© 1995 American Heart Association, Inc.
Articles |
Modulation of Cerebral Arteriolar Diameter by Intraluminal Flow and Pressure
From the Department of Neurological Surgery, University of Washington School of Medicine, Seattle.
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Abstract We determined whether cerebral arterioles in vitro adjust their diameters in response to changes in intraluminal flow rate and pressure. Intracerebral arterioles (38- to 55-µm diameter) were isolated from Sprague-Dawley rats and cannulated with a perfusion system that permitted separate control of intraluminal pressure and flow rates. Increasing pressure at 0 flow, in 20 mm Hg steps from 20 to 100 mm Hg, resulted in myogenic constriction, which was greatest at 60 mm Hg (
20%). Increasing
flow rate at a constant pressure of 60 mm Hg elicited a biphasic
response. At flow rates of up to 10 µL/min, the arterioles dilated by
up to 14.5±2.2% of their control diameter. At higher (>10 µL/min)
flow rates, however, a progressive restoration of resting diameter was
observed. Application of the nitric oxide synthase
inhibitor
NG-monomethyl-L-arginine
(L-NMMA, 0.1 mmol/L) caused a 15.4±1.7% decrease in control diameter
(at 60 mm Hg, zero flow). Although L-NMMA did not affect the responses
to increases in pressure or to vasodilators (adenosine and pH
6.8 buffer), it abolished the dilator responses to flow rate increases
and to acetylcholine. In contrast, inhibition of
prostaglandin synthesis by indomethacin (10
µmol/L) had no effect on flow-induced dilation. These results
show that changes in intraluminal flow rates and pressure can
independently influence cerebral arteriolar tone and suggest that the
flow-induced dilator responses of cerebral arterioles are mediated
by an arginine metabolite, such as nitric oxide.
Key Words: shear stress • flow velocity • cerebral circulation • nitric oxide • myogenic response
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Introduction |
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As blood flows through the lumen of a vessel, it exerts a frictional drag on the endothelial cells that line the vascular wall. Until recently, little was known about the physiological role and effect of this frictional force, or shear stress, in the vascular system. The discovery that endothelial cells can respond to external stimuli by releasing an endothelium-derived relaxing factor,1 now identified as nitric oxide (NO)2 or a closely related compound,3 provided impetus for studies on shear-induced responses of blood vessels. Subsequently, an increase in intraluminal flow was found to induce relaxation of vessels in a wide variety of vascular beds.4 5
In the brain, flow-induced dilation has been demonstrated at the arterial level.6 7 8 Whether cerebral arterioles also possess flow sensitivity is unknown. Such flow sensitivity, however, has important functional implications. Because increased functional activity in the brain is accompanied by a local increase in parenchymal blood flow,9 10 subsequent flow-mediated dilation of upstream penetrating arterioles as well as pial arterioles may facilitate tissue blood flow by restoring downstream perfusion pressure.11 Flow-induced dilation is also potentially important in establishing collateral flow when there is local occlusion, for example, by microvascular embolism.
In various arteries12 13 and arterioles,14 15 flow-induced dilation required the integrity of the endothelium. Cultured bovine aortic endothelial cells released a nitrovasodilator identified as NO in response to shear stress stimuli.16 17 L-Arginine analogues, which competitively inhibit NO synthase (NOS), the enzyme that catalyzes the formation of NO from L-arginine,18 blunted the flow-induced response.19 20 21 Furthermore, the inhibition was reversed by L-arginine, thus implicating NO as the mediator of flow-induced dilation. In rat cremaster muscle arterioles, however, indomethacin but not arginine analogues abolished flow-induced dilator responses,15 22 suggesting that prostaglandins may be a mediator of flow-induced dilation in some tissues.
In addition to shear stress, changes in intravascular pressure may also modulate vascular tone. Blood vessels react to an increase or decrease in transmural pressure by constriction and dilation, respectively.23 This ability to respond to pressure was originally proposed by Bayliss24 to reside in vascular smooth muscle cells and was therefore termed a myogenic response. Myogenic responses have been well documented in both arteries25 26 and arterioles27 28 29 of the cerebral circulation.
In the present study, we determined the effects of increases in flow velocity on intracerebral arterioles with an in vitro method that allowed flow-induced changes in vessel diameter to be evaluated while holding constant other variables, such as pressure and metabolism. For comparison, we also investigated the responses of intracerebral arteries to changes in intraluminal pressure. In addition, we explored the mechanism of flow-induced dilation by testing for the possible involvement of both NO and prostaglandins.
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Vessel Isolation and Cannulation
A total of 32 male Sprague-Dawley rats, weighing between 350 and 400 g, were anesthetized with pentobarbital (50 mg/kg IP) and decapitated. The brain was rapidly removed from the skull, immersed in buffered saline solution containing 1% dialyzed bovine serum albumin, and cooled to 4°C. A piece of cerebral cortex
2 mm thick containing the first portion of the middle
cerebral artery was dissected from the brain. The pia mater and its
attached penetrating intracerebral arterioles were then
separated from the parenchyma, and a segment of an
intracerebral arteriole 0.5 to 1 mm in length was
severed from the pia and transferred to a temperature-controlled
vessel chamber (1-mL volume) mounted on the stage of an inverted
microscope.
The isolated vessel was cannulated at both ends by using a system of
concentric glass pipettes consisting of a perfusion pipette within a
holding pipette, as described previously.30 31 The
pipettes were shaped with a microforge (Stoelting Co) according to a
design that minimized flow resistance.32 The holding
pipette was narrowed near its tip to form a constriction 40 to 45 µm
wide, whereas the perfusion pipette was tapered to a tip of 25- to
30-µm diameter. The downstream end of the vessel was connected to a
manometer used to set intraluminal pressure via an outflow reservoir
(Fig 1
). The upstream end was connected to a
microinfusion pump for intraluminal fluid perfusion. A fluid reservoir
pressurized by the manometer could be inserted into the fluid path
between the vessel and the pump by means of a three-way liquid
switch. Upstream pressure was monitored with a pressure transducer. The
cannulated vessel was observed on a video monitor via a video camera,
and lumen diameter was measured with a video dimension
analyzer.
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Fluid resistance in the perfusion apparatus resided for the
most part in the perfusion pipette, which was fabricated from glass
tubes of 1.0-mm internal diameter. The rest of the system consisted
mainly of PE-50 tubing (internal diameter, 58 mm) that was considerably
larger in diameter. We measured the back pressure generated by flow in
either the upstream or downstream apparatus by connecting
the perfusion pump to each side separately (at points A and B in Fig 1
)
and found it to critically depend on pipette tip diameter. Thus, the
balance of upstream and downstream resistances could be primarily
achieved by using perfusion pipettes of similar tip diameter and shape
and secondarily fine-tuned by matching the lengths of the PE-50
tubing. With such a procedure, the pressure heads generated by a flow
rate of 10 µL/min at either upstream (point A, Fig 1) or downstream
(point B) sites did not differ by >2 mm Hg between each of five pairs
of matched pipettes. With a vessel in place in such a "matched
resistance" system, the increase in upstream pressure generated by
flow could be countered by an equal reduction of downstream pressure,
such that intravascular pressure at the middle of the vessel remained
unchanged. Thus, independent control of flow and pressure could be
achieved. The rise in pressure gradient generated by increasing flow
rates was documented in 10 experiments. As shown in Fig 2, there was a linear increase of 2.5
mm Hg/µL · min-1, indicating steady
nonturbulent flow in the system up to 25 µL/min. However, the data do
reveal greater deviation from linearity at the higher flow rates.
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After cannulation, intraluminal pressure was set at 60 mm Hg. Before
tone development, "passive" vessel diameter was measured.
Treatment with a supramaximal concentration of a potent vasodilator (1
mmol/L sodium nitroprusside) at the end of five experiments verified
that passive diameter indeed represented the maximally
dilated state. The bath solution was next changed to one without
albumin, and bath temperature was raised to 37°C. The vessel
was perfused at a rate of 2 µL/min. After an equilibration period of
40 minutes, during which time the bath solution was changed once
every 5 to 10 minutes, viable arterioles developed vasomotion and
spontaneously contracted. Control diameter was measured after the
development of steady tone. Reactivity of the vessels was assessed by
changing the extraluminal pH from 7.3 to 6.8 and from 7.3 to 7.6.
Vessels with weak pH response (<15% dilation or constriction) were
excluded from data collection. In addition, responses to
endothelium-dependent (acetylcholine) and
-independent (adenosine) vasoactive agents were evaluated.
Because extraluminal acetylcholine had little effect on
intracerebral arterioles,31 33
acetylcholine was applied by intraluminal infusion, whereas
adenosine was applied extraluminally.31 The time
course of tone development was also found to be an important indicator
of vascular viability. Only vessels that displayed contractions within
5 minutes after the onset of bath warming generated satisfactory tone
and responsiveness to vasoactive agents such as H+ ion,
adenosine, and acetylcholine.
Acetylcholine was dissolved in buffered saline containing 1% albumin for intraluminal perfusion. Before the start of each solution change, the upstream end of the vessel was opened to the pressurized fluid reservoir, which offers less flow resistance than the cannulated arteriole. Rapid solution change could thus be accomplished at a high flow rate (30 µL/min for 5 minutes) with minimal (<5 mm Hg) increase in upstream pressure. Since the perfusate conduits occupied a volume of 20 µL, total replacement could be achieved within 5 minutes. Flow to the reservoir was then switched off, and the vessel was perfused with the new solution at 2 µL/min for 5 to 10 minutes until a steady vessel diameter was measured.
Protocols
After the development of spontaneous tone at 60 mm Hg, the
relation between pressure and vessel diameter was studied under
zero-flow conditions. Pressure was initially decreased to 20 mm Hg
and then raised in 20-mm Hg steps from 20 to 100 mm Hg. This pressure
range corresponds to the autoregulatory range of similarly sized pial
arterioles in vivo.34 At each step, vessel diameter was
monitored for 5 minutes to determine steady state diameter. Pressure
was then reset to 60 mm Hg, and preheated saline (pH 7.3) containing
1% albumin was infused into the vessel by means of the
infusion pump. The relation between flow rate and vessel diameter was
determined by increasing flow from 0 to 25 µL/min in 5-µL/min
increments. Each step increase in flow rate led to a rise in upstream
pressure, and downstream pressure was adjusted (within 20 seconds) so
that upstream and downstream pressure changed by an equal and opposite
magnitude, thus maintaining intravascular pressure constant at 60
mm Hg. The vessel was allowed to adjust to the new flow rate for 10
minutes, and steady state diameter was measured.
Pharmacological Treatments
To test the involvement of NO in the pressure and flow response
of intracerebral arterioles, the above procedures were
repeated in the presence of the NOS inhibitor
NG-monomethyl-L-arginine
(L-NMMA). Vessels were treated with L-NMMA (0.1 mmol/L) for 30 minutes
until a new steady state diameter was reached. This was followed by
reassessment of the pressure- and flow-diameter relations. When
response alteration by L-NMMA was observed, L-NMMA was replaced by
L-arginine (1 mmol/L), and the protocol was repeated in an
effort to reverse the effects of L-NMMA.
Because cyclooxygenase reaction products such as prostaglandins have been implicated as a mediator of flow-mediated dilation, flow-diameter relations were also determined in the present study before and after vessel treatment with indomethacin (10 µmol/L).
In a separate series of experiments, the efficacy and specificity of NO blockade by L-NMMA was evaluated by determining the response of intracerebral arterioles to acetylcholine (1 µmol/L), adenosine (1 µmol/L), and H+ ion (pH 6.8) before and after L-NMMA (0.1 mmol/L) treatment. Acetylcholine was applied by intraluminal perfusion, whereas adenosine and pH 6.8 solutions were applied extraluminally.
Drugs and Solutions
The composition of the buffered saline solution is as follows
(mmol/L): NaCl 144.0, KCl 3.0, CaCl2 2.5, MgSO4
1.5, glucose 5.0, pyruvate 2.0, EDTA 0.02, MOPS 2.0, and
NaH2PO4 1.2. L-NMMA, sodium nitroprusside, and
adenosine were dissolved directly into this buffered solution.
Indomethacin was dissolved in a 0.1 mol/L
NaHCO3/ethanol mixture (3:1 [vol/vol]) to
produce a concentration of 1 mmol/L. L-Arginine was made up
in saline to yield a stock concentration of 10 mmol/L. Subsequent
dilutions were made with buffered saline, and pH was adjusted to 7.3.
Intraluminally applied saline solutions contained 1% bovine
albumin. All drugs were obtained from Sigma Chemical Co.
Data Analysis
All data are expressed as mean±SEM. Only one vessel was studied
from each animal. For comparison of responses to vasoactive agents,
internal vessel diameters were normalized as percentage of control
diameters (steady state diameters measured before treatment at 60
mm Hg intraluminal pressure and 37°C). Statistical analyses
were performed with SYSTAT software (SYSTAT Inc).
One-way ANOVA with repeated measures was used to determine if
responses to pressure or flow were statistically significant.
Comparisons of vascular diameters and responses between two groups (eg,
control and L-NMMA–treated groups) were made by performing
repeated-measures ANOVA on the paired differences between the two
groups. Differences in the responses to pressure or flow between two
groups were determined with the F test. Differences in diameters
between two groups were determined by testing whether the sum of the
differences in diameters was significantly different from zero. Mean
values were compared using paired Student's t tests. The
Bonferroni correction was applied when there were multiple groups. A
value of P<.05 was considered significant.
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Results |
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Isolated intracerebral arterioles (n=32) developed myogenic tone at 37°C and 60 mm Hg and constricted to 55% to 70% (mean, 65.8±1.0%) of their passive diameters. Vessel diameter after spontaneous tone development at 37°C ranged from 38 to 55 µm. As shown in the Table
, these vessels were responsive to
vasoactive stimuli including pH, adenosine, and acetylcholine.
As is characteristic of cerebral vessels, intracerebral
arterioles exhibited marked sensitivity to pH changes. Constriction was
observed when extraluminal pH was raised from 7.3 to 7.6, and dilation
ensued when pH was lowered to 6.8. In contrast, intraluminal infusion
of pH 6.8 buffer (n=5) had no significant dilator effect (data not
shown).
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Effects of Pressure and Flow on Arteriolar Diameter
The steady state response of intracerebral
arterioles (n=8) to stepwise increases in intraluminal pressure under
zero-flow conditions is shown in Fig 3. Changes in
diameter were overall statistically significant (P<.01,
ANOVA). In response to a step increase in pressure from 20 to 40
mm Hg, the vessels constricted by 16% and in most cases required 1 to
2 minutes to attain steady state diameter. The next step increase in
pressure (from 40 to 60 mm Hg) induced a smaller constrictor response
(5%). Further increase in pressure did not enhance tone but instead
led to a progressive increase in vessel diameter. Elevating pressure to
or beyond 100 mm Hg in a few experiments resulted in failure to regain
control diameter, probably because of irreversible damage caused by
forced distension.
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The steady state response to flow increase at constant intravascular
pressure was examined in an additional four vessels (total n=12). After
each step increase in flow rate, pressure was adjusted to maintain a
constant intravascular pressure of 60 mm Hg. As shown in Fig 3, the
flow-induced response also exhibited a biphasic profile.
Vasodilation was observed at the slower flow rates of 5 and 10
µL/min. The diameter increases of 4.9±1.6% at 5 µL/min and
14.5±2.2% at 10 µL/min were statistically significant. Further
increase in flow did not cause diameter increase but instead led to a
progressive decrease in vessel diameter. ANOVA indicated significant
differences in diameter overall (P<.01).
Effects of L-NMMA and Indomethacin on Pressure and
Flow-Induced Response
In control conditions (no flow, 60 mm Hg intravascular pressure),
intracerebral arterioles (n=12) constricted by an
average of 15.4±1.7% after incubation in L-NMMA. However, L-NMMA did
not appear to affect the pressure-diameter relation (n=5, Fig 4). There was no significant difference between
pressure-induced responses before and after L-NMMA treatment, as
indicated by ANOVA of the paired differences between control and
L-NMMA–treated groups. The pressure-induced response, calculated
as the percent reduction in vessel diameter from 20 to 60 mm Hg
intravascular pressure, was not significantly affected by L-NMMA
(20±2% before L-NMMA versus 22±1% after L-NMMA application). Thus,
NO inhibition did not appear to influence the response of
intracerebral arterioles to pressure.
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Significant difference in diameters between control and
L-NMMA–treated groups (P<.01). L-NMMA did not
significantly alter pressure-induced responses.
On the other hand, application of L-NMMA completely abolished
(P<.05 versus control) the dilator response (14.9±3.1% at
10 µL/min) of arterioles (n=7) to flow increase (Fig 5). Application of L-arginine caused the
vessels to regain control diameter within 5 minutes and appeared to
induce a slight dilation (5.6±4.6% increase of control diameter),
although the diameter change was not statistically significant.
L-Arginine restored the ability of the vessels
(P<.05 versus control) to dilate in response to flow
(11.4±1.6% at 10 µL/min). There was no difference between the
flow-diameter relations in the control condition and after
L-arginine treatment.
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In a separate series of experiments (n=5), the effect of flow increase
on vessel diameter was evaluated before and after inhibition of
prostaglandin synthesis by indomethacin
(Fig 6). Indomethacin alone led to
13.6±3.7% constriction of intracerebral arterioles in
the absence of flow but did not affect flow-induced dilation. In
untreated vessels, flow increase caused a peak dilation of 13.4±2.0%,
whereas peak dilator response was 12.2±1.9% after
indomethacin treatment. These results suggested that
prostaglandins did not mediate flow-induced dilation of
intracerebral arterioles. Furthermore, because both
indomethacin and L-NMMA constricted
intracerebral arterioles to a similar extent, these
experiments provided evidence that the inhibition of flow-induced
dilation by L-NMMA could not be attributed to an increase in vascular
tone.
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Pharmacological Blockade by L-NMMA
As shown in Fig 7, intraluminal acetylcholine (1
µmol/L) dilated intracerebral arterioles
significantly by 14.7±2.2%. L-NMMA abolished this response. In
contrast, the more potent dilator effects of adenosine (1
µmol/L) and reduced pH (6.8) were not significantly affected by
L-NMMA.
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The present study provided the first description of the response profile of brain arterioles to increases in intraluminal flow. Infusion of buffered saline elicited flow rate–dependent dilation. The peak dilation of 15% was observed at a flow rate of 10 µL/min. However, faster flow rates did not evoke further relaxation but instead led to the restoration of resting diameter. The latter response is unlikely to be mediated by a pressure-sensitive myogenic mechanism, because luminal pressure was maintained constant at 60 mm Hg. On the other hand, blockade of the flow-induced response by the NOS inhibitor L-NMMA suggested that an arginine metabolite, such as NO, may mediate flow-induced dilation in cerebral parenchymal arterioles.
Methodology and Vascular Reactivity
A major concern in studies involving isolated arterioles is
whether the vessels might have incurred injury during the isolation and
cannulation procedure. Another potential problem is that isolated
arterioles removed from their normal environment may lose
responsiveness to vasoactive stimuli. Therefore, it is of paramount
importance to establish the viability of isolated arterioles and to
ensure that their physiological responsiveness was
not compromised by the in vitro methodology.
Previous studies have established several criteria19 30
for arteriolar reactivity in vitro. These requirements are development
of spontaneous myogenic tone at 37°C, vasomotion (rhythmic activity),
and responsiveness to vasoactive agents. Intracerebral
arterioles in the present study fulfilled such criteria. These
vessels spontaneously constricted to 55% to 70% of their passive
diameter as the bathing medium was warmed to 37°C. As shown in Fig 3,
these vessels exhibited marked myogenic responses within the
intravascular pressure range of 20 to 60 mm Hg, relaxing when pressure
was lowered and constricting when pressure was raised. Furthermore,
rhythmic contractions were consistently observed during tone
development and persisted throughout the experiment. The degree of tone
generation in vessels in the present study matched that achieved in
previous studies.28 29 33
We assessed the responsivity of intracerebral
arterioles to three vasoactive agents: pH, acetylcholine, and
adenosine. The in vivo responses of pial arterioles to changes
in perivascular pH have previously been examined in
cats.35 Superfusion of pH 6.8 cerebrospinal fluid induced
a dilation of 18%, whereas pH 8 led to 15% constriction. Responses of
intracerebral arterioles to similar pH values in the
present study exceeded (Table) the pH reactivity of pial arterioles
in vivo. The high pH responsivity of rat parenchymal arterioles agreed
with values from previous work28 29 33 using a similar rat
preparation and may therefore be characteristic of
intracerebral arterioles in the rat. The response of
rat pial arterioles superfused in situ with 1 µmol/L
adenosine was between 17% and 21%.36 37 These in
vivo responses were also lower than the 26% dilation obtained in the
present study, but the difference may be attributed to the lack of
parenchymal uptake and metabolism of adenosine in
isolated vessels. In contrast to both adenosine and pH
responses, isolated intracerebral arterioles were
relatively unresponsive to extraluminally applied acetylcholine.
However, intraluminal acetylcholine in the present study induced
12% dilation, which is comparable to the in vivo dilator effect of
acetylcholine observed in rat pial arterioles.38 39
In the present study, intracerebral arteriole
segments were cannulated and sealed from the external medium so that
the vessel lumen could be pressurized and perfused. This method allowed
the independent control of pressure and flow. The dissociation of
pressure changes from flow stimuli was important because of the marked
pressure-induced myogenic responses observed in the present
study that may confound interpretation of the response to flow alone. A
limitation of the present study is that intraluminal pressure was
not directly measured. Inasmuch as upstream and downstream resistances
were matched, it was assumed that pressure in the middle portion of the
arteriole remained fixed at 60 mm Hg despite an increase in flow, by
balancing the increase in upstream pressure with an equal decrease in
downstream pressure. Nevertheless, local variations in pressure may
occur, for instance, when there is regional turbulence, which may also
cause rapid fluctuations in wall shear rate. Two observations suggest
that intravascular pressure remained steady during high flow rates.
First, the diameters of three passive, maximally dilated arterioles
were measured during perfusion at rates of up to 20 µL/min while
midpoint pressure was maintained at 40 mm Hg (which was chosen because
the passive arteriole was relatively compliant at this pressure). No
change in vessel diameter was observed, indicating a lack of change in
intravascular pressure. Second, as shown in Fig 2, perfusion pressure
increased linearly up to a flow rate of 25 µL/min, suggesting that
flow conditions in the arterioles remained laminar even at the higher
flow rates.
Flow-Induced Response
Flow-induced responses have been investigated in both arteries
and arterioles.4 5 Although in most studies the response
was dilation, flow-induced constriction has also been
observed.40 41 In the present study, the response of
intracerebral arterioles to increasing flow rate was
biphasic. At lower flow rates, the response was dilation, whereas at
higher flow rates (>10 µL/min) the vessels progressively restored
their resting (no-flow) diameter. There is precedent for such a
biphasic response, however, as Hoogerwerf et al40 had
described a similar response profile to increases in flow in rabbit
femoral arteries, which displayed an initial marked dilation, followed
by constriction toward initial diameter at progressively higher flow
rates.
With regard to the cerebral circulation, Garcia-Roldan and Bevan6 reported that both constrictor and dilator responses can be evoked by a flow stimulus (20 µL/min) in cannulated pial arteries (>200-µm diameter) from the rabbit. The direction of the response appeared to be pressure dependent. When intraluminal pressure was high (90 mm Hg), flow-induced constriction was observed, but when pressure was low (30 mm Hg), the response to the same rate of flow was dilation. Subsequently, Gaw and Bevan8 showed that middle cerebral artery segments (200- to 250-µm diameter) from the rabbit relaxed in response to an increase in intraluminal flow rate. In an in vivo study in the rat, Fujii et al7 observed by means of a cranial window the response of the basilar artery to occlusion of the common carotid artery. During occlusion, an increase in flow velocity was followed by dilation of the basilar artery.
The present study extended the above observations to the arteriolar level. The maximal dilation of intracerebral arterioles, elicited by an increase in flow rate from zero to 15 µL/min, was 15%. For comparison, isolated rabbit pial arteries exhibited an 8% dilation at a flow rate of 20 µL/min,6 whereas rat basilar arteries in vivo dilated by as much as 29% in response to a 203% increase in flow velocity.7 No data on flow-induced dilation are available for comparison in cerebral arterioles. However, arterioles from other vascular beds exhibited greater flow sensitivity. For example, flow induced a maximal 29% increase in the diameter of pig coronary arterioles19 and a 46% dilation in rat cremaster muscle arterioles.15
In arteries and arterioles from a wide variety of vascular beds, flow-induced dilation requires an intact endothelium and probably involves NO release by the endothelium.4 18 In the present study, the dilator responses of intracerebral arterioles to increases in intraluminal flow rate were inhibited by L-NMMA. Moreover, these vessels recovered their ability to dilate after treatment with the NOS substrate L-arginine. The present results therefore suggest that an arginine metabolite, such as NO, is the mediator of flow-mediated dilation in cerebral arterioles. Previous studies on the mechanism of flow-induced dilation in the cerebral vasculature, however, have yielded disparate results. Gaw and Bevan8 showed that NOS inhibitors attenuated, but did not abolish, the relaxation response of rabbit middle cerebral artery segments to an increase in intraluminal flow. Furthermore, neither aspirin nor indomethacin affected the relaxation response. In contrast, Fujii et al7 showed that shear-induced dilation of the basilar artery was unaffected by a host of pharmacological agents, including indomethacin and L-NMMA. Although the lack of effect of indomethacin on the flow-induced dilator response of cerebral arterioles in the present study is consistent with the above findings, the observation that L-NMMA completely abolished the dilator response is not. This discrepancy may be related to differences in vessel size or location (intraparenchymal versus extraparenchymal) or to differences in experimental procedures. The present study used a cannulated and pressurized preparation, which is considered to be more physiological than the isometric vessel ring technique used by Gaw and Bevan. The study of Fujii et al, on the other hand, was conducted in vivo. In such a preparation, it is often difficult to completely rule out the participation of other mechanisms of vascular communication, such as neurogenic or propagated dilator responses.42
The mechanism underlying the biphasic flow response, ie, the decrease in diameter at high (>10 µL/min) flow rates, is unknown. Such a response may represent a homeostatic mechanism that acts to prevent harmful rises in capillary perfusion pressure resulting from large flow increases. Because intraluminal pressure was maintained constant at 60 mm Hg, the constriction observed after the vessel had reached its maximally dilated state was unlikely to be a myogenic response. On the other hand, the possibility that flow-induced constriction may contribute to this response should be considered. Bevan and Joyce41 suggested that flow-induced changes in vascular tone may represent the net result of competition between flow-dependent constrictor and dilator responses. One may therefore speculate that flow-induced constriction may dominate over dilation at higher flow rates. In support of this hypothesis is the observation by Kuo et al43 that pig coronary venules constricted slightly (2% to 4%) at high flow rates. In the same study, venules responded to flow by constriction after endothelium denudation, suggesting that smooth muscle cells may contract in response to shear stress and that this flow-induced constriction could be unmasked by removing the dilator effect of endothelial cells. In the present study, however, NO blockade by L-NMMA abolished the dilator response but did not result in net constriction. This observation therefore suggests that intracerebral arterioles did not constrict in response to flow stimuli or that the blockade of flow-mediated dilation was incomplete, either because of incomplete NOS inhibition or because of the existence of an NO-independent mechanism of flow-induced dilation.
Little is known about the normal in vivo range of blood flow rates in
cerebral arterioles. Such information, however, may impart functional
significance to the flow-response curve (Fig 3) of
intracerebral arterioles in the present study. Flow
rate in a cerebral arteriole may be estimated, assuming a circular
vascular profile, with the following formula:
Q=
D2
/4, where Q is flow rate, is mean
velocity, and D is vessel diameter. In a preliminary
study44 we have measured red blood cell velocity in pial
arterioles in the rat with the dual-slit technique.45
The average control centerline velocity (equal to 1.6 times ) of
pial arterioles (mean diameter, 44 µm) similar in size to
intracerebral arterioles in the present study is
18.5 mm/s. This value is compatible with data provided by Ma et
al46 in the rat (21.0±2.3 mm/s in 49.3±1.5-µm pial
arterioles). Calculation with the above equation yields a
"resting" flow rate of 1 µL/min. Taking viscosity of blood
(2 cp in rat arterioles)47 as three times that of
saline (0.7 cp at 37°C), blood flow at 1 µL/min would produce a
level of wall shear stress (40 dyne/cm2) in
intracerebral arterioles similar to that produced by
saline flow of 3 µL/min in the present in vitro system. Thus, our
diameter-flow data (Fig 3) indicate that
intracerebral arterioles under resting conditions in
vivo are capable of significant dilation in response to an increase in
intraluminal flow rate. On the other hand, cerebral arterioles during
normal functional activity are unlikely to be exposed to the high shear
forces caused by saline flow of >10 µL/min. Such a pronounced
increase in flow rate, however, may occur in extreme conditions of
enhanced activity, such as during seizures.48
Pressure-Induced Responses
The in vitro responses of brain parenchymal arterioles to changes
in intravascular pressure have been examined in two previous studies in
the rat. Dacey and Duling28 found that arterioles of
19-µm diameter constricted by 8% as pressure was raised from 20 to
60 mm Hg, whereas in larger (44-µm) arterioles Takayasu and
Dacey29 found a 12% increase in diameter as pressure was
lowered from 60 to 20 mm Hg. In the present study, the same change
in pressure resulted in a 21% change in diameter. The greater myogenic
response observed in the present study may be attributed to the
extra care taken to preserve vessel viability and responsivity in the
present experiment. A comparison with the two studies mentioned
above revealed that arterioles in the present study exhibited a
greater response to pH and other vasoactive agents.
On the other hand, it is difficult to assess the effect of transmural
pressure per se on cerebral vessels in vivo, because a reduction in
blood pressure may have metabolic consequences. Bohlen and
Harper27 used a method that allowed them to raise
transmural pressure without affecting perfusion pressure. They placed
craniotomized rats in a sealed box with only the head exposed to
atmospheric pressure. Changing the pressure in the box altered both
arterial and venous pressure by equal amounts, thus
maintaining constant perfusion pressure in the cerebral arterioles.
Since the pial arterioles were exposed to atmospheric pressure, such
maneuvers changed the transmural pressure in these vessels. With such a
technique, Bohlen and Harper found that pial arterioles (30- to 60-µm
diameter) constricted by 16% when ambient pressure was reduced by 16
mm Hg from control (50 mm Hg) but dilated by 6% when pressure was
raised by 10 mm Hg. Their data also showed a 22% change in diameter
when transmural pressure was changed from 60 to 40 mm Hg. These
changes are comparable to those observed in the present in vitro
study.
Ever since the first description of the myogenic response by Bayliss,24 the site of mechanoreception in the vessel wall to pressure has been attributed to the vascular smooth muscle.23 More recently, however, there is dispute as to whether the endothelium may act as the sensor in contractile responses to pressure.49 Furthermore, transmural pressure inhibited NO release from human endothelial cells,50 suggesting that endothelium-derived NO may take part in pressure-induced constriction. If NO is involved in the myogenic response of intracerebral arterioles to pressure, then inhibition of NO formation by arginine analogues should attenuate the constrictor response to pressure. In the present study, however, neither the response profile nor the degree of constriction to stepwise increases in intraluminal pressure was altered after treatment with L-NMMA (0.1 mmol/L), which completely abolished the dilator response to acetylcholine. The present study thus suggested that NO was not involved in pressure-induced responses of intracerebral arterioles.
Action of L-NMMA
NOS immunoreactivity has been localized in the
endothelium but not in the smooth muscle of rat
cerebral arteries,51 and a constitutive form of NOS in
cerebral endothelium has been cloned and
characterized.52 Local or systemic application of arginine
analogues caused constriction of cerebral vessels,53
suggesting that NO may be chronically released in cerebral vessels.
Consistent with these findings, the present experiment
demonstrated that intracerebral arterioles were
remarkably sensitive to L-NMMA inhibition, constricting by 15% even
under no-flow conditions.
In the brain, both selective destruction of the endothelium and arginine analogues abolished the relaxation of arteries and arterioles in response to acetylcholine.53 Consistent with these data, L-NMMA completely inhibited acetylcholine-induced dilation of intracerebral arterioles in the present study. In contrast, the action of adenosine, an endothelium-independent dilator of cerebral vessels,54 was not altered by L-NMMA. This lack of effect of L-NMMA on adenosine-induced dilation of intracerebral arterioles is consonant with findings in cat pial arterioles in vivo.55 L-NMMA also had no effect on the dilator response of intracerebral arterioles to pH 6.8 buffer, suggesting that NO is not involved in the dilator response of cerebral arterioles to hydrogen ion. This observation is consistent with a recent finding in isolated rat cerebral arteries56 but is at variance with the in vivo finding that NOS inhibition markedly attenuated the increase in cortical blood flow elicited by extracellular acidosis in the rat.57
Summary
Rat penetrating arterioles were perfused while maintaining
intravascular pressure constant. Increasing flow rates elicited a
biphasic response. At flow rates up to 10 µL/min, progressive
dilation (up to 15% of control diameter) was observed. At higher flow
rates, the vessels did not dilate further but instead constricted until
resting diameter was restored at 20 µL/min. The vessels also
exhibited myogenic constriction from 20 to 60 mm Hg intravascular
pressure in the absence of flow. The dilator response to flow increase
was abolished by the NOS inhibitor L-NMMA but was
unaffected by indomethacin. These results thus suggest
that NO or a related L-arginine metabolite, but not
prostaglandin, mediates flow-induced dilation in rat
cerebral arterioles. On the other hand, NO was not involved in the
myogenic response of these arterioles to pressure changes.
|
Acknowledgments |
|---|
This study was supported by grants NS07144, NS21076, and NS30305 from the National Institutes of Health.
|
Footnotes |
|---|
Reprint requests to H. Richard Winn, MD, Department of Neurological Surgery, Box 359766, Harborview Medical Center, 325 Ninth Ave, Seattle, WA 98104.
Received February 2, 1995; accepted June 22, 1995.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res. 1983;53:557-573.
2. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327:524-526. [Medline] [Order article via Infotrieve]
3. Myers, PR, Minor RL Jr, Guerra R Jr, Bates JN, Harrison DG. Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrocysteine than nitric oxide. Nature. 1990;345:161-163. [Medline] [Order article via Infotrieve]
4.
Koo L, Davis MJ, Chilian WM.
Endothelial modulation of arteriolar
tone. News Physiol Sci. 1992;7:5-9.
5.
Smiesko V, Johnson PC. The arterial
lumen is controlled by flow-related shear stress.
News Physiol Sci. 1993;8:34-38.
6.
Garcia-Roldan J-L, Bevan JA. Flow-induced
constriction and dilation of cerebral resistance arteries.
Circ Res. 1990;66:1445-1448.
7.
Fujii K, Heistad DD, Faraci FM.
Flow-mediated dilation of the basilar artery in
vivo. Circ Res. 1991;69:697-705.
8.
Gaw AJ, Bevan JA. Flow-induced relaxation
of the rabbit middle cerebral artery is composed of both
endothelium-dependent and -independent
components. Stroke. 1993;24:105-110.
9. Sokoloff L. Relationship among local functional activity, energy metabolism and blood flow in the central nervous system. Fed Proc. 1981;40:2311-2316. [Medline] [Order article via Infotrieve]
10.
Ginsberg MD, Dietrich WD, Busto R. Coupled
forebrain increases of local cerebral glucose utilization and blood
flow during physiologic stimulation of a somatosensory pathway in the
rat: demonstration by double label
autoradiography. Neurology. 1987;37:11-19.
11.
Faraci FM, Heistad DD. Regulation of large
cerebral arteries and cerebral microvascular pressure.
Circ Res. 1990;66:8-17.
12. Hull SS Jr, Kaiser L, Jaffe MD, Sparks HV Jr. Endothelium-dependent flow-induced dilation of canine femoral and saphenous arteries. Blood Vessels. 1986;23:183-198. [Medline] [Order article via Infotrieve]
13. Smiesko V, Kozik J, Dolezel S. The control of the arterial diameter by blood flow velocity is dependent upon intact endothelium. Physiol Bohem. 1983;32:558. Abstract.
14.
Koller A, Kaley G. Endothelium
regulates skeletal muscle microcirculation by a blood flow
velocity-sensing mechanism. Am J Physiol. 1990;258:H916-H920.
15.
Koller A, Sun D, Kaley G. Role of shear stress
and endothelial prostaglandins in flow- and
viscosity-induced dilation of arterioles in vitro.
Circ Res. 1993;72:1276-1284.
16.
Cooke JP, Stamler JS, Andon N, Davies PR, Loscalzo J.
Flow stimulates endothelial cells to release a
nitrosovasodilator that is potentiated by reduced thiol.
Am J Physiol. 1990;259:H804-H812.
17.
Buga, GM, Gold ME, Fukuto JM, Ignarro LJ. Shear
stress-induced release of nitric oxide from
endothelial cells grown on beads.
Hypertension. 1991;17:187-193.
18. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109-141. [Medline] [Order article via Infotrieve]
19.
Kuo L, Davis MJ, Chilian WM.
Endothelium-dependent, flow-induced
dilation of isolated coronary arterioles. Am J
Physiol. 1990;259:H1063-H1070.
20. Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest. 1991;88:1663-1671.
21.
Pohl U, Herlan K, Huang A, Bassenge E.
EDRF-mediated shear-induced dilation opposes myogenic
vasoconstriction in small rabbit arteries. Am J
Physiol. 1991;261:H2016-H2023.
22.
Koller A, Kaley G. Prostaglandins
mediate arteriolar dilation to increased blood flow velocity in
skeletal muscle microcirculation. Circ
Res. 1990;67:529-534.
23. Johnson PC. The myogenic response. In: Bohr DF, Somlyo AP, Sparks HV Jr, eds. Handbook of Physiology, Section 2: The Cardiovascular System, Volume II: Vascular Smooth Muscle. Bethesda, Md: American Physiological Society; 1980:409-442.
24. Bayliss WM. On the local reaction of the arterial wall to changes of internal pressure. J Physiol (Lond). 1902;28:220-231.
25.
Vinall PE, Simeone FA. Cerebral autoregulation:
an in vitro study. Stroke. 1981;12:640-642.
26.
Olso G, Halpern W. Myogenic properties of
cerebral vessels from normotensive and hypertensive rats.
Am J Physiol. 1985;249:H914-H921.
27.
Bohlen HG, Harper SL. Evidence of myogenic
vascular control in the rat cerebral cortex.
Circ Res. 1984;55:554-559.
28. Dacey RG Jr, Duling BR. A study of rat intracerebral arterioles: methods, morphology, and reactivity. Am J Physiol. 1982;243:H598-H606.
29.
Takayasu M, Dacey RG Jr. Calcium dependence of
intracerebral arteriolar vasomotor tone and constrictor
responses in rats. Stroke. 1989;20:778-782.
30.
Duling BR, Gore RW, Dacey RG, Damon DN. Methods
for isolation, cannulation, and in vitro study of single
microvessels. Am J Physiol. 1981;241:H108-H116.
31.
Ngai AC, Winn HR. Effects of adenosine
and its analogues on isolated intracerebral arterioles:
extraluminal and intraluminal application. Circ
Res. 1993;73:448-457.
32.
Davis MJ, Gore RW. Length-tension
relationship of vascular smooth muscle in single arterioles.
Am J Physiol. 1989;256:H630-H640.
33.
Dacey, RG Jr, Bassett JE. Cholinergic
vasodilation of intracerebral arterioles.
Am J Physiol. 1987;253:H1253-H1260.
34.
Harper SL, Bohlen HG, Rubin MJ.
Arterial and microvascular contributions to cerebral
cortical autoregulation in rats. Am J Physiol. 1984;246:H17-H24.
35.
Kontos HA, Wei EP, Raper AJ, Patterson JL. Local
mechanism of CO2 action on cat pial arterioles.
Stroke. 1977;8:226-231.
36. Morii S, Ngai AC, Winn HR. Reactivity of rat pial arterioles and venules to adenosine and carbon dioxide: with detailed description of the closed cranial window technique in rats. J Cereb Blood Flow Metab. 1986;6:34-41. [Medline] [Order article via Infotrieve]
37. Ibayashi S, Ngai AC, Meno JR, Winn HR. Effects of topical adenosine analogs and forskolin on rat pial arterioles in vivo. J Cereb Blood Flow Metab. 1991;11:72-76.
38. Faraci FM. Role of endothelium-derived relaxing factor in cerebral circulation: large arteries vs microcirculation. Am J Physiol. 1991;261:H1033-H1042.
39. Ibayashi S, Ngai AC, Howard MA III, Meno JR, Mayberg MR, Winn HR. Lack of sympathetic and cholinergic influences on cerebral vasodilation caused by sciatic nerve stimulation in the rat. J Cereb Blood Flow Metab. 1991;11:678-683. [Medline] [Order article via Infotrieve]
40. Hoogerwerf N, Van Der Linden PJW, Sipkema P. Effects of oxygen and flow on the diameter of the femoral artery of the rabbit. Blood Vessels. 1989;26:360-367. [Medline] [Order article via Infotrieve]
41.
Bevan JA, Joyce EH. Saline infusion into lumen
of resistance artery and small vein causes contraction.
Am J Physiol. 1990;259:H23-H28.
42.
Segal SS, Duling BR. Conduction of vasomotor
responses in arterioles: a role for cell-to-cell
coupling? Am J Physiol. 1989;256:H838-H845.
43.
Kuo L, Arko F, Chilian WM, Davies MJ.
Coronary venular responses to flow and pressure.
Circ Res. 1993;72:607-615.
44. Ngai AC, Winn HR. Effects of somatosensory stimulation and hypercapnia on flow velocity and diameter of pial arterioles in rats. FASEB J. 1994;8:A867. Abstract.
45.
Wayland H, Johnson PC. Erythrocyte velocity
measurement in microvessels by a two-slit photometric
method. J Appl Physiol. 1967;22:333-337.
46. Ma YP, Koo A, Kwan HC, Cheng KK. On-line measurement of the dynamic velocity of erythrocytes in the cerebral microvessels in the rat. Microvasc Res. 1974;8:1-13. [Medline] [Order article via Infotrieve]
47.
Mayrovitz HN, Roy J. Microvascular blood flow:
evidence indicating a cubic dependence on arteriolar diameter.
Am J Physiol. 1983;245:H1031-H1038.
48.
Meldrum BS, Nilsson B. Cerebral blood flow and
metabolic rate early and late in prolonged seizures induced
in rats by bicuculline. Brain. 1976;99:523-542.
49.
Meininger GA, Davis MJ. Cellular mechanisms
involved in the vascular myogenic response. Am J
Physiol. 1992;263:H647-H659.
50. Hishikawa K, Nakaki T, Suzuki H, Saruta T, Kato R. Transmural pressure inhibits nitric oxide release from human endothelial cells. Eur J Pharmacol. 1992;215:329-331. [Medline] [Order article via Infotrieve]
51. Nozaki K, Moskowitz MA, Maynard KF, Koketsu N, Dawson TM, Bredt DS, Synder SH. Possible origin and distribution of immunoreactive nitric oxide synthase-containing nerve fibers in cerebral arteries. J Cereb Blood Flow Metab. 1993;13:70-79. [Medline] [Order article via Infotrieve]
52.
Lamas S, Marsden PA, Li GK, Tempst P, Michel T.
Endothelial nitric oxide synthase: molecular
cloning and characterization of a distinct constitutive enzyme
isoform. Proc Natl Acad Sci U S A. 1992;89:6348-6382.
53. Faraci FM, Brian JE. Nitric oxide and the cerebral circulation. Stroke. 1994;25:692-703. [Abstract]
54. Hardebo JE, Kahstrom J, Owman C. P1- and P2-purine receptors in brain circulation. Eur J Pharmacol. 1987;144:343-352. [Medline] [Order article via Infotrieve]
55.
Wei EP, Kukreja R, Kontos HA. Effects in cats of
inhibition of nitric oxide synthesis on cerebral vasodilation and
endothelium-derived relaxing factor from
acetylcholine. Stroke. 1992;23:1623-1629.
56.
Tian R, Vogel P, Lassen NA, Mulvany MJ, Andreasen F,
Aalkjær C. Role of extracellular and intracellular acidosis for
hypercapnia-induced inhibition of tension of isolated rat cerebral
arteries. Circ Res. 1995;76:269-275.
57. Niwa K, Lindauer U, Villringer A, Dirnagl U. Blockade of nitric oxide synthesis in rats strongly attenuates the CBF response to extracellular acidosis. J Cereb Blood Flow Metab. 1993;13:535-539.[Medline] [Order article via Infotrieve]
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