© 2001 American Heart Association, Inc.
Integrative Physiology |
Cyclooxygenase-1 Participates in Selected Vasodilator Responses of the Cerebral Circulation
From the Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minn.
Correspondence to Costantino Iadecola, MD, Department of Neurology, University of Minnesota, MMC 295, 420 Delaware St SE, Minneapolis, MN 55455. E-mail iadec001{at}tc.umn.edu
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Abstract |
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Abstract—Cyclooxygenase (COX) is a prostanoid-synthesizing enzyme present in 2 isoforms: COX-1 and COX-2. Although it has long been hypothesized that prostanoids participate in cerebrovascular regulation, the lack of adequate pharmacological tools has led to conflicting results and has not permitted investigators to define the relative contribution of COX-1 and COX-2. We used the COX-1 inhibitor SC-560 and COX-1–null (COX-1-/-) mice to investigate whether COX-1 plays a role in cerebrovascular regulation. Mice were anesthetized (urethane and chloralose) and equipped with a cranial window. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry or by the 14C-iodoantipyrine technique with quantitative autoradiography. In wild-type mice, SC-560 (25 µmol/L) reduced resting CBF by 21±4% and attenuated the CBF increase produced by topical application of bradykinin (-59%) or calcium ionophore A23187 (-49%) and by systemic hypercapnia (-58%) (P<0.05 to 0.01). However, SC-560 did not reduce responses to acetylcholine or the increase in somatosensory cortex blood flow produced by vibrissal stimulation. In COX-1-/- mice, resting CBF assessed by 14C-iodoantipyrine was reduced (-13% to -20%) in cerebral cortex and other telencephalic regions (P<0.05). The CBF increase produced by bradykinin, A23187, and hypercapnia, but not acetylcholine or vibrissal stimulation, were attenuated (P<0.05 to 0.01). The free radical scavenger superoxide dismutase attenuated responses to bradykinin and A23187 in wild-type mice but not in COX-1-/- mice, suggesting that COX-1 is the source of the reactive oxygen species known to mediate these responses. The data provide evidence for a critical role of COX-1 in maintaining resting vascular tone and in selected vasodilator responses of the cerebral microcirculation.
Key Words: cerebral blood flow • endothelium dependent vasodilators • 14C-2-deoxyglucose • 14C-iodoantipyrine • laser Doppler flowmetry
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cyclooxygenase (COX) is a rate-limiting enzyme in the synthesis of prostanoids from arachidonic acid (AA).1 Two isoforms of COX have been identified: COX-1 and COX-2.2 COX-1 is expressed constitutively in most cells and is thought to be involved in the physiological synthesis of prostanoids.2 COX-2 is characteristically upregulated by inflammatory mediators, and its reaction products have been implicated in the toxicity associated with inflammation.3 In brain, however, COX-2 is expressed in excitatory neurons and may play a role in synaptic transmission.4
COX reaction products have long been hypothesized to participate in the regulation of the cerebral circulation.5 6 7 For example, indomethacin, an agent that inhibits both COX-1 and COX-2, attenuates resting cerebral blood flow (CBF) and reduces the elevations in CBF produced by selected endothelium-dependent vasodilators or hypercapnia.8 9 10 11 12 However, indomethacin has pharmacological effects unrelated to COX inhibition, such as inhibition of the prostacyclin receptor and cAMP-dependent protein kinase,13 14 that raise questions about its mechanism of action. Furthermore, the cerebrovascular effects of indomethacin are not reproduced by other COX inhibitors, including diclofenac, sulindac, or aspirin.15 16 17 18 Therefore, the role of COX in the regulation of the cerebral circulation has not been firmly established.
In the present study, we used the highly selective COX-1 inhibitor SC-56019 and COX-1–null (COX-1-/-) mice20 to test the hypothesis that COX-1 contributes to cerebrovascular regulation. We found that COX-1 is involved in maintaining resting CBF and in the increase in CBF produced by hypercapnia, AA, A23187, and bradykinin (BK). However, COX-1 is not involved in the increase in CBF produced by activation of the whisker barrel cortex or by acetylcholine (ACh). Furthermore, we provide evidence that COX-1 is the source of the reactive oxygen species (ROS) known to mediate the vasodilation produced by BK and A23187.8 9 21 These data, in concert with the finding that COX-2 contributes to CBF responses evoked by neural activity,22 suggest that COX-1 and COX-2 play distinct roles in cerebrovascular regulation.
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Materials and Methods |
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Experimental protocols were approved by the Institutional Animal Care Committee. Techniques for surgical preparation of the mice and for monitoring CBF and cerebral glucose utilization (CGU) were similar to those previously described22 23 and are briefly summarized below.
Animals
C57BL/6J mice were purchased from Jackson
Laboratories (Bar Harbor, Maine).
COX-1-/- (homozygous) mice (-/-) and
their wild-type (+/+)
littermates20 were obtained
from breeding pairs provided by Jackson laboratories. Mice were
back-crossed to C57BL/6J mice 6 to 8 times and were studied at ages 2
to 3 months. The genotypes of all COX-1 mice were determined by
polymerase chain reaction.20
COX-2 expression is not altered in
COX-1-/-
mice.20
General Surgical Procedures
Mice were anesthetized with urethane (750
mg/kg) and chloralose (50 mg/kg). The trachea was intubated, and mice
were artificially ventilated with an oxygen-nitrogen mixture. The
femoral vessels were cannulated for recording mean
arterial pressure (MAP) and for collecting blood samples. A
small craniotomy (2x2 mm) was performed to expose
the whisker-barrel area of the somatosensory cortex, the dura was
removed, and the site was superfused with Ringer solution (37°C; pH
7.3 to 7.4). Rectal temperature was maintained at 37°C, end-tidal
CO2 was monitored by a
CO2 analyzer (Capstar-100, CWE Inc), and
arterial blood gases were measured. The level of
anesthesia was monitored by testing corneal reflexes and
motor responses to tail pinch.
Cerebral Blood Flow Monitoring by Laser
Doppler Flowmetry
CBF was continuously monitored at the site of the
cranial window with a laser Doppler probe (Vasamedic) positioned
stereotaxically 0.5 to 1 mm from the cortical
surface.22 23 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.
Cerebral Blood Flow Monitoring by
Quantitative Autoradiography
Because laser Doppler flowmetry is not
adequate to quantify resting
CBF,24 regional CBF was also
measured using 14C-labeled iodoantipyrine
(IAP) as a tracer.23
14C-labeled IAP (American Radiolabeled
Chemicals, 13 to 20 µCi/100 g in 0.1 mL) was infused
intravenously, and timed arterial samples were
collected.23 For
determination of tissue 14C concentration,
brains were removed and frozen. Serial sections (20 µm) were cut
using a cryostat (Hacker-Bright, model OTF), mounted on glass slides,
and apposed to X-ray film (Sterling Diagnostic Imaging Inc)
together with calibrated 14C standards. Ten
days later, the film was developed, and the
14C concentration (nCi/g) of regions of
interest was determined using an image analyzer (MCID system,
Imaging Research Inc). CBF (mL/100 g per min) was calculated using the
equation described by
Kety.25
Cerebral Glucose Utilization
CGU was determined by using a modification of the
14C-2-deoxyglucose (2-DG) method of
Sokoloff.22 23
14C-labeled 2-DG (20 µCi/100 g in 1 mL
0.9% NaCl; New England Nuclear) was injected
intraperitoneally, and about 60 µL of
arterial blood was collected 1, 5, 7, 10, 15, 20, 25, 35,
and 45 minutes later for determination of 2-DG and glucose
concentration
(Table 1
). Brain 14C
concentration was determined by quantitative
autoradiography (see IAP). CGU (µmol/100 g per min)
was calculated from the radioactivity of the regions of interest and
the arterial time course of
2-DG.22 23
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Experimental Protocol
Effect of SC-560 on Cerebrovascular Responses
in C57BL/6J Mice
After stabilization of MAP and blood gases
(Table 1
), ACh (10 µmol/L; Sigma), BK (50 µmol/L;
Sigma), the calcium ionophore A23187 (3 µmol/L; Sigma), and
S-nitroso-N-acetylpenicillamine
(SNAP) (100 or 500 µmol/L; RBI) were superfused on the cerebral
cortex until the evoked change in CBF reached a steady state (usually 3
to 5 minutes). The concentrations of ACh, BK, and A23187 were chosen to
produce 50% of maximal responses, as determined by dose-response
curves.26 To study the
increase in CBF produced by systemic hypercapnia,
CO2 was introduced in the circuit of the
ventilator until arterial
PCO2
reached 50 to 60 mm Hg. In mice in which the CBF response
produced by vibrissal stimulation was investigated, the right vibrissae
were cut to a length of 5 to 10 mm and stimulated for 1 minute by
gently stroking them (3 to 4 Hz) with a cotton-tipped
applicator.22 23
CBF responses to ACh, BK, A23187, and vibrissal stimulation were tested
in random order before and after topical neocortical superfusion of the
COX-1 inhibitor SC-560 (10 to 100 µmol/L; provided by
Searle-Monsanto, Skokie,
Ill).19 SC-560
[5-(4-chlorophenyl)-1-(4-metoxyphenyl)-3-trifluoromethy- pyrazole]
inhibits COX-1 1000 times more potently than COX-2 and, unlike other
COX-1 inhibitors (eg, resveratrol), it does not act as a
free-radical scavenger.19
SC-560 was dissolved in dimethylsulfoxide (DMSO) and then diluted with
Ringer to the desired concentration. The final DMSO concentration was
<0.2%, which does not affect the cerebrovascular responses
tested.23 27 Each
concentration of SC-560 was applied for 40 minutes, a period previously
determined to be maximally effective.
Effect of SC-560 Superfusion on Local
CGU
In C57BL/6J mice, the cranial window was superfused
with normal Ringer or with Ringer containing SC-560 (50 µmol/L).
Forty minutes later, 2-DG was infused for CGU measurement. At the end
of the experiment, the position of the window was marked with black ink
so that the superfusion site could be identified at the time of brain
cutting. The brain was removed and processed for quantitative
autoradiography (see above). CGU was measured at the
superfusion site, in the contralateral homotopic cortical area, and in
other neocortical regions listed in
Table 2.
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CBF and Cerebrovascular Responses in
COX-1-/- Mice
In these studies, the increase in CBF produced by
topical application of ACh, BK, A23187, AA (1 or 10 µmol/L; Sigma),
and SNAP and by arterial hypercapnia or vibrissal
stimulation were studied in COX-1+/+ and
COX-1-/- mice. CBF responses, assessed
by laser Doppler flowmetry, were studied before and after
superfusion with SC-560 (50 µmol/L) for 40 minutes. In experiments in
which the effect of superoxide dismutase (SOD; 500 U/mL) was studied,
responses to BK, A23187, and hypercapnia were tested before and 30
minutes after superfusion of the cranial window with this
enzyme.26 In studies in
which CBF was measured by the IAP technique, mice were
anesthetized and surgically prepared as in the CGU experiments,
with the exception that the cranial window was not drilled. After
stabilization of the preparation, IAP was infused and CBF was
determined by quantitative autoradiography in the brain
regions listed in
Table 3.
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Data Analysis
Data in text, tables, and figures are expressed as
mean±SE. Two-group comparisons were analyzed by Student’s
paired or unpaired t test, as
appropriate. Multiple comparisons were evaluated by ANOVA and Tukey’s
test. P<0.05 was considered
statistically significant.
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Results |
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Effect of SC-560 on Resting CBF and on Cerebrovascular Responses
Topical application of SC-560 (10 to 100 µmol/L) reduced resting CBF dose-dependently. The effect reached a plateau at a concentration of 25 µmol/L (-21%; P<0.01; ANOVA; Figure 1
). SC-560 attenuated the increase in CBF produced by
hypercapnia (-58% at 25 µmol/L;
P<0.01;
Figure 1), BK (-59%;
P<0.01), and A23187 (-49%;
P<0.01;
Figure 1). In contrast, SC-560 (10 to 100 µmol/L) did not
affect the CBF response evoked by topical application of ACh or by
vibrissal stimulation (P>0.05;
Figure 2). Similarly, SC-560 (100 µmol/L) did not affect
the vasodilation produced by the nitric oxide (NO) donor SNAP (100
µmol/L: Ringer: 26±1%; SC-560: 26±1%; 500 µmol/L: Ringer:
49±4%; SC-560: 49±2%;
P>0.05).
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Effect of SC-560 on CGU
Cerebral energy metabolism, a variable
closely related to neural activity, has profound effects on CBF and its
reactivity.28 To rule out
the possibility that the cerebrovascular actions of SC-560 are related
to reduction in cerebral metabolism, the effect of SC-560
on CGU was investigated. In agreement with previous
studies,27 superfusion of
the cerebral cortex with normal Ringer produced a slight increase in
CGU at the site of superfusion
(Table 2; P<0.05;
Student’s paired t test).
SC-560 (50 µmol/L) did not affect CGU at the site of superfusion or
in other neocortical regions
(P>0.05).
Resting CBF in
COX-1-/- Mice
In these experiments, we used
COX-1-/- mice to provide independent
evidence for a role of this enzyme in the maintenance of
resting CBF. No differences in size and distribution of large cerebral
vessels were detected between COX-1+/+ and
-/- mice, in which the cerebral
arterial tree was injected with India ink. Resting CBF,
measured by the quantitative IAP technique, was reduced in selected
brain regions of COX-1-/- mice
(Table 3). Statistically significant reductions (13% to
20%; P<0.05; Student’s
unpaired t test) were observed
in the cerebral cortex, thalamus, hippocampus, amygdala, and
hypothalamus
(Table 3). No significant reductions
(P>0.05) were observed in
regions of the lower brain stem
(Table 3).
Cerebrovascular Responses in
COX-1-/- Mice
In these experiments, CBF was monitored
continuously by laser Doppler flowmetry. In
COX-1+/+ mice, SC-560 (50 µmol/L)
attenuated resting CBF, as well as the increase in CBF produced by
hypercapnia, BK, A23187, and AA
(Figure 3; P<0.05 to
0.01; ANOVA). In COX-1-/- mice, CBF
responses to hypercapnia, BK, A23187, and AA were reduced
(Figure 3; P<0.01).
Superfusion with SC-560 in COX-1-/- mice
did not attenuate the response additionally
(Figure 3; P>0.05).
Increases in CBF produced by ACh, SNAP, or vibrissal stimulation did
not differ between COX-1+/+ and
-/- mice and were not affected by SC-560
(Figure 4).
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Effect of SOD on Responses to BK,
A23187, and Hypercapnia in COX-1-/-
Mice
COX-derived ROS have been implicated in the mechanisms
of the cerebrovasodilation produced by BK and
A23187.7 In these
experiments, we used SOD in COX-1-/-
mice to determine whether COX-1 is the source of the ROS. Superfusion
with SOD did not affect resting CBF in
COX-1+/+ and
COX-1-/- mice
(Figure 5; P>0.05).
In COX-1+/+ mice, in agreement with previous
findings,8 9 21
SOD superfusion attenuated the increase in CBF produced by BK and
A23187 but not by hypercapnia
(Figure 5). However, in
COX-1-/- mice, SOD failed to
additionally reduce the increase in CBF produced by these vasodilators
(Figure 5).
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Discussion |
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We used SC-560, a highly selective COX-1 inhibitor,19 to examine the contribution of COX-1 to cerebrovascular regulation. We found that SC-560 reduces resting CBF and attenuates the CBF increase produced by hypercapnia, BK, AA, and A23187. In contrast, the increase in CBF produced by ACh, vibrissal stimulation, and SNAP are not affected. To provide nonpharmacological evidence for a role of COX-1, we also used mice with a null mutation of the COX-1 gene.20 We found that resting CBF, assessed quantitatively by the IAP technique, is reduced in selected telencephalic regions of COX-1-/- mice. Furthermore, responses to hypercapnia, BK, AA, and A23187 are attenuated in COX-1-/- mice, whereas responses to ACh, vibrissal stimulation, and SNAP are not affected. These data collectively provide strong evidence that COX-1 plays an important role in the maintenance of resting CBF and in the vasodilation produced by selected endothelium-dependent vasodilators or hypercapnia.
The cerebrovascular actions of SC-560 cannot be attributed to nonspecific effects resulting in vasoparalysis or to a progressive deterioration of the preparation, because this inhibitor affected only selected cerebrovascular responses and did not alter the vasodilation elicited by ACh, functional activation, and SNAP. The cerebrovascular actions of SC-560 are not attributable to effects on cerebral metabolism, a variable tightly linked to CBF, because SC-560 did not attenuate resting CGU. Furthermore, it is unlikely that SC-560 exerts its effects by mechanisms unrelated to COX-1 inhibition. This is because SC-560 produced cerebrovascular alterations identical to those observed in COX-1-/- mice. In addition, treatment of COX-1-/- mice with SC-560 failed to influence CBF and its reactivity, indicating that this drug was ineffective in the absence of COX-1. Differences in the genetic background of null mice can have profound effects on the phenotype.29 To minimize this problem, we used mice that were back-crossed several times into the C57BL/6J strain and used wild-type littermates as controls. Therefore, the cerebrovascular alterations observed in COX-1-/- mice cannot be attributed to heterogeneity of the genetic background.
Recent data suggest that COX-2 is also involved in the regulation of the cerebral circulation. In brain, COX-2 is constitutively expressed in glutamatergic neurons.4 Pharmacological inhibition of COX-2 by NS-398 or genetic deletion in COX-2-/- mice attenuates the increase in CBF produced in the whisker-barrel cortex by vibrissal stimulation.22 Resting CBF and the CBF increase produced by hypercapnia or by endothelium-dependent vasodilators are not affected by COX-2 inhibition or in COX-2-/- mice.22 These findings, in concert with the results of the present study, indicate that COX-1 and COX-2 have distinct roles in the regulation of the cerebral circulation. Whereas COX-2 contributes exclusively to vascular responses initiated by neural activity, COX-1 participates in responses initiated at the vascular level, such as the endothelium-dependent vasodilation produced by BK or A23187.
The responses to hypercapnia, BK, A23187, and AA are attenuated but not abolished in COX-1-/- mice or in wild-type mice treated with SC-560. In contrast, investigations using the nonselective COX inhibitor indomethacin found that this drug virtually abolishes the vasodilation produced by BK.30 Considering that COX-2 does not contribute to the response to BK,22 it is unlikely that the greater potency of indomethacin is attributable to the inhibition of both COX-1 and COX-2. Therefore, a plausible explanation for the effect of indomethacin is that this drug also acts through pharmacological effects unrelated to COX inhibition.13 14
COX-1 inhibition or genetic deletion in COX-1-/- mice also attenuates the response to hypercapnia. The mechanisms of the increase in CBF produced by hypercapnia are complex and depend on both vascular and parenchymal factors.31 Although the ultimate mechanisms of the vasodilation is likely to involve the action of H+ on cerebral smooth muscle cells,32 33 many factors intrinsic and extrinsic to the vascular wall are potent modulators of this response. For example, in some species, prostanoids and neurally derived NO act as permissive factors that facilitate, rather than mediate, the hypercapnic vasodilation.34 35 Our data would indicate that COX-1 is the source of the prostanoids serving as permissive factors. However, it is of interest that the hypercapnic vasodilation is also attenuated in COX-1-/- mice. This observation suggests that in COX-1-/- mice, the role of COX-1 in the vasodilation was not replaced by other factors, as is often the case in null mice. For example, although pharmacological inhibition of NO synthesis attenuates the hypercapnic vasodilation,36 null mice lacking either the endothelial or neuronal isoform of NO synthase have a normal CBF response to hypercapnia,37 38 suggesting that the role of NO was taken over by other factors. Therefore, the observation that the hypercapnic vasodilation is attenuated both by acute inhibition of COX-1 and in COX-1-/- mice raises the possibility that COX-1 plays an obligatory role in the response and, as such, cannot be compensated.
The cellular source of COX-1 and the reaction products responsible for its cerebrovascular effects remain to be determined. In the ovine brain, COX-1 seems to be localized to the wall of cerebral blood vessels and to selected neurons, most abundantly in cerebral cortex, hippocampus, amygdala, and hypothalamus.39 However, a more detailed analysis of COX-1 localization in the murine brain using more specific antibodies is needed to define the potential source of COX-1 in the cerebral circulation. As for the COX-1 reaction products, PGE2 and prostacyclin are vasoactive40 41 and could be the effector of the vasodilation. Indeed, the observation that the effect of the nonselective COX inhibitor indomethacin on the hypercapnic vasodilation is reversed by prostacyclin suggests that this prostanoid contributes to the vascular actions of COX-1.35
On the other hand, COX-1–derived reactive oxygen species could also play a role, particularly in the vasodilation produced by BK, AA, and A23187.8 9 21 This possibility is supported by our finding that SOD attenuates the increase in CBF produced by BK and A23187 in wild-type mice but not in COX-1-/- mice. This observation indicates that in the absence of COX-1, SOD is not effective in attenuating these responses and suggests that COX-1 is the source of the ROS mediating the vasodilation. The finding that the response to hypercapnia is not attenuated by SOD provides additional evidence that the role of COX-1 in the hypercapnic vasodilation is distinct from that in responses to BK and A23187. Similarly, the observation that SOD does not reduce resting CBF suggests that COX-1–derived prostanoids, rather than ROS, contribute to maintain resting cerebrovascular tone.
The vasodilator action of ROS is mediated by potassium channels 21 42 However, it is unlikely that the effects of SC-560 are mediated by inhibition of potassium channels, because COX-1-/- mice exhibit cerebrovascular alterations identical to those produced by SC-560. Furthermore, the increases in CBF produced by the NO donor SNAP or by functional activation, responses mediated in part by potassium channels,43 44 45 46 are not altered by SC-560 or in COX-1-/- mice. However, we cannot rule out the possibility that the effect of COX-1 reaction products on cerebral blood vessels is mediated through downstream effects on vascular potassium channels.
In conclusion, we have demonstrated that the COX-1 inhibitor SC-560 attenuates resting CBF and blunts the CBF increases produced by BK, AA, A23187, and hypercapnia. Responses to ACh and functional activation are not affected. The cerebrovascular actions of SC-560 could not be attributed to effects on cerebral metabolism. Importantly, COX-1-/- mice exhibited cerebrovascular alterations identical to those observed in wild-type mice treated with SC-560. Furthermore, experiments with SOD in COX-1-/- mice indicated that COX-1–derived ROS mediate responses to BK and A23187. The data provide evidence for a critical role of COX-1 in the maintenance of resting cerebrovascular tone and in selected response of the cerebral circulation. These observations, in concert with the finding that COX-2 contributes to the increase in CBF produced by neural activation,22 indicate that COX-1 and COX-2 subserve distinct roles in cerebrovascular regulation.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (NS35806 and NS38252). C.I. is the recipient of a Javits Award from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. SC-560 was provided by Searle-Monsanto, Skokie, Ill. The editorial assistance of Andrea Hyde is gratefully acknowledged.
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Footnotes |
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Original received December 8, 2000; revision received February 1, 2001; accepted February 20, 2001.
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