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From the Stroke Research Center (R.V.) and Department of Physiology and
Pharmacology (R.V., F.D., F.B., D.W.B.), Bowman Gray School of Medicine, Wake
Forest University, Winston-Salem, NC; and Department of Physiology, Albert
Szent-Györgyi Medical University, Szeged, Hungary (F.D., F.B.).
Correspondence to Roland Veltkamp, MD, Stroke Research Center, Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1083. E-mail veltkamp{at}bgsm.edu
Methods—Pial arteriolar diameters were measured in
anesthetized piglets with the use of a closed cranial window
and intravital microscopy. Arteriolar responses to NMDA
(10-5, 5x10-5, and 10-4 mol/L)
were recorded before and 1 hour after 10 minutes of hypoxia
(8.5% O2 in N2) plus 10 minutes of
ischemia (H/I). Ischemia was induced by increasing
intracranial pressure. Subgroups were topically pretreated with
10-5 mol/L NS1619, 10-6 mol/L aprikalim,
10-6 mol/L calcitonin gene–related peptide (CGRP), or
10-5 mol/L papaverine. We also examined the effects of H/I
on vascular responses to kainate (10-4 mol/L) to
assess specificity of neuronal injury.
Results—Arteriolar responses to NMDA were significantly
attenuated after H/I. Baseline compared with post-H/I arteriolar
diameters were 9±4% versus 3±2% at 10-5 mol/L, 22±4%
versus 4±2% at 5x10-5 mol/L, and 33±4% versus 7±2%
at 10-4 mol/L (mean±SE; all P<.05, n=7).
Pretreatment with NS1619 and aprikalim preserved the arteriolar
responses to NMDA after H/I. For NS1619 (n=6), values were as follows:
9±2% versus 6±4% at 10-5 mol/L, 19±6% versus 21±5%
at 5x10-5 mol/L, and 35±3% versus 31±5% at
10-4 mol/L. For aprikalim (n=7), values were as follows:
6±2% versus 8±2% at 10-5 mol/L, 22±6% versus 15±3%
at 5x10-5 mol/L, and 41±5% versus 32±6% at
10-4 mol/L. In contrast, piglets pretreated with CGRP
(n=6) or papaverine (n=5) showed no preservation of the vascular
response to NMDA after H/I, although these compounds dilated the
arterioles to an extent similar to that with NS1619/aprikalim.
Kainate-induced arteriolar dilation (n=6) was largely preserved
after H/I compared with preischemic responses.
Conclusions—(1) Vascular responses of cerebral arterioles
to NMDA after H/I are preserved by pretreatment with NS1619 or
aprikalim, indicating a neuroprotective effect. (2) CGRP and papaverine
do not preserve the vascular response to NMDA despite causing
vasodilation similar to that with NS1619 or aprikalim. This suggests
that activation of potassium channels on neurons accounts for the
protective effect of potassium channel agonists. (3) Preserved
arteriolar dilation to kainate suggests largely intact functioning
of neuronal nitric oxide synthase after H/I.
We and others have shown that global H/I
severely attenuates or abolishes the arteriolar response to
NMDA7 8 9 as well as to other vasodilating agents
such as CGRP and aprikalim.10 11 Impaired
neuronal-vascular coupling in combination with pathological
metabolic and
electrophysiological processes may
contribute to delayed cerebral damage in brain
H/I.12
From an experimental point of view, the integrity of the
neuronal-vascular axis can be used as a model for the study of
potential neuroprotective agents. The rationale of this model is based
on the observation that the arteriolar response to a neuron-mediated
vasodilator (eg, NMDA) is attenuated after ischemia compared
with preischemic baseline measurements. An experimental
intervention is considered neuroprotective if it preserves the original
vascular responsiveness to NMDA after ischemia.
Recent advances in the molecular biology and pharmacology of potassium
channels13 have enabled the investigation of
potential therapeutic effects of K+ channel
agonists. Different types of ligand-operated channels have been
characterized according to their primary regulatory or gating
mechanism. Opening of K+ channels leads to efflux
of K+ ions, which is a mechanism for recovering
(repolarization) and/or enhancing
(hyperpolarization) the membrane potential of a
cell.14 Potassium channel activation may
therefore counteract ischemia-induced depolarizations. In
previous studies K+ channel agonists blocked
ischemia-induced glutamate release in rat hippocampal
slices15 and prevented the
ischemia-induced expression of immediate early genes in a rat
model of global ischemia.16
The purpose of the present study was to test the hypothesis that
potassium channel agonists preserve the NMDA-induced cerebral
arteriolar dilation after consecutive H/I. Specifically, we examined
the effects of NS1619 and aprikalim, putatively specific openers of
calcium-dependent potassium channels (KCa) and
ATP-dependent potassium channels (KATP),
respectively. We also examined the effects of CGRP and papaverine to
determine whether protective effects were independent of arteriolar
dilation. Furthermore, we investigated whether the combined H/I
protocol attenuated the kainate-induced arteriolar dilation, which
had been resistant to ischemia alone in an earlier
study.6 Kainate-induced arteriolar dilation
shares features of NMDA-induced arteriolar responses in that at least
one half of the vascular response is NO dependent.
Cerebral H/I
Cerebral ischemia was produced by implantation of a hollow
brass bolt in the left parietal cranium 20 mm rostral to the
cranial window. A 3-mm hole was drilled in the skull with an electric
drill with a toothless bit, and the dura was exposed. The hollow bolt
was inserted and secured in place with cyanoacrylate ester and dental
acrylic. After implantation of the window and the bolt, aCSF was
allowed to equilibrate with the periarachnoid CSF for 20 minutes. To
induce ischemia, aCSF was infused to maintain intracranial
pressure above mean arterial pressure so that blood flow
through pial vessels was stopped. Venous blood was withdrawn as
necessary to maintain mean arterial pressure near normal
values. At the end of the 10-minute period of ischemia, the
infusion tube was clamped, and the intracranial pressure was allowed to
return to preischemia values. The heparinized blood was
reinfused intravenously.
Experimental Design
Animals were divided into five experimental groups. In group 1 (n=7)
arteriolar responses to NMDA were recorded before (see above) and 1
hour after 10 minutes of hypoxia plus 10 minutes of global
ischemia. In addition to this protocol, the other four groups
were pretreated with a topical infusion 10 minutes before H/I of either
NS1619 10-5 mol/L (group 2, n=6); aprikalim
10-6 mol/L (group 3, n=7); CGRP
10-6 mol/L (group 4, n=6); or papaverine,
10-5 mol/L (group 5, n=5). Arteriolar responses
to these drugs were recorded during the infusion period. The drugs
were washed away just before the beginning of hypoxia. In
groups 1 and 4, 10-4 mol/L sodium nitroprusside
was applied topically after the NMDA responses 1 hour after H/I were
measured to examine the vascular responsiveness to exogenous NO.
In another experiment, the cerebral arteriolar responses to
10-4 mol/L kainate (group 5, n=6) before and
1 hour after H/I were determined.
Drugs
Statistical Analysis
Arterial blood gases and pH were monitored regularly during
the experiments and were generally kept within the
physiological range. At baseline, pH was 7.45±0,
PCO2 was 32±1 mm Hg, and
PO2 was 106±4 mm Hg (n=32).
After 8 minutes of hypoxia, pH was 7.40±0,
PCO2 was 32±2 mm Hg, and
PO2 was 27±1 mm Hg (n=24).
Arterial blood gases were similar to baseline after
recovery from H/I. Blood gases and pH did not differ significantly
among groups.
Application of NMDA before H/I caused a reproducible, dose-dependent
cerebral arteriolar dilation (Table
Topical administration of the drugs 10 minutes before H/I caused
arteriolar dilation by 15±4% for NS1619, 26±7% for aprikalim,
15±4% for CGRP, and 20±2% for papaverine.
Pretreatment with NS1619 (10-5 mol/L) resulted
in an almost complete preservation of the arteriolar dilation to the
different concentrations of NMDA 1 hour after H/I (Table
Administration of kainate (10-4 mol/L)
before H/I dilated cerebral arterioles from a baseline of 106±3
µm by 27±4%. One hour after H/I kainate induced a 21±3%
dilation from a baseline of 110±6 µm (P>.05).
Cerebral arterioles do not possess NMDA
receptors.17 18 Consequently, the NMDA-induced
cerebral arteriolar dilation can only take place through an indirect
pathway involving production, release, and action of NO. While
the complete sequence of mechanisms involved is currently unknown, NMDA
mainly causes cerebral arteriolar dilation through the sequential
production of neuronal NO and vascular smooth muscle
cGMP.1 2 3 4 5 19
In the present study the combined stress of H/I markedly
attenuated the response of cerebral arterioles to NMDA as measured 1
hour after the insult. Previously, we have shown that a period of 5 to
15 minutes of either ischemia, asphyxia, or hypoxia is
able to attenuate the NMDA-induced arteriolar
dilation.7 8 20 Administration of either NS1619
or aprikalim, putatively selective agonists of
KCa channels13 21 22 and
KATP channels,23 24 25
respectively, essentially preserved the response of cerebral arterioles
to NMDA. The mechanism leading to this unprecedented finding is as yet
unclear. NS1619 and aprikalim can dilate cerebral arterioles by the
direct stimulation of potassium channels on vascular smooth muscle
cells.25 26 27 28 Therefore, hypothetically, the
preservation of the NMDA-induced vascular response may take place as a
consequence of vasodilation before ischemia. This hypothesis,
however, is hard to reconcile with the observation that the similar
dilation of cerebral arterioles to CGRP and papaverine before
ischemia had little or no effect on the
postischemic vascular response to NMDA.
Several different subtypes of potassium channels (eg,
voltage-gated, ATP-dependent, calcium-dependent, inward rectifier
potassium channels) have been identified on
cells,14 and all subtypes are present on
neurons.29 The interaction of NS1619 and
aprikalim with their respective potassium channels on neurons therefore
represents an alternative mechanism through which their
preservative effect on the NMDA-mediated neuronal-vascular coupling may
have taken place. Although the gating mechanism and conduction
properties differ between subtypes, opening of potassium channels
generally leads to hyperpolarization of excitable
cells by increasing the efflux of potassium ions from the relatively
negatively charged intracellular compartment into the extracellular
space. Current concepts of H/I brain damage include the deleterious
effects of excessive secretion of neurotoxic excitatory
neurotransmitters30 and the intracellular
accumulation of calcium.31 Theoretically,
potassium channel openers may counteract these effects by
hyperpolarizing presynaptic and postsynaptic
neurons.14 29 Potassium channel openers also may
inhibit the release of calcium from intracellular
stores.14 This may lead to decreased glutamate
secretion, slowing of the depolarization rate, diminished intracellular
calcium accumulation, lower energy consumption, and reduced
production of free oxygen radicals (Fig 3
Experimental data supporting this attractive neuroprotective
concept are sparse. Wind et al32 found protection
of cultured neurons against chemically induced hypoxia by
bimakalim, a KATP activator. Suzuki
and coworkers33 showed that pretreatment with
pinacidil, a partial KATP agonist, shortened the
recovery time of spinal reflexes after spinal ischemia in cats.
When glibenclamide, an inhibitor of
KATP, was coadministered, the protective effect
was absent. Similarly, in a study by Riepe et
al,34 glibenclamide partly reversed increased
hypoxic tolerance after chemical inhibition of oxidative
phosphorylation in hippocampal slices. Zini et
al15 reported that K+
channel agonists blocked ischemia-induced glutamate release in
rat hippocampal slices. Using a rat model of global ischemia,
Heurteaux et al16 demonstrated that several
KATP openers administered
intracerebroventricularly blocked the
expression of immediate early genes in the hippocampus. The same and a
similar study by these authors16 35 also showed a
decrease in delayed neuronal death in hippocampal CA1 neurons. We are
not aware of other studies examining the neuroprotective effect of
KCa openers in cerebral hypoxia and
ischemia.
The methods in the present study do not allow us to identify
the precise molecular site at which NS1619 and aprikalim preserved the
NMDA-mediated neuronal-vascular coupling after H/I. We speculate that
both types of potassium channel openers preserved the NMDA-mediated
response by indirectly protecting the NMDA receptor complex. Based on
the results of previous work, we suggested that the affected step in
the NMDA-vasodilating sequence may be the neuronal NMDA receptor rather
than NO synthesis or the action of subsequent
metabolites.8 20 The present study partly
supports this concept since the arterioles, which did not respond to
NMDA after H/I, still dilated to sodium nitroprusside, an NO donor.
Indeed, the postischemic dilation to sodium nitroprusside
(25±2%) was of an extent similar to that of previous
preischemic control measurements in the same experimental
setup. Moreover, the partially (approximately 80%) preserved
arteriolar response to kainate, which has been shown to be mediated
equally by NO and prostaglandins6 in
this model, suggests that neurons carrying glutamate receptors maintain
some signaling mechanisms including stimulus-dependent NO synthesis.
However, we cannot rule out a compensatory role of
prostaglandins in kainate-induced arteriolar dilation
after H/I.
Holland et al36 demonstrated a
neuroprotective effect of intravenous CGRP in a rat model
of focal ischemia. Since CGRP does not easily cross the
blood-brain barrier, the authors speculated that the recorded
increase in cerebral blood flow may account for their findings. In
contrast, CGRP failed to preserve the NMDA-mediated neuronal-vascular
coupling in our experiments, although it dilated cerebral arterioles
before ischemia. CGRP exerts its vasodilating effect largely
through activation of KATP on smooth muscle
cells.37 In contrast to direct
activators of potassium channels (eg, aprikalim, NS1619),
which are known to hyperpolarize neurons, the effect of CGRP on neurons
is probably more complex and may depend on the neuronal circuit
involved. CGRP receptors have been shown to be present in the
porcine cortex,38 but we are not aware of any
study investigating the receptor density in certain cortical layers or
even colocalization with NMDA receptor–positive neurons. To our
knowledge the relationship of CGRP to neuronal potassium channels has
never been studied. From our experiments we can only conclude that CGRP
does not have a sufficient (if any) effect on neuronal
K+ channels to preserve the NMDA-mediated
vasodilating sequence. The modest preservation of NMDA-induced dilation
by papaverine may be due to effects on neuronal
K+ channels or to other yet undisclosed
neuroprotective effects.
Even after the severe consecutive H/I stress, the vascular
responses to kainate were only attenuated by approximately 20%.
This confirms the remarkable resistance of the kainate-mediated
neuronal-vascular sequence in general and of the kainate receptor
in particular, which we reported recently.6 It
also illustrates the selectivity of damage caused by cerebral H/I
affecting the response linked to one glutamate receptor subtype while
in part sparing another.
We cautiously interpret our findings as indicative of a
neuroprotective effect of potassium channel agonists on the
postischemic function of neurons carrying the NMDA
receptor. The immediate implications of this specific preservative
effect for the overall protection of the brain against ischemia
are currently unknown. We suggest, however, that the protective
mechanisms of potassium channel openers are unlikely to be confined to
the NMDA receptor but rather express their beneficial effect on
another, more general pathophysiological mechanism
in H/I.
The presented results may have clinical implications for
focal ischemic stroke or cerebral global ischemia after
heart arrest. Our experimental paradigm circumvents some of the
problems associated with the systemic administration of central nervous
system drugs.39 In addition,
postischemic treatment may encounter altered receptor
interfaces favoring or disfavoring particular therapeutic strategies.
In the present study the drugs were applied before H/I when
receptors and signaling mechanisms were evidently intact. Our recent
work has shown that postischemic vasodilation to
KCa openers40 but not to
KATP agonists is resistant to
ischemia.11 Although the vasodilation
induced by potassium channel openers is probably caused mainly by
immediate interaction with potassium channels on vascular smooth muscle
cells, the attenuated response to KATP agonists
may indicate the vulnerability and transient nonresponsiveness of the
targeted receptor and pathway. If this also involved neuronal
KATP channels, they would become a less
attractive target for neuroprotection than KCa
channels for treatment started in the early postischemic
period.
In summary, our findings show that topical pretreatment with the
selective potassium channel openers NS1619 and aprikalim preserves the
NMDA-mediated neuronal-vascular coupling after H/I in newborn piglets.
This finding suggests considerable neuroprotective potential of these
agents.
Received October 1, 1997;
revision received December 18, 1997;
accepted January 13, 1998.
Department
of Physiology and Biophysics,
University of Nebraska Medical Center,
Omaha, Nebraska
Recent evidence suggests that activators of K+ channels may
have potential therapeutic implications. It is possible that
K+ channel activators, by stimulating the efflux of
potassium ions from cellular compartments, may counteract
ischemia-induced depolarizations and thus protect the cerebral
circulation. Glutamate is an important neurotransmitter in the brain
and produces dilation of cerebral blood vessels, in part, through
activation of NMDA receptors and synthesis/release of NO. Previous
studies by this group6 and others7 have shown
that cerebral H/I impairs or abolishes dilation of cerebral arterioles
in response to NMDA. The purpose of the present study was to determine
whether treatment with K+ channel activators before
cerebral H/I preserves NMDA-induced arteriolar dilation.
These investigators measured in vivo responses of piglet cerebral
arterioles to topical application of NMDA before and after periods of
cerebral H/I. The authors report impaired responses of cerebral
arterioles to NMDA after H/I. Pretreatment with K+ channel
activators (aprikalim and NS1619), however, preserved arteriolar
dilation to NMDA after cerebral H/I. Restoration in responses to NMDA
after treatment with K+ channel activators was specific
since CGRP did not alter responses to NMDA.
Thus, it appears that activation of K+ channels, presumably
on neurons, accounts for preservation in cerebrovascular responses to
NMDA after cerebral H/I. These findings suggest a potentially important
therapeutic role for activation of K+ channels after
cerebral ischemia.
Received October 1, 1997;
revision received December 18, 1997;
accepted January 13, 1998.
© 1998 American Heart Association, Inc.
Original Contributions
Potassium Channel Activators Protect the N-Methyl-D-Aspartate–Induced Cerebral Vascular Dilation After Combined Hypoxia and Ischemia in Piglets
Abstract
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Background and Purpose—Cerebral
arteriolar dilation to N-methyl-D-aspartate
(NMDA) is a neuronally mediated multistep process that is sensitive to
cerebral hypoxia and ischemia (H/I). We tested the
hypothesis that topical pretreatment with the selective potassium
channel agonists NS1619 and aprikalim preserves the vascular response
to NMDA after consecutive H/I.
Key Words: cerebral arterioles • neuronal protection • N-methyl-D-aspartate • potassium channels
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Glutamate is an
important excitatory amino acid neurotransmitter in the central nervous
system. It can bind to three different ionotropic glutamate receptor
subtypes on neurons named after specific synthetic analogues: NMDA,
kainate, and AMPA. Activation of neuronal NMDA and kainate
receptors causes cerebral arteriolar dilation in different animal
species, which is mediated in part or even totally by NO-dependent
mechanisms.1 2 3 4 5 6 This sequence may
represent one of the mechanisms coupling local cerebral
metabolism to blood flow.
Materials and Methods
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Surgical Preparation
Experiments were performed on newborn pigs (1 to 7 days) of
either sex weighing 1 to 2 kg. The procedures used in the study were
approved by the Institutional Animal Care and Use Committee. The
piglets were initially anesthetized with sodium thiopental (30
mg/kg IP) and later with 
-chloralose (75 mg/kg IV). Additional
amounts of -chloralose were given as needed to maintain a stable
level of anesthesia. The piglets were intubated by a
tracheotomy and artificially ventilated. A femoral artery and vein were
cannulated with polyethylene tubing (PE-90). Arterial blood
gases and pH were repetitively measured, and rectal temperature was
continually monitored. These parameters were kept within
the normal physiological range. The head of each
piglet was fixed in a stereotaxic apparatus.
Approximately 3 mL of CSF was withdrawn from the cisterna magna. The
scalp was cut, and the connective tissue over the parietal bone was
removed. A circular craniectomy (19 mm in diameter) was made in
the left parietal bone. The dura was cut and reflected over the skull.
A stainless steel and glass cranial window with three ports was put
into the opening, sealed with bone wax, and cemented with cyanoacrylate
ester (SuperGlue) followed by one or two layers of dental acrylic. The
closed window was filled with aCSF that was warmed to 37°C and
equilibrated with 6% O2, 6.5%
CO2, balance N2. Arterioles
were observed with a microscope (Wild M36) equipped with a television
camera (Panasonic), and arteriolar diameter was measured with a video
microscaler (IV-550, For-A Co).
Cerebral hypoxia was induced by artificial ventilation
with 8.5% O2, balance N2
over 10 minutes. Arterial blood gases were measured 8
minutes after hypoxia was started. Ten minutes of
hypoxia were immediately followed by 10 minutes of global
cerebral ischemia.
At the beginning of each experiment the cranial window was
flushed several times with aCSF until a stable baseline was observed.
Then arteriolar responses to NMDA (10-5,
5x10-5, 10-4 mol/L) were
determined. Each dose of NMDA was introduced into the window, the
infusion was stopped, and arteriolar diameter was recorded over the
next 5 to 10 minutes. Afterward the window was flushed with aCSF. The
arteriolar diameter returned to baseline within 15 to 20 minutes.
We used NMDA (Sigma), kainate (Sigma), sodium nitroprusside
(Sigma), NS1619 (Research Biochemicals International), aprikalim
(Rhone-Roulenc Rorer), CGRP (Research Biochemicals International), and
papaverine (Sigma).
Data are expressed as mean±SEM. A paired t test was
used for comparing data between two groups. For repeated-measurement
analysis, ANOVA was used, and the Student-Newman-Keuls test was
then performed. Data analyses were performed on absolute and
percent change data. A P value <.05 was regarded as
statistically significant.
Results
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Before and after H/I, mean arterial blood pressures
were stable and within normal limits for piglets. For example, in the
NS1619 group, during baseline conditions arterial blood
pressures were 64±4 mm Hg before H/I and 63±2 mm Hg 1
hour after H/I. Arterial blood pressures were not affected
by the topical application of the drugs used in these experiments. 
, Fig 1). After H/I, however, arteriolar
responses to NMDA were markedly reduced (Table, Fig 1). Subsequent
administration of sodium nitroprusside (10-4
mol/L) caused consistent dilation of the same vessels by
25±2% compared with baseline.
View this table:
[in a new window]
Table 1. Arteriolar Dilation to NMDA Before and After
H/I
View larger version (13K):
[in a new window]
Figure 1. Effects of H/I on cerebral arteriolar dilation to
NMDA. Cerebral arteriolar dilator responses to NMDA were significantly
decreased 1 hour after 10 minutes of hypoxia plus 10 minutes of
ischemia. Values are mean±SEM for 7 piglets. *Significantly
different from preischemic dilation
(P<.05). 
, Fig 2), indicating no statistically
significant difference between the preischemic and
postischemic arteriolar responses. Similarly,
administration of aprikalim (10-6 mol/L)
preserved the post-H/I vascular response to NMDA (Table). Percent
changes in vascular diameter to NMDA before and after H/I were as
follows: 6±2% versus 8±2% at 10-5 mol/L,
22±6% versus 15±3% at 5x10-5 mol/L, and
41±5% versus 32±6% at 10-4 mol/L (n=7,
P>.05). In contrast, piglets pretreated with CGRP
(10-6 mol/L) showed a severe attenuation of the
vascular response to NMDA comparable to the group that did not receive
any pretreatment (Table). Vascular diameter increased by 6±2% versus
0±0% at 10-5 mol/L, 22±5% versus 2±1% at
5x10-5 mol/L, and 28±7% versus 2±1% at
10-4 mol/L of NMDA. In addition, vascular
responses to NMDA were markedly attenuated after pretreatment with
papaverine (10-5 mol/L). Arteriolar dilation
before compared with after H/I was 7±1% versus 3±1% at
10-5 mol/L NMDA and 38±4% versus 16±6% at
5x10-5 mol/L NMDA (n=5, P<.05).
View larger version (13K):
[in a new window]
Figure 2. Effects of NS1619 pretreatment on cerebral
arteriolar dilation to NMDA after H/I. Cerebral arteriolar responses to
NMDA were preserved 1 hour after 10 minutes of hypoxia plus 10
minutes of ischemia by NS1619 (10-6 mol/L). Values
are mean±SEM for 6 piglets. n.s. indicates not significantly different
from preischemic dilation (P>.05).
Discussion
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
There are three major new findings from these experiments:
First, the vascular responsiveness of cerebral arterioles to NMDA,
which is attenuated after consecutive H/I, was preserved by topical
pretreatment with either NS1619 or aprikalim. Second, CGRP and
papaverine did not preserve the vascular response to NMDA, although
they caused dilation of the cerebral arterioles to an extent similar to
that of the potassium channel agonists before H/I. Third, the
kainate-induced arteriolar dilation was largely preserved after
H/I. ).
View larger version (10K):
[in a new window]
Figure 3. Potential mechanisms by which potassium channel
activators may protect the NMDA-induced cerebral arteriolar
dilation during and after H/I. Efflux of K+ through
activated K+ channels leads to
hyperpolarization of neurons. KATP/Ca
indicates ATP-dependent/calcium-dependent potassium channels;
Cai++, intracellular calcium concentration; and
ROS, reactive oxygen species.
Selected Abbreviations and Acronyms
aCSF
=
artificial cerebrospinal fluid
AMPA
=
-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
CGRP
=
calcitonin gene–related peptide
H/I
=
hypoxia/ischemia
KATP
=
ATP-dependent potassium channels
KCa
=
calcium-dependent potassium channels
NMDA
=
N-methyl-D-aspartate
NO
=
nitric oxide
Acknowledgments
This study was supported by grants HL-30260, HL-46558, and
HL-50587 from the National Institutes of Health and a grant from the
Hungarian Ministry of Education (FKFP 0713/1997). We gratefully
acknowledge that aprikalim was a gift from Rhone-Poulenc-Rohrer.
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Editorial Comment
Introduction
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
Acute episodes of cerebral ischemia followed by reperfusion
produce reactive hyperemia1 with subsequent reductions in
cerebral blood flow,2 disruption of the blood-brain
barrier,3 damage to cerebrovascular
endothelium,4 and impairment of NO synthase–dependent
reactivity of cerebral arteries.5 Mechanisms that
contribute to impaired NO synthase–dependent reactivity of cerebral
arteries after cerebral ischemia are unclear.
Selected Abbreviations and Acronyms
aCSF
=
artificial cerebrospinal fluid
AMPA
=
-amino-3-hydroxy-5-methyl-4-isoxazolepropionate
CGRP
=
calcitonin gene–related peptide
H/I
=
hypoxia/ischemia
KATP
=
ATP-dependent potassium channels
KCa
=
calcium-dependent potassium channels
NMDA
=
N-methyl-D-aspartate
NO
=
nitric oxide
References
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Introduction
References
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W. M. Armstead NOC/oFQ contributes to age-dependent impairment of NMDA-induced cerebrovasodilation after brain injury Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2188 - H2195. [Abstract] [Full Text] [PDF]
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 F. Domoki, J. V. Perciaccante, R. Veltkamp, F. Bari, D. W. Busija, and R. M. Bryan Jr Mitochondrial Potassium Channel Opener Diazoxide Preserves Neuronal-Vascular Function After Cerebral Ischemia in Newborn Pigs • Editorial Comment Stroke, December 1, 1999; 30(12): 2713 - 2719. [Abstract] [Full Text] [PDF]
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R. Veltkamp, F. Domoki, F. Bari, T. M. Louis, D. W. Busija, and F. M. Faraci Inhibitors of Protein Synthesis Preserve the N-Methyl-D-Aspartate–Induced Cerebral Arteriolar Dilation After Ischemia in Piglets • Editorial Comment Stroke, January 1, 1999; 30(1): 148 - 152. [Abstract] [Full Text] [PDF]
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