(Stroke. 2001;32:218.)
© 2001 American Heart Association, Inc.
Original Contributions |
Role of Potassium Channels in Regulation of Brain Arteriolar Tone
Comparison of Cerebrum Versus Brain Stem
From the Department of Neurosurgery, Washington University School of Medicine, St Louis, Mo.
Correspondence to Hans H. Dietrich, PhD, Department of Neurosurgery, Washington University School of Medicine, Box 8057, 660 S Euclid Ave, St Louis, MO 63110. E-mail dietrich_h{at}kids.wustl.edu
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Background and Purpose—Potassium channels are important regulators of resting tone in large cerebral arteries, but their activity and distribution may vary according to vessel location and species studied. In the cerebral microcirculation in vivo, however, these channels appear to be silent at rest. Our goal was to determine the activity of potassium channels of brain arterioles from 2 origins under basal conditions in vitro.
Methods—Penetrating cerebral (40.9±2.2 µm control diameter) and brain stem (36.2±1.2 µm) arterioles of rats were prepared from middle cerebral and basilar arteries, respectively. The internal diameter of cannulated and pressurized vessel was monitored with the inverted microscope before and after administration of potassium channel inhibitors. In addition, we studied the effect of nitric oxide synthase inhibition on potassium channel activity.
Results—Cerebral
and brain stem arterioles were significantly constricted by
4-aminopyridine and low concentration of
BaCl2 but not by glibenclamide. The addition of
N
-nitro-L-arginine
to 4-aminopyridine further decreased diameters of both
arterioles. Tetraethylammonium ion caused a
significant constriction of brain stem but not cerebral arteriole. The
brain stem arteriole was further constricted by additional
N-nitro-L-arginine.
Conclusions—Voltage-dependent and inward-rectifier, but not ATP-sensitive, potassium channels are active under basal conditions of rat cerebral and brain stem arterioles. There is a regional difference in the activity of calcium-activated potassium channels, which, at rest, are open in brain stem but silent in cerebral arterioles. In addition, basal endogenous nitric oxide may not contribute to the activation of voltage-dependent and calcium-activated potassium channels.
Key Words: arterioles • brain stem • microcirculation • potassium channels • rats
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The brain circulation is characterized by autoregulation of blood flow over wide ranges of perfusion pressure.1 2 Interestingly, effective autoregulation is more potent in the brain stem than in the cerebrum.3 4 5 The basal vascular tone is known to be responsible in part for this regional difference in autoregulation in the brain.3 4 In general, development of the tone involves pressure- and/or stretch-dependent (myogenic tone) mechanisms.1 6 7 This basal tone is influenced by many regulatory systems, including endothelium-derived relaxing factors such as nitric oxide (NO),8 9 endothelium-derived contracting factors such as prostaglandin H2,10 and smooth muscle potassium (K+) channels.11 12
Recently, vascular smooth muscle K+ channels have drawn attention as a regulator of basal tone in cerebral arteries. K+ channels play a major role in the regulation of both membrane potential and arterial diameter under resting conditions.11 12 13 14 15 16 17 Furthermore, changes in K+ channel activity after subarachnoid hemorrhage may contribute to vascular insufficiency.11 Cerebral vessels may express at least 4 different types of K+ channels, including ATP-sensitive K+ (KATP) channels, calcium-activated K+ (KCa) channels, voltage-dependent K+ (KV) channels, and inward rectifier K+ (KIR) channels.11 12 13 14 15 16 17 18 In vivo and vitro studies demonstrated that all types except KATP channels may be active under resting conditions in large cerebral arteries.13 14 15 16 17 19 In addition, it is interesting that basal NO may hyperpolarize vascular muscle through activation of K+ channels in cerebral vessels.20 21 Thus, basal NO regulates vascular tone not only via K+ channel–independent mechanisms but also via K+ channel–dependent mechanisms, most likely by activating KCa or KV channels.12 16 20 21 22 23 24
In the cerebral microcirculation, however, it has been reported that arteriolar K+ channels are present but are generally silent at resting states.11 12 These findings are based on in vivo studies reporting that K+ channel inhibitors did not affect the resting vessel diameter in pial arterioles in cranial window experiments.23 25 26 To our knowledge, there is no in vitro study concerning the basal activity of brain arteriolar K+ channels and comparing microvessels from different distributions, such as penetrating arterioles from the cerebrum and brain stem. Penetrating arterioles are important regulators of cerebral blood flow and may contribute as much as 23% of total arterial cerebrovascular resistance.27
The present study was therefore conducted to determine (1) the activity of K+ channels in isolated and pressurized brain arterioles under basal conditions in which the vessels had developed spontaneous tone, (2) regional differences between arterioles originating from cerebrum and brain stem, and (3) the role of basal NO in Kv and KCa channel activities.
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Materials and Methods |
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Studies were approved by the Washington University Advisory Committee for Animal Resources. Adult male Sprague-Dawley rats (n=39; weight, 350 to 450 g) were anesthetized with pentobarbital sodium (60 mg/kg IP) and killed. Brain was rapidly removed and placed in a cooled (4°C) dissection chamber filled with physiological salt solution (see below) containing 1% dialyzed bovine serum albumin. For this study we used 2 kinds of penetrating arterioles in the distribution of the upper basilar artery or the proximal middle cerebral artery. The techniques for dissection and cannulation of rat intracerebral arterioles were previously reported in detail.8 28 Cerebral and brain stem arterioles were prepared in the same manner. Briefly, a rectangular section of brain with its overlying pia and artery (basilar or middle cerebral artery) was removed from the lateral cerebral hemispheric surface or the ventral portion of the midbrain and upper pons. The pial membrane was then reflected gently from the brain surface. Arterioles originating in the middle cerebral artery and the basilar artery are usually supplied from the internal carotid artery (anterior circulation) and vertebral artery (posterior circulation), respectively.29 These brain stem arterioles supply the midbrain and upper pons. The isolated arteriole was carefully transferred from the dissection chamber to a temperature-controlled cannulation chamber (volume, 2.5 mL) mounted on a stage of an inverted microscope. The unbranched penetrating arteriole was cannulated at one end with a perfusion pipette. The opposite end of the arteriole was occluded by the collecting pipette. All experiments were performed without intraluminal flow.
We applied 60 mm Hg as the transmural pressure to both arterioles after cannulation. There is a regional difference of pial arteriolar pressure between anterior and posterior circulations.3 30 Penetrating arterioles represent the last smooth muscle vessels before the blood is distributed into the capillary bed. As such, they maintain the capillary pressure constant under physiological conditions.3 Thus, the terminal pressure of rat brain arterioles was estimated to be in the order of 60 mm Hg.31
To measure the internal vessel diameter, we used both a calibrated video-dimensional analyzer (modified model 321, Colorado Video) and a computerized diameter tracking system (video resolution 320x200 pixels with 256 shades of gray; Diamtrak, Montech Pty Ltd). The extraluminal solution was then warmed from room temperature to 37.5°C, and the organ bath was continuously perfused at a rate of 0.5 mL/min with a peristaltic pump (model 203, Scientific Industries, Inc). Over approximately 45 minutes, spontaneous vessel tone developed, and control diameter was measured. Vessels with poor tone (<20% decrease from the maximum diameter) were discarded for further studies. Before the experiment, vessel responsiveness was evaluated and compared by rapidly changing the pH of the extraluminal solution from 7.3 to 6.8 and from 7.3 to 7.65. Vessels with poor response (<15% diameter change) were discarded at this point.
The composition of the
physiological salt solution (in mmol/L) was as
follows: 144 NaCl, 3 KCl, 2.5 CaCl2, 1.4
MgSO4, 2.0 pyruvate, 5.0 glucose, 0.02
ethylenediaminetetraacetic acid, 2.0
3-(N-morpholino)propanesulfonic
acid (MOPS), and 1.21
NaH2PO4. Solutions used
for dissection and cannulation contained 1% bovine serum
albumin. The following drugs were purchased:
tetraethylammonium ion (TEA),
glibenclamide, 4-aminopyridine (4-AP),
BaCl2,
N-nitro-L-arginine
(L-NNA), and pinacidil (Sigma).
To test the activity of various K+ channels in isolated brain arterioles under basal conditions, we applied 4 K+ channel inhibitors: TEA (a specific inhibitor of KCa channel), glibenclamide (a specific inhibitor of KATP channel), 4-AP (a specific inhibitor of KV channel), and low concentration of BaCl2 (a specific inhibitor of KIR channel). Some of the TEA- or 4-AP–treated arterioles were additionally treated with 10 µmol/L L-NNA (a NO synthase inhibitor). We also examined the effect of L-NNA followed by additional TEA or 4-AP.
In a separate series of experiments, we tested pinacidil (a KATP channel opener) to determine whether KATP channels were present in the brain stem arteriole. To activate KIR channels in these vessels, we also elevated extracellular K+ concentration ([K+]o) from 3 to 8 mmol/L. Isotonic K+ MOPS-buffered saline was prepared by substituting NaCl with an equimolar amount of KCl.
Each value represents the mean±SEM. One or 2 arterioles were studied from each animal. Single comparisons were made with Student’s paired or unpaired t test, as appropriate. For comparison of the various treatments, results were compared by ANOVA, followed by the Student-Newman-Keuls test. Values of P<0.05 were considered statistically significant.
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Results |
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All vessels developed spontaneous tone and responded to pH challenge (summarized in the Table
).
There were no significant differences in passive diameter, spontaneous
tone, dilation to acidosis, and constriction to alkalosis between
cerebral and brain stem arterioles.
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Effect of KCa Channel
Inhibitor
TEA did not cause a significant change in diameter of
cerebral arteriole (96.1±2.3% of the control diameter) (n=5;
Figure 1). On the other hand, TEA (1 and 3 mmol/L)
significantly constricted the brain stem arteriole (83.1±2.5% and
74.4±2.4% of the control diameter, respectively) (n=5;
Figure 1). TEA-induced constriction of brain stem arteriole
started within 5 minutes and reached a stable maximum approximately 15
minutes after the solution was changed. Additional treatment with L-NNA
(10 µmol/L) further decreased the diameter of brain stem arteriole
(79.0±3.8% of the 3 mmol/L TEA–treated diameter). Since TEA
showed no effect on cerebral arterioles, L-NNA was not tested in these
vessels.
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Significant differences (P<0.05) from control and 3 mmol/L TEA, respectively. Note that TEA significantly reduced the control diameter of brain stem arteriole but not cerebral arteriole. L-NNA further constricted the TEA-treated brain stem arterioles.
L-NNA decreased the control diameter of brain stem
arterioles (76.7±4.0%), and additional TEA induced further
significant constriction (79.6±4.9% of the 10 µmol/L
L-NNA–treated diameter) (n=4;
Figure 2A).
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These results suggest the following: (1) KCa channels are either not present in cerebral arterioles or are silent during resting conditions in these vessels; (2) KCa channels are present in brain stem arteriole, and some of them are activated under basal conditions; and (3) basal NO may not contribute to KCa channel activity in brain stem arteriole.
Effect of KATP Channel
Inhibitor
Glibenclamide (3 µmol/L) had no significant effect on
the diameter of cerebral (99.0±3.2% of the control diameter) and
brain stem (91.8±5.0%) arterioles within 30 minutes of application
(n=5;
Figure 3). Glibenclamide (3 µmol/L) tended to reduce the
diameter of brain stem arteriole; however, this was not significant. A
higher concentration of glibenclamide (10 µmol/L) also did not cause
significant constriction of these vessels (n=5;
Figure 3). These results indicate that
KATP channels are either absent or silent in
both arterioles under resting conditions.
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Effect of KV Channel
Inhibitor
4-AP (0.1 and 1 mmol/L) significantly constricted
cerebral arterioles (89.4±2.6% and 77.5±3.5% of the control
diameter, respectively) (n=5;
Figure 4). Additional treatment with L-NNA (10 µmol/L)
further reduced the diameter of cerebral arterioles (67.8±3.4% of the
1 mmol/L 4-AP–treated diameter). In brain stem arterioles, 4-AP
(0.1 and 1 mmol/L) produced a significant constriction
(83.5±2.5% and 69.9±4.0% of the control diameter) (n=5;
Figure 4). Brain stem arterioles treated with 1 mmol/L
4-AP were also constricted by 10 µmol/L L-NNA (68.8±2.5% of the
1 mmol/L 4-AP–treated diameter). The time course of 4-AP–induced
constriction was similar to that of TEA-induced
constriction.
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Cerebral and brain stem arterioles were significantly
constricted by 10 µmol/L L-NNA (78.0±2.5% and 75.9±5.3% of the
control diameter, respectively), and the subsequent application of
1 mmol/L 4-AP further decreased diameters of these vessels
(73.1±5.0% and 77.0±2.7% of the 10 µmol/L L-NNA–treated
diameter, respectively) (n=4;
Figure 2B
).
These results suggest the following: (1) KV channels are active under basal conditions of both arterioles, and (2) basal release of NO may not contribute to activation of KV channels.
Effect of KIR Channel
Inhibitor
BaCl2 (30 and 100 µmol/L)
significantly decreased the resting diameter of cerebral (90.0±1.8%
and 86.8±3.3% of the control diameter) and brain stem arterioles
(90.6±2.5% and 81.4±3.2%, respectively) (n=5;
Figure 5). Our results are consistent with the
presence of KIR channels that are open under
basal conditions of both arterioles.
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Effect of KATP Channel
Opener
In brain stem arterioles, pinacidil (1 µmol/L)
significantly dilated the vessel (n=4; 117.8±4.6%), and the
pretreatment with 3 µmol/L glibenclamide almost abolished the
dilation (100.7±0.4%;
P<0.05). This demonstrates
that KATP channels are present in brain stem
arterioles.
Effect of
[K+]o
The small elevation of
[K+]o (8
mmol/L) induced strong dilation of brain stem arterioles, and 30
µmol/L BaCl2 significantly attenuated this
dilation from 159.5±12.7% to 131.2±14.3% (n=4). This result
supports the hypothesis that there are KIR
channels in brain stem arterioles.
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Discussion |
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The present study characterized, for the first time, the basal activity of K+ channels in rat brain penetrating arterioles from 2 distributions in vitro. The major findings are as follows: (1) KV and KIR channels are present and contribute to the resting tone of both arterioles. (2) KATP channels are silent at resting states. (3) There is a regional difference in the basal activity of KCa channels. In cerebral arteriole these channels are either absent or silent under resting conditions, while some are open in brain stem arteriole. (4) The basal production of NO may not contribute to the activity of either KCa or KV channels.
Role of KCa
Channel
The KCa channel is abundantly
present in vascular smooth muscle and is activated both by
elevated concentrations of intracellular calcium and by membrane
depolarization.11 12
It acts as the modulator of vasoconstrictor responses as well as the
mediator of vasodilation. In addition, this type of
K+ channel regulates resting membrane
potential and influences the resting diameter of cerebral blood
vessels, especially large vessels such as rat
basilar,16 32 rat
middle cerebral,33 and human
pial14 arteries.
In contrast, it is generally accepted that KCa channels are present but silent in cerebral arterioles in vivo.23 25 26 However, Régrigny et al34 recently reported that TEA induced significant constriction of rat pial arterioles in vivo. Thus, in the cerebral microcirculation, there may be regional or species-dependent differences in magnitude of influence of these channels on basal tone. Our results support this heterogeneity and indicate that the regulatory mechanism of basal tone in the territories of cerebral and brain stem arterioles may be different because KCa channels in brain stem, but not in cerebral arterioles, are active under basal conditions. Since there are no specific activators of KCa channels,11 we cannot test for the presence of KCa channels in cerebral arterioles. We can only speculate on the physiological significance of this regional difference. If KCa channels are modulators of vasoconstrictor response,12 one consequence could be a difference in autoregulatory response between the cerebral and brain stem arterioles.4 5 During severe hypertension, autoregulation is more effective in the brain stem than cerebrum of cats.4 5 This potency of the brain stem circulation may be due to greater resistance of small vessels compared with the cerebrum. In addition, microvascular pressure in similar-sized arteries and arterioles is higher in the brain stem than in the cerebrum.3 4 5
This suggests that the basal tone of small vessels would be stronger in the brain stem than in the cerebrum. In the present study there was no difference in basal tone between the brain stem and the cerebral arterioles. Nevertheless, KCa channels were active in brain stem arterioles in our experimental conditions. This may indicate that in these vessels KCa channels serve as a negative feedback mechanism to regulate arteriolar tone and contribute to the enhanced autoregulation observed in the brain stem.4 5
The inactivity of KCa channels at resting states has been reported in other microcirculatory beds such as cremasteric microcirculation.35 36 Although the lack of activity of these channels at basal tone in the microcirculation remains unclear, this inactivity could be explained by a low voltage sensitivity, a low calcium sensitivity, or a high calcium set point of the channel.35 36 37 Recently, in cremasteric microcirculation, Jackson and Blair35 proposed that the high calcium set point was responsible for the inactivity of KCa channels by pharmacological and patch-clamp techniques. Thus, KCa channels in cremasteric arteriolar muscle cells require relatively higher concentrations of calcium than usual to be active at physiological membrane potentials.
Role of KATP
Channel
KATP channels are
activated by several stimuli, such as reductions in
intracellular ATP,
PO2,
and pH.11 12 This
type of K+ channel is distributed in both
large cerebral arteries and pial
arterioles.11 12 18 26
It is generally known that KATP channels are not
activated under resting conditions in both cerebral arteries
and
arterioles.26 32 38
In rat cerebral penetrating arterioles, similar to our preparation, it
was found that KATP channels are present but
inactive under resting
conditions.39 40
In our study we confirmed the presence of KATP
channels in brain stem arteriole using the KATP
channel opener pinacidil and inhibitor glibenclamide. Thus,
KATP channels are distributed in both
arterioles, but they are silent under basal conditions. On the other
hand, Nagao and coworkers18
reported that glibenclamide significantly caused substantial
depolarization in rabbit vertebral arteries, suggesting that some
KATP channels may be open under resting
conditions. These data suggest that the basal activity of
KATP channels in the anterior circulation is
different from that in the posterior circulation. In addition, they
proposed that the distribution of KATP channels
decreased along the vascular tree from vertebral to superior cerebellar
arteries because there was a regional heterogeneity in
the sensitivity to an opener of KATP
channels.
In other organs, glibenclamide depolarized the membrane and/or decreased the diameter in both arteries and arterioles such as the rabbit mesenteric artery41 and the hamster cremaster arteriole,36 supporting the hypothesis that the activity of KATP channels contributes to and influences the basal tone. Thus, there is also heterogeneity of basal activity of KATP channels among species and tissues.
Role of KV
Channel
KV channels are
activated by membrane depolarization, similar to
KCa channels; however, this activation dose not
depend on the intracellular calcium
concentration.11 12
4-AP (up to 1 mmol/L), a voltage-dependent potassium channel
inhibitor, significantly reduced the resting diameter of
rat basilar15 and rabbit
middle cerebral13 arteries,
indicating that this type of K+ channel
plays an important role in regulation of membrane potential and tone in
large cerebral
arteries.13 15
Compared with the 2 K+ channels discussed
above, little is known about the basal activity of
KV channels in cerebral microcirculation. On the
other hand, in hamster cremaster arteriolar muscle cell,
KV channels participate in the regulation of
basal membrane potential.36
In the present study both cerebral and brain stem arterioles were
similarly constricted by 4-AP. These findings are consistent
with previous studies using large cerebral arteries and indicate that
KV channels are active under basal conditions of
both arterioles. To the best of our knowledge, we are the first to
provide evidence that KV channels play an
important role in the regulation of brain arteriolar tone in
vitro.
Role of KIR
Channel
KIR channels are characterized
by an inward rectifier current and activated by modest
elevations of
[K+]o.11 17 19 40 42 43 44
Low concentration of BaCl2 (<50 µmol/L) has
been shown to be a selective antagonist of
KIR
channels.17 45
Edwards et
al42 43
previously showed that K+ current of
KIR channel will be outward at membrane
potentials of 
-50 mV. We reported that the resting membrane
potential of isolated rat cerebral arteriole was approximately -40
mV,46 suggesting that
K+ current of KIR
channel may be outward in resting conditions.
KIR channels may participate in regulation of
cerebral vascular tone.17 In
this study BaCl2 (30 µmol/L) significantly
constricted both arterioles. This result indicates that
KIR channel also appears to be present and
open in the resting states of both arterioles.
Small elevations of [K+]o cause dilation of cerebral vessels via stimulation of KIR channels.17 19 40 44 Recently, Nguyen et al40 showed that K+ ion activated KIR channels, resulting in dilation of rat cerebral penetrating arterioles. In the brain stem arteriole, the elevation of [K+]o also caused the dilation that was inhibited by low concentration of BaCl2. These data further support the hypothesis that KIR channels are present in both arterioles.
Role of NO in Potassium Channel
Activity
We previously showed that basal production of
NO contributed to the resting diameter of rat cerebral
arterioles.8 Recently, it was
demonstrated that the vasodilator response to both basal and
agonist-induced NO may cause hyperpolarization via
activation of K+ channels, especially
KV and KCa channels in
cerebral
arteries.12 16 21 22 24
Thus, there are 3 possible ways in which basal NO can regulate
arteriolar tone: (1) via a K+
channel–independent mechanism, (2) directly or indirectly via
stimulation of K+ channels, or (3) through
both
mechanisms.11 12
In the present study the NO synthase inhibitor L-NNA
further constricted the arteriole treated with TEA or 4-AP, and the
L-NNA–treated arterioles were also constricted by 4-AP or TEA. We
reported that L-NNA constricted rat cerebral arterioles without
increasing intracellular calcium
levels,47 and
N-monomethyl-L-arginine
(another inhibitor of NO synthase) caused constriction
without affecting membrane
potential.48 These findings
suggest that a possible stimulation of KV or
KCa channels, if any, might not have a major
role in regulation of arteriolar tone by basal NO because the activity
of K+ channels contributes to both membrane
potential and intracellular calcium
concentration.12 36
In summary, KV and KIR, but not KATP, channel inhibition produces a substantial constriction in both cerebral and brain stem arterioles, while KCa channel inhibition constricts brain stem but not cerebral arterioles. These findings suggest that KV and KIR channels are active and KATP channels are silent under resting conditions in both arterioles. KCa channels appear to be active at basal tone in brain stem but not cerebral arterioles. In addition, basal NO may not contribute to the activity of either KCa or KV channels. Thus, the basal activity of several K+ channels may regulate the spontaneous tone in rat brain microcirculation independent of basal NO.
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL57540 and NS30555. We are very grateful to Robyn L. Reese and Christine M. Pluchinsky for expert technical assistance.
Received May 24, 2000; revision received July 26, 2000; accepted September 7, 2000.
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Editorial Comment
Comparison of Cerebrum Versus Brain Stem
Department of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, Iowa City, Iowa
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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Activity of potassium (K+) channels is a major regulator of membrane potential of vascular muscle, and is therefore an important determinant of vascular tone. At least 4 types of K+ channels are known to be expressed in cerebral arteries: calcium-activated (KCa), voltage-dependent (KV), ATP-sensitive (KATP), and inwardly rectifying (KIR) K+ channels.R1 R2 Activation of K+ channels may influence resting vascular tone and modulate responses to vasoconstrictors, and it is believed to play a major role in the mechanism(s) underlying cerebral vasodilatation in response to a variety of stimuli, including hypoxia and hypercapnia, receptor-mediated agonists, potassium ion, reactive oxygen species, and second messengers.R1 R2 R3
Although studies using pharmacological inhibitors have provided evidence that several K+ channels influence cerebral vascular tone under basal conditions in vitro and in vivo,R3 R4 R5 R6 little is known as to whether there are regional variations in the expression and functional importance of specific K+ channels in the cerebral circulation, as has been reported in the pulmonary circulation.R7 In the accompanying article, Horiuchi et al have examined the role of K+ channels in responses of isolated and pressurized arterioles from brain stem and cerebrum using inhibitors of all major groups of K+ channels. Based on the observations that 4-aminopyridine (4-AP) and barium ion produce constriction of arterioles from both regions, it was concluded that KV and KIR channels, respectively, were active under resting conditions in these vessels. A lack of effect of glibenclamide, an inhibitor of KATP channels, suggested no influence of this type of ion channel under resting conditions. All of these results are consistent with previous findings.R1 R2 R3 R4 R5 R6 A new finding in the study was the observation that tetraethylammonium ion (TEA) caused constriction of arterioles from brain stem, but not cerebrum, suggesting that regional differences in basal KCa channel expression or activity may be present within the cerebral circulation. The mechanism that accounts for this regional difference in the influence of KCa channels was not studied. One possibility is that expression of the genes which encode the 2 proteins that together constitute the KCa channel vary in different brain regions.
A second goal of these studies was to examine the interaction of nitric oxide (NO) with K+ channels in cerebral arterioles. Because cerebral vasodilator responses to NO may be attenuated by application of inhibitors of some K+ channels,R3 R5 it might be expected that at least part of the activity of these channels under resting conditions results from activation by NO produced by endothelium under basal conditions. The finding that TEA and 4-AP caused similar vasoconstrictor responses whether administered in the presence or absence of an inhibitor of NO synthase suggested to the authors that activity of KCa and/or KV channels may not be influenced by NO produced under basal conditions in normal arterioles.
Production and/or activity of NO by endothelium is known to be diminished under pathophysiological conditions.R2 An implication of the present study is that the depolarized state of vascular muscle observed in disease states (eg, hypertension, diabetes, subarachnoid hemorrhage) may not be directly caused by the decreased levels of NO within the vessel wall. Because recent studies suggest that K+ channels in the cerebral circulation may become functionally more important under pathophysiological conditions,R3 it will be of interest to examine the interaction of NO and K+ channels in cerebral vessels in disease states as well.
Received May 24, 2000; revision received July 26, 2000; accepted September 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferencesIntroduction References |
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1. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol. 1995;268:C799–C822.
2. Faraci FM, Heistad DD. Regulation of the cerebral circulation: Role of endothelium and potassium channels. Physiol Rev. 1998;78:53–97.
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