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-peptides enhance vasoconstriction in cerebral
circulation
1 Center for Clinical and Molecular Neurobiology, Department of Neurology, and 2 Division of Pulmonary Critical Care, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota 55455; and 3 McLaughlin Research Institute, Great Falls, Montana 59405
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Amyloid-
(A)-peptides are involved in the
pathophysiology of Alzheimer's dementia. We studied the effects of
A on selected constrictor responses of cerebral circulation. Mice
were anesthetized (by using urethane-chloralose) and equipped with a
cranial window. Arterial pressure and blood gases were monitored and
controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler
probe. Topical superfusion with A1-40 (0.1-10 µM), but
not with the reverse peptide A40-1, reduced resting CBF
(
29 ± 4% at 5 µM; P < 0.05) and augmented
the reduction in CBF produced by the thromboxane analog U-46619
(+45 ± 3% at 5 µM; P < 0.05). A1-40
or A1-42 did not affect the reduction in CBF produced by
hypocapnia. The reduction in resting CBF and the enhancement of
vasoconstriction were reversed by treatment with the free radical
scavengers superoxide dismutase or
manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A to produce free radicals, abolished its vascular effects. Nanomolar concentrations of
A1-40 constricted isolated pressurized middle cerebral artery
segments with intrinsic tone (16 ± 3% at 100 nM;
P < 0.05). We conclude that A acts directly on
cerebral arteries to produce vasoconstriction and to enhance selected
constrictor responses. The evidence supports the idea that A-induced
production of reactive oxygen species plays a role in this effect. The
vascular actions of A may contribute to the deleterious effects
resulting from accumulation of this peptide in Alzheimer's dementia.
Alzheimer's disease; cerebral blood flow; reactive oxygen species; laser Doppler flowmetry
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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STUDIES OVER THE
PAST two decades have indicated that the amyloid precursor
protein (APP) and peptides derived from its processing are involved in
the pathogenesis of Alzheimer's dementia (AD) (for a review, see Ref.
24). Thus mutations of the APP gene are linked to certain
familial forms of AD (14), and amyloid- (A), a
peptide produced by proteolytic processing of APP, is a major
component of the amyloid plaques present in the brain of patients with
AD (4). In addition, overexpression of mutated APP in
transgenic mice increases A concentration in the brain and leads to
formation of amyloid plaques and cognitive impairment, both features
characteristic of AD (21). Thus A-peptides seem to play
a crucial role in the brain dysfunction associated with AD.
Mechanisms by which A exerts its pathogenic effects have not been
fully elucidated (for a review, see Ref. 15). Recent evidence suggests that A in addition to its well-known neurotoxicity impairs the function of the cerebral circulation (11).
Transgenic mice overexpressing APP and A exhibit a profound
attenuation in the increase of cerebral blood flow (CBF) produced by
endothelium-dependent vasodilators or by neural activation (11,
18). These effects are also observed after application of
synthetic A to the cerebral cortex of normal mice and are
counteracted by free radical scavengers (17).
Much less is known about the influence of A on constrictor responses
of the cerebral circulation. Although previous studies have
investigated the constrictor effect of A on isolated arteries, these
studies had limitations related to the use of pharmacologically preconstricted isolated vessels (22, 28, 29). Therefore, in the present study, we investigated the effect of synthetic A on
constrictor responses of the cerebral microcirculation in vivo and
began to study the mechanisms of the effect. We found that topical
application of A to the mouse neocortex reduces resting CBF and
enhances the reduction in CBF produced by the thromboxane analog
U-46619. These effects are reversed by free radical scavengers and do
not occur when a mutated form of A that does not produce reactive
oxygen species (ROS) is used. Furthermore, A produces constriction
in isolated-pressurized mouse middle cerebral arteries with intrinsic
tone. The findings provide evidence that A-peptides render the
cerebral circulation more sensitive to certain vasoconstrictors. The
resulting oligemia may contribute to brain dysfunction in
conditions associated with A accumulation in the brain.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Methods for surgical preparation of mice, for topical application of drugs, and for monitoring CBF using laser Doppler flowmetry have been described in detail in previous publications (11, 16, 17) and are briefly summarized below.
General Surgical Procedures
Studies were conducted in 53 C57BL/6J male mice (age 2-3 mo, body wt 20-30 g) obtained from Jackson Laboratories (Bar Harbor, ME). Mice were anesthetized with halothane in 100% O2 (induction 5%; maintenance 1-2%). Tracheae were intubated and mice were artificially ventilated with an oxygen-nitrogen mixture. The O2 concentration in the mixture was adjusted to provide an arterial PO2 (PaO2) of 120-140 mmHg (Table 1). One of the femoral arteries was cannulated for recording mean arterial pressure (MAP) and collecting blood samples. Rectal temperature was maintained at 37°C using a thermostatically controlled rectal probe connected to a heating lamp. End-tidal CO2, monitored by a CO2 analyzer (Capstar-100, CWE), was maintained at 2.6 to 2.7% (16) (Table 1). After surgery, halothane was discontinued and anesthesia was maintained with urethane (750 mg/kg ip) and chloralose (50 mg/kg ip). Throughout the experiment, the level of anesthesia was monitored by testing corneal reflexes and motor responses to tail pinch. To minimize confounding effects of anesthesia on vascular reactivity, the time interval between the administration of urethane-chloralose and testing of CBF responses was kept consistent among the different groups of mice studied.
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Monitoring CBF
A small craniotomy (2 × 2 mm) was performed to expose the parietal cortex, the dura was removed, and the site was superfused with Ringer solution (37°C; pH 7.3-7.4) (16). CBF was continuously monitored at the site of superfusion with a laser Doppler probe (Vasamedic; St. Paul, MN) positioned stereotaxically on the cortical surface. CBF values were expressed as percent increase relative to the resting level. Zero values for CBF were obtained after the heart was stopped by an overdose of halothane at the end of the experiment. Although laser Doppler flowmetry is not quantitative, it monitors relative changes in CBF quite accurately (see Ref. 10 for a review).Vascular Diameter in Pressurized Middle Cerebral Arteries
Mice were deeply anesthetized with pentobarbital and decapitated. As described in detail elsewhere (13, 20), the brain was removed and quickly transferred to and kept in a normal physiological salt solution (PSS) composed of (in mM) 119 NaCl, 4.7 KCl, 24.0 NaHCO3, 1.2 KH2PO4, 1.6 CaC12, 1.2 MgSO4, 0.023 EDTA, and 11 glucose. PSS was continuously bubbled with 95% O2-5% CO2, adjusted to pH 7.4 with NaOH at 0-4°C on melting ice. The middle cerebral arteries were dissected from the brain and placed in PSS. The resistance-sized (<150 µm diameter at 10 mmHg) sections (1-2 mm length) of artery were cleaned of connective tissue and cannulated using glass micropipettes. The intact artery segment was secured in place on the pipettes with nylon ties and continuously superfused with PSS at 37°C, at a rate of 3-5 ml/min. After a 20-min equilibration period, intravascular pressure was gradually raised from 10 mmHg to 60 mmHg. Arteries that did not constrict in response to pressure were not used. The artery was viewed through an inverted microscope equipped with a video camera. Vessel lumen diameter was continuously measured with a video dimension analyzer (Living Systems; Burlington, VT), recorded via an analog-to-digital converter (DataQ Instruments; Akron, OH), and stored on disk for off-line analysis. The maximal diameter of each artery was measured by removal of Ca2+ from the superfusing PSS. Experiments with A superfusion were performed at an intraluminal
pressure of 60 mmHg. A1-40 was dissolved in PSS and superfused
on the artery.
Experimental Protocols
Effect of A superfusion on vasoconstrictor responses.
After stabilization of MAP and blood gases (Table 1), the thromboxane
A2 analog U-46619 (1 µM; Sigma), a potent vasoconstrictor (e.g., Ref. 6), was superfused on the exposed cerebral
cortex until the evoked change in CBF reached a steady state (usually 3-5 min). The superfusion solution was then switched back to
normal Ringer solution and CBF returned to baseline. Concentration of U-46619 was chosen in preliminary experiments to produce 50% of maximal responses as determined by dose-response curves
(11). The reduction in CBF produced by systemic hypocapnia
was also tested. Hypocapnia [arterial PCO2
(PaCO2) = 18-22 mmHg] was induced by
hyperventilation and by reducing CO2 through the circuit of the ventilator. Hypocapnia was monitored by end-tidal CO2
and by measuring PaCO2 after the reduction reached a
steady state. After responses during Ringer solution superfusion were
tested, the superfusion solution was changed to Ringer solution
containing increasing concentrations of A1-40 (0.01-10
µM), A1-42 (0.01-10 µM), or the control peptide
A40-1 (0.01-10 µM) (Sigma). To minimize aggregation of
the peptide during the experiment and to prevent potential effects on
aggregation by superoxide dismutase (SOD) or
manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin
(MnTBAP), A was freshly solubilized in DMSO and then diluted
in normal Ringer solution. The final DMSO concentration was <0.2%.
This concentration of DMSO does not affect resting CBF, does not
attenuate the reduction in CBF produced by topical application of
U-46619 and hypocapnia, and does not affect vasodilatatory responses of the cerebral circulation (unpublished observations; 17, 18, 26, 35). In
some studies, to rule out the possibility that the biological activity of A1-42 was diminished by DMSO, a ROS scavenger, this peptide was dissolved in Ringer solution without DMSO and the constrictor effect of U-46619 was tested. For each A
concentration, responses to U-46619 or hypocapnia were tested after
30-40 min of superfusion. This time interval was selected on the
basis of preliminary experiments in which the time course of the
cerebrovascular effects of A was investigated.
Effect of superoxide scavengers on the cerebrovascular actions of
A.
The window was superfused with Ringer solution and the effect of
U-46619 on CBF was tested. Ringer solution containing A1-40 (5 µM) was then superfused for 30 min and the effect of U-46619 was
tested again. The superfusion solution was then changed to Ringer
solution containing A1-40 and either SOD (Sigma; 100-500 U/ml) or the SOD mimetic MnTBAP (25-100 µM; Porphyrin Products, Logan, UT). The effect of U-46619 on CBF was tested 30 min later. SOD
is a superoxide scavenger that, due to its molecular weight, is thought
to act on extracellular superoxide (see Ref. 27). MnTBAP
is a cell-permeant agent and is thought to scavenge superoxide both
intracellularly and extracellularly (2, 7, 12). In some
studies, the window was superfused with Ringer solution containing SOD
(100 and 500 U/ml) or MnTBAP (25-100 µM) and the
effects of resting CBF and the response to U-46619 were assessed 30 min later.
Effect of superfusion with A1-40(M35Nle).
In some studies, we investigated the cerebrovascular effects of
A1-40 in which the methionine residue in position 35 was substituted with the norleucine A1-40(M35Nle), an amino acid structurally similar to methionine but lacking the sulfur atom (32). Such substitution eliminates the ability of
A1-40 to generate ROS (32). A1-40(M35Nle)
(purity >95%; lot number 6640; AnaSpec, San Jose, CA) was dissolved
in DMSO and superfused at a concentration of 5 µM. Effects on resting
CBF and on cerebrovascular responses evoked by U-46619 were tested
after 30 min of superfusion.
Data Analysis
Data in text and figures are expressed as means ± SE. Two-group comparisons were analyzed by the two-tailed t-test for dependent or independent samples as appropriate. Multiple comparisons were evaluated by the analysis of variance and Tukey's test. The data on isolated middle cerebral arteries were evaluated by the Dunnett's procedure for comparing multiple treatments with one control. Probability values of <0.05 were considered statistically significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of A ON CBF Reductions Produced by U-46619 or
Hypocapnia
1-40 (0.1-10 µM), but not A1-42 or the
reverse peptide A40-1, reduced resting CBF in a dose-dependent
manner (Fig. 1). The reduction in CBF was
sustained for at least 2 h after the onset of A1-40
superfusion. A dose dependently enhanced the reduction in CBF
produced by U-46619. The effect was more pronounced for A1-40
than for A1-42 and was not observed with A40-1 (Fig. 1). To rule out the possibility that the lower potency of A1-42 was due to DMSO (the solvent used to dissolve A), we also tested A1-42 dissolved in Ringer solution. There were no differences between the enhancement of the U-46619-induced constriction produced by
A1-42 dissolved in Ringer solution (24.4 ± 1.3%) and
DMSO (24.6 ± 1.3%; P > 0.05;
n = 6; t-test). In contrast to U-46619, the
reduction in CBF produced by hypocapnia was not enhanced by A1-40 or 1-42 compared with superfusion with Ringer
solution or with the inactive peptide A40-1 (Fig.
2).
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To confirm that the constrictor effect of A was independent of
parenchymal factors, we studied the effect of this peptide on isolated
pressurized (60 mmHg) middle cerebral arteries with intrinsic myogenic
tone (internal diameter 111 ± 7 µm, n = 7 arteries). A1-40 produced a dose-dependent constriction
statistically significant at a concentration of 1 nM and was well
developed at 100 nM (Fig. 3;
P < 0.05 from control).
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Effect of SOD and MnTBAP on Cerebrovascular Actions of A
are counteracted by superoxide-scavenging agents
(17). Therefore, we investigated whether the constrictor
effects of A1-40 are reversed by the superoxide scavengers SOD
or MnTBAP. During Ringer solution superfusion, A1-40 (5 µM)
attenuated resting CBF and enhanced constrictor response to U-46619
(Fig. 4). Superfusion with SOD
(100-500 U/ml) or MnTBAP (25-100 µM) counteracted the reduction in resting CBF and enhancement of the constrictor effect of
U-46619 (Fig. 4). MnTBAP was more effective than SOD (Fig. 5), a finding probably reflecting the
better brain penetration of MnTBAP, or the fact that MnTBAP scavenges
both superoxide and hydrogen peroxide (2, 7, 12). As for
A1-40, the enhancement of the constrictor effect of U-46619
produced by A1-42 was offset by SOD or MnTBAP (Figs. 4 and 5).
In the absence of A, SOD (500 U/ml; n = 6) or MnTBAP
(100 µM; n = 5) did not influence resting CBF (before
SOD 19.1 ± 4.0 and after SOD 19.4 ± 4.1 perfusion units;
before MnTBAP 18.3 ± 4.4 and after MnTBAP 18.2 ± 4.4 perfusion units; P > 0.05) or the reduction in CBF
produced by U-46619 (before SOD 19.9 ± 3.0 and after SOD
20.0 ± 2.8%; before MnTBAP 18.7 ± 3.7% and after
MnTBAP 19.0 ± 1.3%; P > 0.05; paired
t-test). These observations, in conjunction with previous
observations (17), indicate that SOD and MnTBAP are devoid
of cerebrovascular effects that could confound the interpretation of
the results.
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Effect of A1-40(M35Nle) on the Reduction in CBF Produced by
U-46619
to generate ROS
(32). Therefore, we used A1-40(M35Nle) to provide
additional evidence in support of the hypothesis that the constrictor
effects of A are mediated by ROS. A1-40(M35Nle) (5 µM) did
not reduce resting CBF (before 19.1 ± 3.4 or after 19.2 ± 3.6 perfusion units; P > 0.05; n = 5;
paired t-test) and did not alter the reduction in CBF
produced by U-46619 (before 18.4 ± 4.1 or after 19.3 ± 2.9%; P > 0.05; n = 5; paired
t-test).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have demonstrated that A peptides attenuate resting CBF and
enhance the reduction in CBF produced by the thromboxane analog U-46619
but not by hypercapnia. The enhancement of constriction was more
pronounced for A1-40 than for A1-42, and was not
observed with the reverse peptide A40-1. Furthermore,
A1-40 constricted isolated-pressurized middle cerebral
arteries, indicating that the constrictor effects of the peptide are
independent of parenchymal factors released by A. We then sought to
study the mechanisms of this vascular effect of A with respect to
the role of ROS. We found that the free radical scavengers SOD and
MnTBAP counteract the A-induced reduction in resting CBF and
enhancement of constriction. Furthermore, a mutated form of A that
does not generate ROS (32) was devoid of effects on CBF
and did not alter constriction. These observations provide strong
evidence that the constrictor effects of A peptides are mediated
through production of ROS.
Although it has been shown that A produces constriction of systemic
and cerebral vessels (22, 28, 29), in these studies, arteries were preconstricted with phenylephrine or serotonin (22, 28, 29), and pharmacological interactions between A and the drug used to produce constriction could not be ruled out. In the present study, by using a cranial window preparation, we were able to
demonstrate that the A-induced enhancement of constriction is also
observed in the intact cerebral circulation in vivo. Furthermore, we
found that A is a potent vasoconstrictor also in
isolated-pressurized vessels with intrinsic tone. Constrictor effects
were observed at concentrations smaller than those reported to be
effective in pharmacologically preconstricted arteries (22, 28,
29). Therefore, the constrictor effects of A seem to be more
potent in arteries with intrinsic tone.
It is unlikely that the enhancement of constriction produced by A is
due to nonspecific effects of the peptide on all constrictor responses,
because the enhancement is observed only in the CBF reductions produced
by U-46619 and not by hypocapnia. Therefore, the effect of A is
restricted to specific constrictor responses. It is also unlikely that
the effect of A is mediated by endothelial cell destruction, as
reported in isolated vessel preparations (22, 28, 29).
This is because the effects of A on resting CBF and on the response
to U-46619 is abrogated by SOD or MnTBAP, indicating that the
A-induced alteration is reversible and, as such, cannot be due to
necrosis of endothelial cells. This conclusion is also supported by the
observation that, in this preparation, the A-induced attenuation of
endothelium-dependent CBF responses is counteracted by SOD or MnTBAP
(17). Therefore, the enhancement of constriction is not
related to endothelial destruction but rather to a specific vascular
dysfunction mediated by A.
The cellular mechanisms of the effect of A on constriction remain to
be fully elucidated. The observation that A produced constriction
also in isolated pressurized middle cerebral arteries indicates that
the brain parenchyma is not needed for this action. Therefore, the
effect of A could be mediated by actions on endothelial cells and/or
vascular smooth muscles. The finding that A affects endothelium-dependent vasodilation suggests that this peptide alters
endothelial cell function (11, 17). Therefore, the increased constriction could be due to loss of vasodilator tone provided by endothelium-derived relaxing factors (for a review, see
Ref. 5). If this were the case, one would anticipate that all constrictor responses would be enhanced. However, A did not augment the reduction in CBF produced by hypocapnia. Therefore, it is
unlikely that the enhancement of vasoconstriction is due solely to
increased constrictor tone resulting from impairment of
endothelium-dependent relaxation. On the other hand, A could stimulate the production of endothelium-derived constrictor factors (19, 23, 36). Although we have no data to support or
disprove this hypothesis, this possibility seems unlikely, because
endothelium removal does not affect A vasoactivity in vitro
(1), suggesting that endothelial factors are not involved
in the vascular effect of A. Therefore, A could act directly on
vascular smooth muscle cells to enhance the constrictor response
produced by the U-46619. This possibility seems likely in view of the
fact that both in our in vivo and in vitro preparations, A was
applied only to the abluminal side of the vessel. However, we cannot
rule out the possibility that A also reached the endothelium in our
preparation. Therefore, further experiments in which the role of
endothelial and smooth muscle cells is studied are required to define
the cellular site of action of A.
Irrespective of the cellular target(s) of A, our data suggest that
its constrictor effects are mediated through production of ROS.
However, the free radical species involved remain to be defined. A
is thought to produce ROS through different mechanisms (for a review,
see Ref. 15). Whereas A itself generates free radical
peptides (9), it may also do so by binding to RAGE receptors on endothelial and smooth muscle cells, and by activating NADPH oxidase (3, 34). In addition to NADPH oxidase,
common sources of ROS at the vascular level include cyclooxygenase,
xanthine oxidase, nitric oxide synthase, and mitochondrial enzymes
(30). Therefore, the sources of ROS are likely to be
multiple. It remains to be determined whether ROS are the ultimate
mediator of constriction or whether other factors are also involved.
There is evidence that calcium channels contribute to A vasoactivity
(1). Furthermore, it remains to be established whether, in
addition to ROS, receptor-dependent mechanisms also play a role in the
constrictor effects of A.
The state of aggregation of A, which is influenced by ROS, has a
profound effect on the biological activities of the peptide (9,
15). However, the role of peptide aggregation in A
vasoactivity has not been defined. Differences in aggregation could
explain the difference in vasoactivity between A1-40 and
A1-42. Furthermore, changes in aggregation produced by
substitution of the methionine residue in position 35 with norleucine,
a mutation that abolishes the ability of A to generate ROS
(32), could play a role in the lack of vasoactivity of
A1-40(M35Nle). However, this view is not supported by recent
studies indicating that the ability of mutated A to form fibrils is
not different from that of native A (31).
We have previously demonstrated that in mice overexpressing APP, the
reduction in CBF produced by the thromboxane analog U-46619 is enhanced
(11). The enhancement of constriction is not
observed in double transgenics overexpressing both APP and SOD,
suggesting an involvement of ROS in the effect (11). The
results of the present study complement and extend these observations
by demonstrating that acute application of exogenous A can account
in full for this action. Furthermore, we demonstrated that both the
short (A1-40) and the long (A1-42) form of the peptide
are involved, although A1-40, which is in higher concentration
in APP mice (18), is more potent. The mechanisms for the
difference in vascular actions of the two forms of the peptide remain
to be elucidated.
An important question concerns whether the concentration of A in the
cerebrospinal fluid (CSF) of patients with AD would be sufficient to
produce vascular dysfunction. The CSF concentration of A1-40 is
not increased, whereas A1-42 is reduced compared with
nondemented controls (25). However, A levels are
greatly elevated in brain and blood vessels of AD patients, with
A1-40 being most abundant in vessels (8, 33).
Therefore, A in cerebral and vascular tissues, rather than in CSF,
is likely to produce cerebrovascular dysfunction in AD patients.
We conclude that A-peptides attenuate resting CBF and enhance the
reduction in CBF produced by the vasoconstrictor U-46619, an
effect more potent for A1-40 than A1-42. The
constrictor effects of A are reversed by the free radical scavengers
SOD or MnTBAP. The data are consistent with the hypothesis
that A, through the production of ROS, enhances selected constrictor
responses of the cerebral circulation. These findings raise the
possibility that such enhancement of vasoconstriction could reduce CBF
and contribute to brain dysfunction in diseases associated with A accumulation in the brain parenchyma or blood vessels.
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ACKNOWLEDGEMENTS |
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We thank Andrea Hyde for editorial assistance.
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FOOTNOTES |
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This study was supported by National Institute of Neurological Disorders and Stroke Grants NS-37853 and NS-38252. C. Iadecola was the recipient of a Javits Award from National Institute of Neurological Disorders and Stroke. V. A. Porter is a Parker B. Francis Fellow in pulmonary research.
Address for reprint requests and other correspondence: C. Iadecola, Dept. of Neurology, Univ. of Minnesota, MMC 295, 516 Delaware St. SE, Minneapolis, MN 55455 (E-mail: iadec001{at}tc.umn.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 16 May 2001; accepted in final form 23 August 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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