(Stroke. 1995;26:857-863.)
© 1995 American Heart Association, Inc.
Articles |
Glutamate-Induced Cerebral Vasodilation Is Mediated by Nitric Oxide Through N-Methyl-D-Aspartate Receptors
From the Departments of Physiology and Pharmacology (W.M.), Anesthesiology (J.R.T.), and the Neuroscience Program (D.W.B.), Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC.
Correspondence to David W. Busija, PhD, Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1083.
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Abstract |
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Background and Purpose It was found that glutamate, a major neurotransmitter, is vasoactive in the cerebral circulation. However, the mechanism is unclear. This study was designed to investigate the role of nitric oxide (NO) and N-methyl-D-aspartate (NMDA) receptors in cerebral arteriolar dilation to glutamate.
Methods Newborn, chloralose-anesthetized pigs were equipped with a closed cranial window. The diameter of pial arterioles was measured by means of intravital microscopy, and NO synthase (NOS) activity in brain cortex was determined by the conversion assay of [14C]arginine to [14C]citrulline.
Results Topical application of glutamate at 10-7, 10-6, and 10-5 mol/L (n=5) increased the mean diameter by 12±3%, 13±2%, and 18±3% (±SEM), respectively (baseline, 91±10 µm; P<.05). Similarly, NMDA application at the above doses (n=5) dilated arterioles by 10±2%, 16±3%, and 18±6%, respectively (baseline, 97±4 µm; P<.05). Topical application of 10-4 mol/L NG-nitro-L-arginine (L-NNA), which inhibited NOS activity by 93%, blocked the arteriolar dilation to glutamate or NMDA. Furthermore, administration of MK-801, a potent inhibitor of NMDA receptors, blocked glutamate-induced vasodilation completely in both topical application (10-5 mol/L; n=6) and intravenous administration (5 to 10 mg/kg; n=5). In addition, neither L-NNA nor MK-801 attenuated the vasodilation to hypercapnia (PCO2=40 to 68 mm Hg).
Conclusions Glutamate-induced cerebral arteriolar dilation is mediated by NO through NMDA receptors, and NO does not play a major role in the cerebral arteriolar dilation to hypercapnia (PCO2=40 to 68 mm Hg) in newborn pigs.
Key Words: pigs • cerebral circulation • nitric oxide • glutamate • N-methyl-D-aspartate
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Glutamate is an important neurotransmitter in the brain. Previously, Busija and Leffler1 were the first to demonstrate that glutamate and other excitatory amino acid neurotransmitters as well as N-methyl-D-aspartate (NMDA), a synthetic analogue of glutamate, are vasodilators in the cerebral circulation. Although glutamate increases neuronal activity and cortical metabolic rate,2 the final mediator of arteriolar dilation is unclear. Recently it has been found that inhibition of nitric oxide synthase (NOS) or NMDA receptors prevents cerebral arteriolar dilation to NMDA, suggesting that NMDA-induced vasodilation is mediated by nitric oxide (NO) through NMDA receptors.3 In contrast to NMDA, glutamate can activate NMDA, kainate, and AMPA (
-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors located
on neurons and glial cells.4 5 However, NMDA receptors
mediate most of the neuronal cGMP response to glutamate.5
These findings lead to the hypothesis that glutamate-induced arteriolar
dilation may be mediated by NO, and the activation of NMDA receptors by
glutamate may be at least partially responsible for NO production and
the consequent arteriolar dilation. The present study was designed to examine (1) whether NO mediates glutamate-induced cerebral arteriolar dilation and (2) whether the NMDA receptors are responsible for glutamate-induced vasodilation.
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Materials and Methods |
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Experiments were carried out on newborn (1- to 7-day-old) pigs of either sex (weight, 1.2 to 2.2 kg). The piglets were anesthetized with sodium thiopental (30 mg/kg IP) and then
-chloralose (75 mg/kg
IV). Supplemental doses of -chloralose were injected as needed to
maintain a stable level of anesthesia. The piglets were intubated and
artificially ventilated with room air. A femoral artery and vein were
cannulated with polyethylene (PE-90) tubing. Arterial blood samples
were taken regularly from the femoral artery to measure blood gases,
and the PaCO2, pH, and
PaO2 were maintained within the normal
physiological range. The rectal temperature was maintained at 37°C to
38°C with a heating pad. Each piglet's head was fixed in a
stereotaxic apparatus, the scalp was cut, and the connective tissue
over the parietal bone was removed. A craniectomy of 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
dental acrylic. The closed window was filled with artificial
cerebrospinal fluid (aCSF) that was warmed to 37°C and equilibrated
with 6% O2/6.5% CO2 in N2.
The composition of the aCSF was as follows (mmol/L): KCl 2.9,
MgCl2 1.4, CaCl2 1.2, NaCl 132,
NaHCO3 24.6, urea 6.7, and glucose 3.7. The arterioles on
the cerebral surface were observed under a microscope (Wild M36)
equipped with a television camera (Panasonic) and a monitor
(Panasonic). The diameter of the blood column in arterioles was
measured perpendicularly on the monitor with a video microscaler
(IV-550, For-A Co). At the beginning of each experiment, the cranial
window was gently infused with aCSF several times until a stable
baseline was obtained. Glutamate or NMDA (both from Sigma Chemical Co)
dissolved in aCSF was infused into the window for 10 minutes at each
dose of 10-7, 10-6, and
10-5 mol/L in turn. The arteriolar diameter change at each
minute was recorded for a 10-minute period after the applications. We determined NOS activity by quantification of [14C]citrulline converted from [14C]L-arginine using a modified method based on a principle previously described.6 7 Left brain cortex treated with NG-nitro-L-arginine (L-NNA) under the window and right brain cortex not treated with L-NNA (control) were taken and immediately frozen. The brain cortex was exposed to L-NNA for approximately 60 minutes. At the time of the assay, the tissue was dissolved in 1 mL Tris buffer (50 mmol/L Tris and 2 mmol/L EDTA, pH 7.4), sonicated for 10 seconds, and spun at 10 000g at 4°C. The tissue supernatant (25 µL) was added to 100 µL mixture solution of 1 µmol/L [14C]L-arginine, 1 mmol/L NADPH, and 1 mmol/L CaCl2 for a 30-minute incubation, which was then terminated with 2 mL stop buffer containing 30 mmol/L HEPES and 3 mmol/L EDTA. The mixture solution was applied to 0.5-mL columns of Dowex AG50WX-8 resin (Na+ form, pH 7.0), and the eluate was collected in 10 mL scintillation solution. [14C]Citrulline was quantified by scintillation spectroscopy and the protein concentration in the tissue supernatant determined by the use of the Bradford method.
Protocols
(1) In the time-control group, glutamate was topically applied
at the above doses and intervals. The cerebral surface was then flushed
with aCSF. After recovery, glutamate was applied again in the same way.
Finally, after recovery the piglets inhaled 10% CO2 for 10
minutes. (2) In the L-NNA group (A or B), after the first application
of glutamate (group A) or NMDA (group B), the brain surface was flushed
with aCSF, and 10-4 mol/L L-NNA (Sigma) dissolved in aCSF
was applied twice during a 35-minute period. L-NNA has been shown to be
a potent and selective inhibitor of NOS,8 and the dose of
10-4 mol/L was demonstrated to significantly inhibit
NMDA-induced cerebral vasodilation.3 Then, glutamate or
NMDA at the above doses mixed with 10-4 mol/L L-NNA in
aCSF was applied again. (3) In MK-801 group A, after applying glutamate
and after flushing of the brain surface with aCSF, 10-5
mol/L MK-801
[(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepton-5,10-imine
hydrogen maleate] (RBI Inc) dissolved in aCSF was applied for 15
minutes. Then glutamate at the above doses dissolved with
10-5 mol/L MK-801 in aCSF was applied again. Finally, the
piglets inhaled 10% CO2 for 10 minutes. (4) In MK-801
group B, MK-801 dissolved in saline was administered intravenously
twice in a 20-minute period. The total dose was 10 mg/kg in four
piglets and 5 mg/kg in one piglet. Then glutamate was topically applied
at the above doses. Finally, the pigs inhaled 10% CO2 for
10 minutes. (5) To examine whether L-NNA inhibits hypercapnia-induced
vasodilation, the piglets were made to inhale 5% or 10%
CO2 for 10 minutes. When the blood gases recovered to
pre-CO2 level at 30 to 50 minutes after the inhalation, we
applied 10-4 mol/L L-NNA twice in a 35-minute period, and
then we gave the piglets 5% or 10% CO2 for 10 minutes
again. Blood gas values during hypercapnia were measured at the end of
the 10-minute period of CO2 inhalation.
Diameter responses at each minute from 3 to 10 minutes after application of glutamate or NMDA were averaged and used for analysis because most vessel responses reached a relative steady state after 3 minutes of the applications. All values are expressed as mean±SEM. A repeated-measures ANOVA was used to test the statistical difference among the data groups, followed by the Student-Newman-Keuls test when appropriate. A value of P<.05 was considered statistically significant.
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Results |
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Arterial blood pressure was maintained within the physiological range during all of the topical and intravenous treatments. Topical application of glutamate at 10-7, 10-6, and 10-5 mol/L caused sustained dilation in all of the observed cerebral arterioles; the maximal dilation was 21±3% at 10-5 mol/L. In the time-control group, after flushing out the glutamate with aCSF and waiting for the same time interval as in other groups, the second application of glutamate at the above doses caused similar dilation at 10-6 and 10-5 mol/L (Table
and
Fig 1). However, in L-NNA group A, topical application
of 10-4 mol/L L-NNA, which did not change the baseline
diameter significantly, inhibited arteriolar dilation during the second
application of glutamate at the above doses (Table and Fig 2).
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Similarly, topical application of NMDA (L-NNA group B; n=5) also caused
sustained arteriolar dilation, and the mean diameter increased from
97±4 µm of baseline to 107±3, 113±4, and 115±6 µm at
10-7, 10-6, and
10-5 mol/L, respectively (P<.05 versus
baseline at 10-6 and 10-5 mol/L). Maximal
dilation was 26±7% at 10-5 mol/L. After
10-4 mol/L L-NNA application, the subsequent NMDA
application failed to dilate the arterioles (Fig 3). The
diameter was 101±6, 100±5, and 101±5 µm at the above doses,
respectively (baseline, 100±6 µm).
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In MK-801 group A, the arteriolar diameter was 116±3 µm before and
112±3 µm after topical application of MK-801 (P>.05).
MK-801 completely blocked glutamate-induced vasodilation (Table
and Fig 4). However, during the following inhalation of 10%
CO2 (PCO2=68±1 mm Hg),
arterioles still dilated by 37±8% (P<.05; baseline,
113±6 µm), which was similar to the 33±15% dilation (baseline,
98±12 µm) in piglets in the time-control group (n=4;
PCO2=64±3 mm Hg). In MK-801 group B,
intravenously administered MK-801, which caused a nonsignificant
(P>.05) slight decrease (4.6%) in mean baseline diameter,
completely blocked glutamate-induced vasodilation (Table and Fig 5). After MK-801 treatment, 10% CO2
inhalation (PCO2=65±2 mm Hg) significantly
dilated arterioles by 57% (P<.05). This showed that MK-801
did not have any nonspecific inhibitory effect on the arteriolar
dilation to hypercapnia.
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Before L-NNA application, inhalation of 5% CO2 for 10
minutes increased arterial PCO2 from 26±2 to
41±1 mm Hg, and the hypercapnia-induced maximal arteriolar dilation
was 18±3% (P<.05; n=7; baseline, 88±3 µm). Inhalation
of 10% CO2 for 10 minutes increased arterial
PCO2 from 30±1 to 58±1 mm Hg, and the
hypercapnia-induced maximum arteriolar dilation was 46±5%
(P<.05; n=9; baseline, 94±5 µm). After L-NNA
(10-4 mol/L) application, the inhalation of 5%
CO2 increased PCO2 from 26±2 to
40±2 mm Hg, and the maximal dilation was 30±6% (P<.05;
baseline, 84±3 µm). The inhalation of 10% CO2 increased
PCO2 from 29±2 to 59±2 mm Hg, and the
maximal dilation was 60±4% (P<.05; baseline, 83±4 µm).
Thus, the L-NNA did not inhibit hypercapnia-induced vasodilation at
all. The time course of changes in arteriolar diameter during the above
treatments is shown in Fig 6.
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NOS activity in the cerebral cortex was decreased by 93%
(P<.05; n=7) in the L-NNA–treated left side (1.7±0.5
pmol/mg protein per minute) in comparison with the untreated right side
(24.7±4.2 pmol/mg protein per minute) (Fig 7).
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Discussion |
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The major findings in the present study with newborn pigs are the following: (1) inhibition of NOS prevents glutamate-induced dilation of cerebral arterioles, as it does in NMDA-induced dilation; (2) inhibition of NMDA receptors blocks glutamate-induced dilation of cerebral arterioles; and (3) inhibition of NOS or NMDA receptors does not attenuate cerebral arteriolar dilation induced by hypercapnia (PCO2=40 to 68 mm Hg).
Glutamate is a major excitatory neurotransmitter in the central nervous system. A series of investigations7 9 10 11 12 13 14 indicate that the activation of glutamate receptors can alter action potentials and consequently open calcium channels. The increased calcium influx can activate the Ca2+/calmodulin–dependent NOS and increase NO production from L-arginine. The major source of NO in response to activation of NMDA receptors by glutamate may be granule cells in the brain.5 15 16 Cerebral resistance vessels apparently lack glutamate and NMDA receptors, since isolated cerebral arteries do not respond to these substances3 17 18 and biochemical approaches have not detected NMDA receptors.19 Thus, arteriolar dilation by glutamate or NMDA in piglets probably is due to neuronal release of NO. NO is known as a novel intracellular and intercellular messenger that can diffuse into target cells to activate guanylate cyclase and increase cGMP and then cause various functional changes.5 It is considered that glutamate-induced cGMP generation is mediated primarily through the activation of the NMDA receptors in immature brain tissue.5 20
Recently, Faraci and Breese3 found that cerebral vasodilation induced by NMDA, a synthetic analogue of glutamate, was inhibited by L-NNA or MK-801, suggesting that NMDA-induced vasodilation is mediated by NO through NMDA receptors. In our experiment NMDA caused arteriolar dilation similar to what we found in previous studies.1 21 Our finding that L-NNA inhibited NMDA-induced vasodilation confirms the above finding that NMDA-induced vasodilation is mediated by NO.3
The observed arteriolar responses to glutamate generally are similar to those for NMDA and are in agreement with earlier findings for glutamate.1 We do not know why the dose-response curve for glutamate is relatively flat in some but not all cases, but we speculate that NMDA receptor characteristics or glutamate reuptake mechanisms might participate. Similar dose-response relations over a wide range of values have been reported for agents such as acetylcholine, bradykinin, and sodium nitroprusside.22 23 However, the major point to be considered is that glutamate is unequivocally an important dilator agent in the cerebral circulation. For example, arteriolar dilation of 20%, which we observed with 10-5 mol/L, would double conductance through arterioles with a diameter of 100 µm. In addition, responsiveness to glutamate could be potentiated by physiological status. For example, we have shown that cerebral arteriolar responses to NMDA are potentiated at 4 hours after recovery from asphyxia.21 The major new finding in our study is that glutamate-induced cerebral arteriolar dilation is mediated by NO. We previously reported that glutamate application was able to increase cerebral metabolic rate.2 Thus, it seems likely that NO might link changes in metabolic rate and blood flow.
In contrast to NMDA, glutamate can stimulate three kinds of receptors (NMDA, kainate, and AMPA),5 and it can increase cortical metabolic rate.2 To examine whether NMDA receptors are responsible for glutamate-induced vasodilation, we first compared the vasodilation by glutamate with that by NMDA and the inhibitory effects of L-NNA on them, and we then examined the effect of MK-801 on glutamate-induced vasodilation. MK-801 is a noncompetitive inhibitor of NMDA receptors, and it can potently block all NMDA-induced responses, including Ca2+ influx, redox changes, and deterioration on electroencephalography.24 25 26 27 In topically treated piglets, we applied 10-5 mol/L MK-801 for 15 minutes, which previously was shown to be effective in blocking NMDA-induced vasodilation.3 Furthermore, to examine whether the increased baseline by the first glutamate application could affect the arteriolar response to the second glutamate application and to examine whether intravenous MK-801 could block the vasodilation to glutamate, we administered MK-801 intravenously without the prior (first) application of glutamate. The results that (1) glutamate caused a vasodilation quite similar to that by NMDA, (2) the inhibitory effect of L-NNA on glutamate-induced dilation is also similar to that on NMDA-induced dilation, and (3) both topical and intravenous MK-801 blocked glutamate-induced dilation indicate that NMDA receptors are responsible for glutamate-induced arteriolar dilation.
MK-801 alone reduced resting arteriolar diameter by 3% to 5%, which was not statistically significant. This finding is consistent with the results of Faraci and Breese3 in rabbits. Thus, the effects of glutamate on basal arteriolar tone apparently are minimal in anesthetized piglets. This finding may not be surprising since neuronal activity and cerebral metabolic rate are greatly reduced by chloralose anesthesia.28 29 It is possible that glutamate may have a greater effect on basal cerebrovascular tone in unanesthetized piglets. Although glutamate-containing neurons are widely distributed in brain, the exact concentration around pial arterioles remains unclear and may be below the threshold for vascular effects in anesthetized piglets. It has been reported that extracellular glutamate levels derived via microdialysis in cortex, striatum, and the spinal cord range from 10-7 to 10-6 mol/L under control conditions in fetal lambs30 and rats.31 However, it is not clear how values derived by these procedures relate to glutamate level in intact cortex, since insertion and presence of the microdialysis probe might artificially elevate glutamate level.32
Some studies reported that glutamate at high concentrations (eg, 5x10-3 mol/L) could cause neurotoxicity in mature tissue but not in immature brain tissue.33 34 However, some others reported that neurotoxicity of NMDA is enhanced in the brain of newborn rats.35 36 The differences in experimental conditions, species, and brain regions in these studies might result in the discrepancy. A previous study with the same model in piglets demonstrated that even after 30 minutes of continuous exposure to 10-3 mol/L glutamate plus 10-3 mol/L aspartate, pial arteriolar dilator responses to isoproterenol and constrictor responses to norepinephrine still remained intact.1 In the present study we examined whether the potential neuronal injury by glutamate at the first application could be responsible for the inhibited vasodilation at the second application by using a time-control group without L-NNA or MK-801 treatment. After the first glutamate application, we waited for the same time length as that in L-NNA group A or MK-801 group A. The result that the second glutamate application caused dilation similar to that in the first application indicates that the capacity of arteriolar dilation remained intact after the first glutamate application. This result is consistent with our previous study with the same model.1 It appears that glutamate at the doses we used did not produce evident vasodilation mechanism–related neurotoxicity. Furthermore, without the first glutamate application (MK-801 group B), MK-801 still blocked the glutamate-induced vasodilation. Thus, it can be concluded that the inhibitory effect of L-NNA or MK-801 on the vasodilation induced by glutamate at 10-7 to 10-5 mol/L is not associated with the probable (if any) neuronal injury by the first application of glutamate in the newborn pigs.
The role of NO in hypercapnia-induced cerebral vasodilation seems to be species specific. During hypercapnia (PCO2=40 to 80 mm Hg), the increase in cerebral blood flow was greatly attenuated by L-NNA in rats37 and by L-NAME or L-NNA in rats38 39 40 and cats,41 and cerebral vasodilation was inhibited by L-NAME in rabbits.42 These results indicate that NO mediates a large part of the cerebral vasodilation. But during severe hypercapnia (PCO2=130 to 140 mm Hg), L-NAME did not attenuate the cerebral blood flow increase in cats.40 It was suggested that NO mediates most of the cerebral vasodilation during moderate hypercapnia (PCO2=40 to 80 mm Hg).40 However, in a previous study by Busija et al,43 two other NO inhibitors, NG-methyl L-arginine and methylene blue, did not prevent hypercapnia (10% CO2)-induced cerebral arteriolar dilation in piglets. In the present study with piglets, L-NNA did not attenuate the arteriolar dilation induced by hypercapnia (10% CO2; PCO2=59±2 mm Hg) at all, and the vasodilation to hypercapnia even tended to be larger after L-NNA application. To obtain further information, we induced a low-level hypercapnia (5% CO2; PCO2=40±2 mm Hg) and examined how much L-NNA inhibited NOS activity in brain cortex. L-NNA still could not attenuate the vasodilation induced by the low-level hypercapnia at all, and meanwhile NOS activity was decreased by 93% by L-NNA. It was reported that the mechanism of hypercapnia-induced cerebral vasodilation in newborns involve prostanoids.44 45 Our results indicate that in newborn pigs, NO does not play a major role in the cerebral arteriolar dilation induced by hypercapnia (PCO2=40 to 59 mm Hg). Thus, the selective inhibition of L-NNA on cerebral arteriolar dilation induced by glutamate or NMDA, but not on the dilation induced by hypercapnia, showed the specificity of L-NNA in the cerebral arterioles of newborn pigs. In addition, in the presence of MK-801 (either topical or intravenous), hypercapnia (PCO2=65 to 68 mm Hg) could still dilate arterioles normally, which also indicates the specific inhibitory effect of MK-801 and apparent lack of NMDA-mediated mechanism involved in hypercapnic vasodilation in newborn pigs.
In summary, glutamate-induced cerebral arteriolar dilation is mediated by NO, and activation of NMDA receptors by glutamate is responsible for NO production and consequent arteriolar dilation. Our findings support the concept that glutamate participates in the regulation of the cerebral circulation.
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Acknowledgments |
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This study was supported by grants HL-30260 and HL-46558 from the Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. We thank Lisa Moore for assisting in the NOS activity assay and Christy Barnes for assisting in the preparation of the manuscript.
Received December 23, 1993; revision received December 19, 1994; accepted January 18, 1995.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. Busija DW, Leffler CW. Dilator effects of amino acid neurotransmitter on piglet pial arterioles. Am J Physiol. 1989;257(Heart Circ Physiol 26):H1200-H1203.
2. Armstead WM, Mirro R, Zuckerman S, Busija DW, Leffler CW. The influence of opioids on local cerebral glucose utilization in newborn pig. Brain Res. 1992;571:97-102. [Medline] [Order article via Infotrieve]
3.
Faraci FM, Breese KR. Nitric oxide mediates vasodilatation in
response to activation of N-methyl-D-aspartate
receptors in brain. Circ Res. 1993;72:476-480.
4. Garthwaite J, Southam E, Andert M, Neurocheon J. A kainate receptor linked to nitric oxide synthase from arginine. J Neurochem. 1989;53:1952-1954. [Medline] [Order article via Infotrieve]
5. Garthwaite J. Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci. 1991;14:60-67. [Medline] [Order article via Infotrieve]
6.
Bredt DS, Snyder SH. Nitric oxide mediates glutamate-linked
enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci
U S A. 1989;86:9030-9033.
7.
Bredt DS, Snyder SH. Isolation of nitric oxide synthase, a
calmodulin-requiring enzyme. Proc Natl Acad Sci U S A. 1990;87:682-685.
8.
Buxton ILO, Cheek DJ, Eckman D, Westfall DP, Sanders KM, Keef
KD. NG-Nitro-L-arginine
methyl ester and other alkyl esters of arginine are muscarinic receptor
antagonists. Circ Res. 1993;72:387-395.
9. East SJ, Garthwaite J. NMDA receptor activation in rat hippocampus induces cyclic GMP formation through the L-arginine-nitric oxide pathway. Neurosci Lett. 1991;123:17-19. [Medline] [Order article via Infotrieve]
10. Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988;336:385-388. [Medline] [Order article via Infotrieve]
11. Garthwaite G, Palmer RMJ, Moncada S. NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices. Eur J Pharmacol. 1989;172:413-416. [Medline] [Order article via Infotrieve]
12. Southam E, Garthwaite J. Comparative effects of some nitric oxide donors on cyclic GMP levels in rat cerebellar slices. Neurosci Lett. 1991;130:107-111. [Medline] [Order article via Infotrieve]
13. Southam E, East SJ, Garthwaite J. Excitatory amino acid receptors coupled to the nitric oxide/cyclic GMP pathway in rat cerebellum during development. J Neurochem. 1991;56:2072-2081. [Medline] [Order article via Infotrieve]
14. Wood PL, Emmett MR, Rao TS, Cler J, Mick S, Lyengar S. Inhibition of nitric oxide synthase blocks N-methyl-D-aspartate-, quisqualate-, kainate-harmaline-, and pentylenetetrazol-dependent increase in cerebellar cyclic GMP in vivo. J Neurochem. 1990;55:346-348. [Medline] [Order article via Infotrieve]
15. Garthwaite J, Garthwaite G. Cellular origins of cyclic GMP responses to excitatory amino acid receptor agonist in rat cerebellum in vitro. J Neurochem. 1987;48:29-39. [Medline] [Order article via Infotrieve]
16. Monaghan DT, Cotman CW. Distribution of N-methyl-D-aspartate sensitive L-[3H]glutamate-binding sites in rat brain. J Neurosci. 1986;5:2909-2919. [Abstract]
17. Hardebo JE, Wieloch T, Kahrstrom J. Excitatory amino acids and cerebrovascular tone. Acta Physiol Scand. 1989;136:483-485. [Medline] [Order article via Infotrieve]
18. Takayasu M, Dacey RG. Effects of inhibitory and excitatory amino acid neurotransmitters on isolated cerebral parenchymal arterioles. Brain Res. 1989;482:393-396. [Medline] [Order article via Infotrieve]
19. Beart PM, Sheehan KAM, Manallack DT. Absence of N-methyl-D-aspartate receptors on ovine cerebral microvessels. J Cereb Blood Flow Metab. 1988;8:879-882. [Medline] [Order article via Infotrieve]
20. Garthwaite J. Cellular uptake disguises action of L-glutamate on N-methyl-D-aspartate receptors. Br J Pharmacol. 1985;85:297-307. [Medline] [Order article via Infotrieve]
21. Busija DW, Meng W. Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia on piglets. Am J Physiol. 1993;265(Heart Circ Physiol 34):H389-H394.
22. Baumbach GL, Faraci FM, Heistad DD. Effects of local reduction in pressure on endothelium-dependent responses of cerebral arterioles. Stroke. 1994;25:1456-1462. [Abstract]
23. Rosenblum WI, Nishimura H, Nelson GH. L-NMMA in brain microcirculation of mice is inhibited by blockade of cyclooxygenase and by superoxide dismutase. Am J Physiol. 1992;262(Heart Circ Physiol 31):H1343-H1349.
24. Kemp JA, Forster AC, Wong EHF. Noncompetitive antagonists of excitatory amino acid receptors. Trends Pharmacol Sci. 1987;10:294-298.
25. Ransom WR, Stec NL. Cooperative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. J Neurochem. 1988;51:830-836. [Medline] [Order article via Infotrieve]
26. Uematsu D, Greenberg JH, Araki N. Mechanism underlying protective effect of MK-801 against NMDA-induced neuronal injury in vivo. J Cereb Blood Flow Metab. 1991;11:779-785. [Medline] [Order article via Infotrieve]
27.
Wong EHF, Kemp JA, Priest T, Knight AR, Woodruff GN, Eversen
LL. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate
antagonist. Proc Natl Acad Sci U S A. 1986;83:7104-7108.
28.
Busija DW, Leffler CW. Hypothermia reduces cerebral metabolic
rate and cerebral blood flow in newborn pigs. Am J Physiol. 1987;253:H869-H873.
29. Leffler CW, Busija CW, Beasley DG. Effect of the therapeutic dose of indomethacin on the cerebral circulation of newborn pig. Pediatr Res. 1987;21:188-192. [Medline] [Order article via Infotrieve]
30. Hagberg H, Anderson P, Kjellmer I, Thiringer K, Thordstein M. Extracellular overflow of glutamate, aspartate, GABA and taurine in the cortex and basal ganglia of fetal lambs during hypoxia-ischemia. Neurosci Lett. 1987;78:311-317. [Medline] [Order article via Infotrieve]
31. Skilling SR, Smullin DH, Beitz AH, Larson AA. Extracellular amino acid concentrations in the dorsal spinal cord of freely moving rats following veratridine and nociceptive stimulation. J Neurochem. 1988;51:127-132. [Medline] [Order article via Infotrieve]
32. Verhaeger MJ, Tod MM, Warner DS, James B, Weeks JB. The role of electrode size on the incidence of spreading depression and on cortical reduced blood as measured by H2 clearance. J Cereb Blood Flow Metab. 1992;12:230-237. [Medline] [Order article via Infotrieve]
33. Choi DW, Maulucci-Gedde M, Kriegstein AR. Glutamate neurotoxicity in cortical cell culture. J Neurosci. 1987;7:357-368. [Abstract]
34. Choi DW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett. 1985;58:293-297. [Medline] [Order article via Infotrieve]
35. McDonald JW, Silverstein FS, Johnston MV. Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system. Brain Res. 1988;459:200-203. [Medline] [Order article via Infotrieve]
36. McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Rev. 1990;15:41-70. [Medline] [Order article via Infotrieve]
37. Wang Q, Paulson OB, Lassen NA. Effect of nitric oxide by NG-nitro-L-arginine on cerebral blood flow response to changes in carbon dioxide tension. J Cereb Blood Flow Metab. 1992;12:947-953. [Medline] [Order article via Infotrieve]
38.
Iadecola C. Does nitric oxide mediate the increase in cerebral
blood flow elicited by hypercapnia? Proc Natl Acad Sci
U S A. 1992;89:3913-3916.
39. Pelligrino DA, Keonig HM, Albrecht RF. Nitric oxide synthase and regional cerebral blood flow responses to hypercapnia and hypoxia in the rat. J Cereb Blood Flow Metab. 1993;13:80-87. [Medline] [Order article via Infotrieve]
40. Iadecola C, Zhang E, Li J. Nitric oxide-dependent and independent components of cerebrovascular dilation elicited by hypercapnia. Soc Neurosci Abst. 1993;19:1267. Abstract.
41. Sandor S, Komjati K, Nyary I. Major role of nitric oxide in the mediation of regional CO2 responsiveness of the cerebral and spinal cord vessels of the cat. J Cereb Blood Flow Metab. 1994;14:49-58. [Medline] [Order article via Infotrieve]
42. Faraci FM, Breese KR, Heistad DD. Cerebral vasodilation during hypercapnia: role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke. 1994;25:1679-1683. [Abstract]
43.
Busija DW, Leffler CW, Wagerle LC.
Mono-L-arginine–containing compounds dilate piglet pial
arterioles via an endothelium-derived relaxing
factor–like substance. Circ Res. 1990;67:1374-1380.
44. Hsu P, Shibata M, Leffler CW. Prostanoid synthesis in response to high CO2 in newborn pig brain microvascular endothelial cells. Am J Physiol. 1993;264(suppl 5, pt 2):H1485-1492.
45. Wagerle LC, DeGiulio PA, Mishra OP, Delivora-Papadopoulos M. Effect of dexamethasone on cerebral prostanoid formation and pial arteriolar reactivity to CO2 in newborn pigs. Am J Physiol. 1991;260(suppl 4, pt 2):H1313-H1318.
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