(Stroke. 1996;27:965-970.)
© 1996 American Heart Association, Inc.
Articles |
Glutamate-Induced Disruption of the Blood-Brain Barrier in Rats
Role of Nitric Oxide
From the Department of Physiology and Biophysics, University of Nebraska Medical Center (Omaha).
Correspondence to William G. Mayhan, PhD, Department of Physiology and Biophysics, University of Nebraska Medical Center, 600 S 42nd St, Omaha, NE 68198-4575.
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Abstract |
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Background and Purpose The first goal of this study was to determine the effect of glutamate on permeability and reactivity of the cerebral microcirculation. The second goal of this study was to determine a possible role for nitric oxide in the effects of glutamate on the cerebral microcirculation.
Methods We examined the pial microcirculation in rats with intravital microscopy. Permeability of the blood-brain barrier was quantified by the clearance of fluorescent-labeled dextran (molecular weight, 10 000 D; FITC-dextran-10K) before and during application of glutamate (0.1 and 1.0 mmol/L). In addition, we examined the permeability of the blood-brain barrier during application of a nitric oxide donor, S-nitroso-acetyl-penicillamine (SNAP; 10 µmol/L). Diameter of pial arterioles was measured before and during application of glutamate or SNAP. To determine a potential role for nitric oxide in glutamate-induced effects on the cerebral microcirculation, we examined the effects of NG-monomethyl-L-arginine (10 µmol/L).
Results In control rats, clearance of FITC-dextran-10K from pial vessels was minimal, and the diameter of pial arterioles remained constant during the experimental period. Topical application of glutamate (0.1 and 1.0 mmol/L) and SNAP (10 µmol/L) produced an increase in clearance of FITC-dextran-10K and in diameter of pial arterioles. In addition, NG-monomethyl-L-arginine (10 µmol) attenuated glutamate-induced increases in permeability of the blood-brain barrier and glutamate-induced dilatation of cerebral arterioles.
Conclusions The findings of the present study suggest that glutamate, a major neurotransmitter in the brain, increases permeability of the blood-brain barrier to low-molecular-weight molecules and dilates cerebral arterioles via a nitric oxide–dependent mechanism.
Key Words: blood-brain barrier • cerebral circulation • glutamate • nitric oxide • rats
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Introduction |
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The BBB minimizes the entry of water-soluble molecules into brain tissue. This restriction is accomplished by the presence of tight junctions between adjacent endothelial cells and a paucity of pinocytotic vesicles in cerebral arterioles, venules, and capillaries.1 Glutamate is an important excitatory neurotransmitter in the brain. Under normal conditions, the concentration of glutamate in the brain is much higher in the intracellular space compared with the extracellular space.2 3 This compartmentalization presumably prevents glutamate from exerting toxic effects on the brain. Previous studies have shown that brain injury can lead to an increase in extracellular levels of glutamate in the brain.2 3 Furthermore, antagonists of glutamate reduce brain edema after opening of the BBB by cerebral ischemia/reperfusion or infusion of protamine sulfate.4 5 6 7 Thus, it appears that glutamate may play an important role in regulating brain edema after traumatic brain injury.
No studies have directly examined the effects of glutamate on the permeability of the BBB in vivo. Thus, the first goal of this study was to examine the direct effect of glutamate on the permeability of the BBB to low-molecular-weight molecules and on the reactivity of cerebral arterioles in vivo. The second goal of this study was to examine a possible role for NO in glutamate-induced increases in permeability of the BBB and reactivity of cerebral arterioles in vivo.
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Materials and Methods |
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Preparation of Animals
This study was approved by the Institutional Animal Care and Use Committee and is in compliance with the guidelines of the National Institutes of Health for care and handling of animals. Male Wistar-Furth rats (n=27) were anesthetized (Inactin; thiobutabarbital, 80 to 100 mg/kg IP), and tracheotomy was performed. The rats were mechanically ventilated with room air and supplemental oxygen. A catheter was placed in a femoral artery for the measurement of systemic blood pressure. A catheter was placed in a femoral vein for injection of the intravascular tracer FITC-dextran-10K (molecular weight, 10 000 D).
To visualize the cerebral microcirculation, a cranial window was prepared over the right parietal cortex with methods we have described previously.8 9 10 An incision was made in the skin to expose the skull. The skin was retracted with sutures and served as a well for the suffusion fluid. An inlet and outlet port were made in the skin to allow for the constant flow of suffusate across the cerebral (pial) microcirculation. Finally, a craniotomy was performed, the dura was incised, and the cerebral microcirculation was exposed. The suffusion fluid (artificial cerebrospinal fluid) was heated (37°C to 38°C) and bubbled continuously with 95% nitrogen and 5% carbon dioxide to maintain gases within normal limits. Blood gases were also monitored and maintained within normal limits. At the end of the experiment, all anesthetized rats were killed with an injection of saturated potassium chloride.
Permeability of the BBB
The permeability of the BBB was evaluated by examining the
clearance of FITC-dextran-10K
(mL/sx10-6) by pial vessels as we have
described previously.8 9 10 The suffusate fluid was
collected in glass test tubes with the aid of a fraction collector, and
we determined the concentration of FITC-dextran-10K in the suffusate
fluid during topical application of vehicle, glutamate, glutamate in
the presence of L-NMMA, and SNAP. Arterial blood samples
(approximately 60 µL per sample) were drawn at various intervals
throughout the experiment during a constant infusion of
FITC-dextran-10K (40 mg/mL at 0.06 mL/min). To quantify the
concentration of FITC-dextran-10K in the suffusate fluid and plasma
samples, standard curves for concentration of FITC-dextran-10K versus
percent transmission were obtained with a spectrophotofluorometer
(Perkin-Elmer). The standard (FITC-dextran-10K) was prepared on a
weight-per-volume basis. The suffusate concentration was used
as background, a standard curve was generated for each experiment, and
each curve was subjected to linear regression analysis. The
percent transmission for unknown samples (suffusate and plasma) was
measured on the spectrophotofluorometer, and the concentration was
calculated from the standard curve. The clearance of FITC-dextran-10K
was calculated by multiplying the ratio of suffusate-to-plasma
concentration by the suffusate flow rate.8 9 10
In the present studies, we depict the clearance of FITC-dextran-10K in two ways. First, we show the entire time course for clearance of FITC-dextran-10K during suffusion with vehicle, glutamate, and glutamate in the presence of L-NMMA. In addition, we compare the clearance of FITC-dextran-10K at distinct time periods during topical application of vehicle, glutamate, glutamate in the presence of L-NMMA, and SNAP.
Pial Arteriolar Diameter
Diameter of pial arterioles was measured on-line with a
video image shearing device (model 908, Instrumentation for Physiology
and Medicine Inc). We measured the diameter of the largest pial
arteriole exposed by the craniotomy before and during
application of vehicle, glutamate, glutamate in the presence of L-NMMA,
and SNAP.
Experimental Protocol
The first group of rats served as time controls (n=6). Sixty
minutes after the preparation of the craniotomy, a
continuous injection of FITC-dextran-10K was started. At various
intervals for the next 80 minutes, we determined the clearance of
FITC-dextran-10K and measured the diameter of pial arterioles.
In a second group of rats (n=6), we examined the effects of topical application of glutamate (0.1 mmol/L) on the permeability of the BBB and reactivity of cerebral arterioles. A similar protocol was followed as described above, with the exception that the cranial window preparation was suffused with glutamate (0.1 mmol/L) during the constant infusion of FITC-dextran-10K. Clearance of FITC-dextran-10K and diameter of cerebral arterioles were determined as described above.
In a third group of rats (n=6), we examined the effects of topical application of glutamate (1.0 mmol/L) on the permeability of the BBB and reactivity of cerebral arterioles. A similar protocol for evaluation of permeability of the BBB and diameter of pial arterioles was followed as described above.
In a fourth group of rats (n=5), we examined the role of NO in glutamate-induced increases in permeability of the BBB and reactivity of cerebral arterioles. Thus, in these studies we suffused the cranial window preparation with L-NMMA (10 µmol/L) 30 minutes before starting topical application of glutamate (1.0 mmol/L) and infusion of FITC-dextran-10K. Clearance of FITC-dextran-10K was determined during suffusion with glutamate (1.0 mmol/L) in the presence of L-NMMA (10 µmol/L). Diameter of cerebral arterioles was measured under control conditions, during topical application of L-NMMA, and during topical application of glutamate plus L-NMMA.
In a fifth group of rats (n=4), we examined whether topical application of a donor of NO, SNAP (10 µmol/L),11 could increase the permeability of the BBB to FITC-dextran-10K. A similar protocol was followed as described above, with the exception that the cranial window preparation was suffused with SNAP (10 µmol/L) during the constant infusion of FITC-dextran-10K. Clearance of FITC-dextran-10K and diameter of cerebral arterioles were determined as described above.
Statistical Analysis
An unpaired t test was used to compare clearance of
FITC-dextran-10K and diameter of pial arterioles among the various
groups of rats. A value of P<.05 was considered to be
significant.
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Results |
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Control Conditions
In control rats, clearance of FITC-dextran-10K over the experimental period was modest during the constant infusion of FITC-dextran-10K (Figs 1
and 2). In
addition, diameter of pial arterioles during the time course of the
experiment was not altered in control rats during superfusion with
vehicle (saline). Diameter of pial arterioles was 52±4 µm before
superfusion with vehicle and remained at 51±4 µm during superfusion
with vehicle (P>.05).
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Thus, it appears that the integrity of the BBB remains intact during the time period required to complete the proposed studies and that vehicle does not have a significant effect on diameter of cerebral arterioles.
Response to Glutamate and SNAP
Topical application of glutamate (0.1 and 1.0 mmol/L) produced an
increase in clearance of FITC-dextran-10K (Figs 1
and 2). In addition,
the increase in clearance of FITC-dextran-10K during application of
glutamate (0.1 and 1.0 mmol/L) was significantly greater than that
observed in rats superfused with vehicle (Fig 2). Clearance of
FITC-dextran-10K appeared to increase more rapidly for 1.0 mmol/L
glutamate than for 0.1 mmol/L glutamate (Figs 1 and 2); however, the
magnitude of the increase in clearance was similar for 0.1 and 1.0
mmol/L glutamate (Fig 2 at 80 minutes).
In addition, topical application of glutamate (0.1 and 1.0 mmol/L)
produced dilatation of pial arterioles (Fig 3). During
superfusion with 0.1 mmol/L glutamate, diameter of pial arterioles
increased from 42±3 to 49±5 µm (P<.05). During
superfusion with 1.0 mmol/L glutamate, diameter of pial arterioles
increased from 45±4 to 53±5 µm (P<.05).
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Topical application of SNAP (10 µmol/L) produced an increase in
clearance of FITC-dextran-10K (Fig 4). Clearance of
FITC-dextran-10K during application of SNAP was significantly greater
than that observed in rats superfused with vehicle. In addition,
application of SNAP (10 µmol) produced marked dilatation of pial
arterioles. Under control conditions, diameter of pial arterioles was
38±3 µm and increased to 55±5 µm (45±5%) during suffusion with
SNAP (P<.05).
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Response to Glutamate in the Presence of L-NMMA
L-NMMA (10 µmol/L) significantly inhibited the clearance of
FITC-dextran-10K during application of glutamate (1.0 mmol) (Figs 1 and 5). In addition, L-NMMA significantly attenuated
glutamate-induced dilatation of pial arterioles (Fig 3). Diameter
of pial arterioles was 47±4 µm under basal conditions, 42±4 µm
after application of L-NMMA (10 µmol/L), and 44±5 µm after
application of glutamate (1.0 mmol/L) in the presence of L-NMMA (10
µmol/L). Thus, it appears that NO plays a role in basal diameter of
pial arterioles, glutamate-induced increases in permeability of the
BBB, and glutamate-induced dilatation of rat pial arterioles.
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Discussion |
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There are four major new findings of the present study. First, an important excitatory amino acid known to be increased during cerebrovascular trauma, ie, glutamate, produces an increase in permeability of the BBB to low-molecular-weight molecules. Second, application of a donor of NO, SNAP, produces an increase in permeability of the BBB to low-molecular-weight molecules. Third, the synthesis/release of NO or an NO-containing compound appears to account for increases in permeability of the BBB to FITC-dextran-10K after application of glutamate. Fourth, dilatation of pial arterioles in response to topical application of glutamate appears to be related to the synthesis/release of NO or an NO-containing compound.
Consideration of Methods
Permeability of the BBB under control conditions and during
application of agonists was quantified by calculating the clearance of
FITC-dextran-10K with methods we have described
previously.8 9 10 No leakage of FITC-dextran-10K was
observed from dura or bone, and we suggest that changes in clearance of
FITC-dextran-10K during topical application of agonists
represent changes in permeability that are occurring in pial
vessels. Thus, we used a well-established methodology to evaluate
changes in permeability of the BBB under control conditions and during
application of agonists.
We examined the effect of topical application of glutamate on the BBB. We found that the clearance of FITC-dextran-10K increased during application of glutamate. Previous studies have suggested that the concentration of excitatory amino acids, including glutamate, in the cerebrospinal fluid increases after disruption of the BBB with protamine sulfate3 4 and/or cerebral ischemia/reperfusion.12 Thus, it appears that an examination of the effects of topical application of glutamate on the BBB is an appropriate methodology.
We used an enzymatic inhibitor of NO synthase, L-NMMA, to examine a role for NO in dilatation of pial arterioles and disruption of the BBB after topical application of glutamate. The concentration of L-NMMA used in the present study has been shown to be specific and efficacious in inhibition of the effects of NO or an NO-containing compound on cerebral arterioles,13 14 15 disruption of the BBB during acute hypertension,16 and peripheral microvascular permeability.17 18 19 We found that L-NMMA significantly inhibited dilatation of pial arterioles and permeability of the BBB in response to topical application of glutamate. Thus, we suggest that the concentration of L-NMMA used to evaluate the role of NO in disruption of the BBB during topical application of glutamate is specific and efficacious.
We examined the effects of SNAP, an NO donor,11 on dilatation of pial arterioles and clearance of FITC-dextran-10K. We found that SNAP produced dilatation of pial arterioles and increased the clearance of FITC-dextran-10K across the BBB. The magnitude of dilatation of rat pial arterioles in response to SNAP observed in the present study is similar to that reported by other investigators.20 21 Although no studies have examined the effects of SNAP on the permeability of the BBB, previous studies have suggested that donors of NO (ie, sodium nitroprusside) produce an increase in peripheral vascular permeability.22 23 24 25 In contrast, other studies suggest that donors of NO (sodium nitroprusside and SIN-1) reduce increases in peripheral vascular permeability stimulated by ischemia/reperfusion or NO synthase inhibition. The discrepancy between these studies is not clear but may be related to the vascular bed examined. The findings of the present study support results from previous studies22 23 24 25 that suggest that donors of NO increase vascular permeability.
Topical application of glutamate and SNAP produced dilatation of pial arterioles and increased clearance of FITC-dextran-10K. We considered the possibility that vasodilatation produced by these agonists could contribute to changes in permeability of the BBB. However, previous studies26 27 28 29 30 suggest that vasodilatation per se does not produce an increase in the permeability of the BBB. Thus, we suggest that increases in clearance of FITC-dextran-10K across the BBB observed during suffusion with glutamate and SNAP are not related to vasodilatation but are related to an effect of these agents on the BBB.
Consideration of Previous Studies
Glutamate activates distinct receptor subtypes, including
NMDA, 
-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA),
and kainate. Previous studies suggest that inhibition of NO
synthase attenuates dilatation of cerebral arterioles in response to
NMDA,31 kainate,32 and
glutamate.33 The mechanism of glutamate-induced
dilatation of cerebral blood vessels, however, does not appear to be
related to receptor-mediated stimulation of the release of NO from
cerebrovascular endothelium. It appears that cerebral
arteries lack glutamate receptors, since application of glutamate or
NMDA to isolated cerebral arteries fails to produce
vasorelaxation.33 34 In addition, a recent study suggests
that dilatation of cerebral arterioles in response to NMDA can be
attenuated by treatment with 7-nitroindazole, an inhibitor
of neuronal NO synthase.35 Thus, it appears that glutamate
may dilate cerebral blood vessels via neuronal release of NO. The
results of the present study are in agreement with these previous
studies.31 32 33 We found that glutamate produced dilatation
of pial arterioles that was attenuated by an enzymatic
inhibitor of NO synthase.
Previous studies have suggested that excitatory amino acids, including glutamate, may play a role in the brain damage that follows cerebrovascular trauma. Investigators have measured cerebrospinal fluid concentration of glutamate after intravascular administration of protamine sulfate to disrupt the BBB3 4 and after ischemia/reperfusion.12 Results of these previous studies3 4 12 suggest that intracarotid infusion of protamine sulfate and/or cerebral ischemia/reperfusion produce an increase in glutamate concentration in the cerebrospinal fluid to levels used in the present studies.2 3 However, the precise consequences of the increase in extracellular levels of excitatory amino acids cannot be determined from these previous studies.3 4 12
Other studies, using glutamate receptor antagonists, have examined the role of glutamate in cerebrovascular damage and cerebral edema after intracarotid infusion of protamine sulfate7 and cerebral ischemia/reperfusion.5 6 The results of these previous studies suggest that blockade of glutamate receptors attenuates ischemia-induced damage to the brain and cerebral edema after opening of the BBB.5 6 7 Thus, it appears that glutamate may contribute to cerebrovascular damage following trauma to the brain.
Investigators have examined the effect of NMDA on the permeability of the BBB.36 37 These previous studies suggest that stimulation with NMDA increases the permeability of the BBB.36 37 In addition, MK-801, a specific NMDA receptor antagonist, attenuated disruption of the BBB after application of NMDA. The results of the present study support these previous studies.5 6 7 36 37 We found that topical application of glutamate produced a marked increase in permeability of the BBB to low-molecular-weight molecules. In addition, our findings extend those of previous studies by examining a potential cellular mechanism that may account for the effect of glutamate on the BBB. We found that increases in permeability of the BBB after topical application of glutamate could be inhibited by L-NMMA and thus were related to the synthesis/release of NO or an NO-containing compound.
In summary, we found that topical application of glutamate produced a dose-related dilatation of cerebral arterioles and increased the permeability of the BBB to low-molecular-weight molecules. The mechanism for the effect of glutamate on cerebral arterioles and the BBB appears to be mediated by the synthesis/release of NO or an NO-containing compound. We suggest that an increased release of excitatory amino acids during cerebrovascular trauma may contribute to the disruption of the BBB observed during brain injury.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute grant HL-40781; a Grant-in-Aid from the American Heart Association, Nebraska Affiliate (9307792S); and a grant from the Nebraska Smoking and Cancer Research Foundation (96-47).
Received October 30, 1995; revision received January 17, 1996; accepted January 22, 1996.
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F. Bari, R. A. Errico, T. M. Louis, D. W. Busija, and F. M. Faraci Differential Effects of Short-term Hypoxia and Hypercapnia on N-Methyl-D-Aspartate–Induced Cerebral Vasodilatation in Piglets Stroke, September 1, 1996; 27(9): 1634 - 1640. [Abstract] [Full Text]
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