemic arterial pressure is acutely reduced
to an organ, flow is better maintained in vital organs
such as brain132 and myocardium6 than in skin,139
skeletal muscle, 615 liver56 and the gastrointestinal
tract.10-57140 This comes about because autoregulation
is stronger in brain and myocardium and also because
sympathetic innervation is considerably weaker in the
latter organs. 6121
When systemic arterial pressure is acutely elevated,
the autoregulatory response in kidney, brain, and myo-
cardium would tend to prevent an increase in flow
while organs that do not autoregulate well would expe-
rience overperfusion. Assuming nutritional supply is
adequate initially, perhaps the most important homeo-
static consequence of the elevated flow in poorly auto-
regulating organs would be the rise in capillary pres-
sure. The fact that some vascular beds-do not
autoregulate well provides a safety valve for the arteri-
al circuit that would tend to attenuate the pressure
increase. From a homeostatic standpoint it would seem
optimal if the less vital organs had a lesser degree of
autoregulation than the vital organs such as brain. In
respect to the brain, when arterial pressure is above th^e
autoregulatory range, the rise in capillary pressure can
lead to disruption of the blood-brain barrier.121
Organs which autoregulate blood flow incompletely
in the resting state (skeletal muscle, intestine) are capa-
ble of a high degree of autoregulation under conditions
of increased metabolic demand. Under such conditions
these organs would behave, to a large degree, like
brain and myocardium when systemic pressure is al-
tered, with die proviso that their greater sympathetic
innervation would probably render them more suscept-
ible to baroceptor reflex control.
An obvious beneficial aspect of autoregulation that
apparently has not been fully explored to date is the
ability of the vascular bed to compensate for increased
resistance in the large arteries in atherosclerosis. When
arteries become stenosed to the degree that down-
stream pressure is appreciably reduced, it is to be ex-
pected that there will be dilation of the arterioles and
maintenance of constant flow, although the vasodilator
reserve of these vessels will be diminished. In accor-
dance with this, a study of atherosclerosis in mon-
keys141 indicated that cerebral blood flow autoregula-
tion was not impaired in the pressure range of 86-51
mm Hg and control blood was normal. However,
maximal vasodilator response to hypercapnia was
impaired.
Conclusions
Over the past 20 years, substantial new evidence has
been obtained in support of the metabolic, myogenic,
 492
and tubuloglomerular feedback mechanisms of blood
flow autoregulation. The relative contribution of the
metabolic and myogenic mechanisms varies consider-
ably among vascular beds, and in a few tissues, appar-
ently, a single mechanism is responsible for autoregu-
lation. In organs where both mechanisms are present
we do not have a good idea of their relative impor-
tance. Moreover, the contribution of each may vary
according to the metabolic activity of the tissue as well
as experimental conditions of the study.
The metabolic or flow-dependent mechanism of
blood flow autoregulation appears to depend on tissue
levels of oxygen, probably acting through alterations
in tissue metabolism. However, a direct effect of oxy-
gen on the resistance vessels cannot be excluded. The
heterogeneous nature of tissue PO2 distribution sug-
gests that areas of low oxygen tension may act as
primary sites offlowregulation by producing vasodila-
tor substances as oxygen delivery falls. The identity of
specific chemical mediators produced in such hypoth-
esized areas remains to be determined.
The myogenic mechanism may be due to a sensitiv-
ity of the vascular smooth muscle cell to tension in the
arteriolar wall. How this takes place is not clear, but
stretch-sensitive ionic channels in the cell membrane
such as described in skeletal muscle could act as the
force sensor. Changes in smooth muscle transmem-
brane potential observed with transmural pressure ele-
vation suggest that a membrane event may be in-
volved. Clearly, more information is needed at the
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cellular level to understand the operative mechanisms.
The tubuloglomerular feedback mechanism contrib-
utes importantly to autoregulation in the kidney, ap-
parently by sensing changes in tubular solute concen-
tration. The nature of the stimulus to the
juxtaglomerular apparatus and from the latter to the
afferent arteriole is not yet established. Since the
tubuloglomerular feedback mechanism also contrib-
utes importantly to other aspects of renal function it
will no doubt continue to be an area of intensive
research.
The homeostatic importance of autoregulation has
usually been seen in terms of maintaining constant
blood flow and nutrient supply. However, it can also
maintain a relatively constant capillary pressure that is
important for tissue fluid balance. Autoregulation also
serves an important protective role in preventing capil-
lary pressure from rising to levels that would damage
the exchange vessels, especially in the brain, with
acute elevation of arterial pressure.
The importance of the autoregulatory mechanism in
disease states has been examined to a relatively small
extent. While it doubtless serves as a valuable local
homeostatic mechanism when arterial pressure is al-
tered, it is possible that it accentuates at least modest-
ly the systemic arterial pressure rise in acute hyperten-
sion by contributing to the increase in total vascular
resistance.
Clarification of the uncertainties that still surround
the phenomenon of autoregulation will probably arise
in part from studies of other fundamental questions
Circulation Research Vol 59, No 5, November 1986
rather than autoregulation itself. It is to be expected,
however, that autoregulation of blood flow will contin-
ue to interest many researchers because of its normal
and pathophysiological importance and because it re-
veals the behavior of local mechanisms offlowregula-
tion without the complication of simultaneously in-
volving other, i.e., central, control mechanisms.
Acknowledgments
Research from the author's laboratory cited in this
review was supported by NIH grants HL AM 15390
and HL 17421. The expert secretarial work of Lura
Hanekamp and Joan Lavoie in preparation of this re-
view is most gratefully acknowledged.
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KEY WORDS • autoregulation • local regulation of blood
flow • myogenic response • vascular smooth muscle