(Stroke. 1995;26:2172-2176.)
© 1995 American Heart Association, Inc.
Articles |
7-Nitroindazole Inhibits Brain Nitric Oxide Synthase and Cerebral Vasodilatation in Response to N-Methyl-D-aspartate
From the Departments of Internal Medicine (F.M.F.), Pharmacology (F.M.F.), and Anesthesia (J.E.B.), Cardiovascular Center, University of Iowa College of Medicine, Iowa City.
Correspondence to Frank M. Faraci, PhD, Department of Internal Medicine, Cardiovascular Center, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Background and Purpose N-Methyl-D-aspartate (NMDA) produces dilatation of cerebral arterioles that is dependent on production of nitric oxide (NO). In these experiments we examined the hypothesis that cerebral vasodilatation in response to NMDA is mediated by the neuronal isoform of NO synthase.
Methods We measured diameters of cerebral arterioles (baseline diameter, 89±7 µm) using a closed cranial window in anesthetized rabbits that received either vehicle (10 mL/kg IP peanut oil) or 7-nitroindazole (7-NI; 50 mg/kg IP). 7-NI is reported to be a selective inhibitor of neuronal NO synthase.
Results Two hours after administration of 7-NI, activity of brain NO synthase (measured by conversion of L-arginine to L-citrulline) was reduced by 33% compared with vehicle (24±1 versus 16±3 pmol/min per milligram protein; n=7; P<.05). Dilatation of cerebral arterioles in response to NMDA (100 and 300 µmol/L) was inhibited by 30% to 40% by 7-NI compared with responses in the presence of vehicle (23±6% versus 14±5% and 30±4% versus 21±5%, respectively; P<.05 for both concentrations; n=10). In contrast, vasodilatation in response to acetylcholine (1 µmol/L) was similar in vehicle- and 7-NI–treated animals (17±5% versus 21±4%; P>.05).
Conclusions These findings suggest that vasodilatation in response to NMDA is mediated by neuronally derived NO. 7-NI appears to produce selective inhibition of brain NO synthase but not endothelial NO synthase.
Key Words: acetylcholine • arterioles • N-methyl-D-aspartate • nitric oxide • vasodilation • rabbits
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Glutamate and agonists that activate glutamate receptor subtypes including NMDA cause neuronal production and release of NO in cell culture and in brain slices.1 2 3 4 5 NMDA and glutamate also produce dilatation of cerebral arterioles in vivo6 7 8 9 10 11 that is attenuated by inhibitors of NO synthase.7 10 These findings suggest that vasodilatation in brain in response to activation of receptors for NMDA is dependent on production of NO and may be mediated by neuronal NO synthase.
7-NI is a recently described inhibitor of NO synthase that is considered to be relatively selective for the neuronal isoform of NO synthase.12 13 14 15 In vivo, 7-NI has been found to inhibit activity of brain NO synthase without inhibiting vasodilatation of cerebral arterioles in response to acetylcholine (which acts through activation of endothelial NO synthase).16 Based on these findings, we hypothesized that if NMDA acts through activation of neuronal NO, 7-NI would selectively inhibit vasodilatation in response to NMDA. Thus, the goal of this study was to determine effects of 7-NI on responses of cerebral arterioles to NMDA and acetylcholine.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal Preparation
Experiments were performed on 34 New Zealand White rabbits (weight, 2.5 to 3.5 kg) that were anesthetized with pentobarbital sodium (40 mg/kg IV). Pentobarbital was supplemented regularly at approximately 10 mg/kg per hour. The trachea was cannulated, and the animals were ventilated mechanically with air and supplemental oxygen. Arterial blood gases were monitored and were stable throughout the experiment (Pco2=35±1 mm Hg, Po2=126±3 mm Hg, and pH=7.45±0.02 [mean±SE]). A femoral artery was cannulated for measurement of systemic pressure and to sample arterial blood. A femoral vein was cannulated for infusion of drugs.
Rabbits were placed in a head-holder, and a closed cranial window was placed over the parietal cortex as described previously.17 The cranial window was filled with artificial CSF warmed to 37°C. Diameters of pial arterioles were measured with a microscope equipped with a TV camera coupled to a video monitor. Images were recorded on videotape, and vessel diameters were measured later with an image analyzer. In all animals, responses of cerebral arterioles to acetylcholine (1 and 10 µmol/L) were measured initially to establish reactivity of the vessels. Flushing the window with artificial CSF maintained at 37°C did not alter the baseline diameter of arterioles.
Experimental Protocol
Three groups of animals were studied. In the first group (n=8),
arteriolar diameter was measured under control conditions and 1 to 2
minutes after the window was filled with CSF containing NMDA (30, 100,
and 300 µmol/L ). Concentrations of NMDA were applied in a cumulative
manner. After application of NMDA, the cranial window was flushed
several times, and the diameter of cerebral arterioles returned to
baseline. Application of NMDA was then repeated 60 and 120 minutes
after injection of vehicle for 7-NI (10 mL/kg IP peanut oil). Peanut
oil was used as a vehicle because of the solubility characteristics of
7-NI.12 13 14 This group of animals served as a time control
to establish whether responses to NMDA were reproducible in the
presence of vehicle. Measurements were made at 60 and 120 minutes based
on previous studies that reported that maximum effects on activity of
brain NO synthase occurred 30 to 120 minutes after treatment with
7-NI.16 18
In a second group of rabbits (n=10), arteriolar diameter was measured under control conditions and 1 to 2 minutes after the window was filled with CSF containing NMDA (30, 100, and 300 µmol/L). After application of NMDA, the cranial window was flushed several times, and the diameter of cerebral arterioles returned to baseline. Application of NMDA was then repeated 60 and 120 minutes after injection of 7-NI (50 mg/kg IP). 7-NI (Aldrich) was suspended in peanut oil and sonicated before injection. This set of experiments was performed to determine whether responses to NMDA were inhibited by 7-NI.
In a third group, arteriolar diameter was measured under control conditions and 1 to 2 minutes after the window was filled with CSF containing acetylcholine (1 and 10 µmol/L). Concentrations of acetylcholine were applied in a cumulative manner. After application of acetylcholine, the cranial window was flushed several times, and the diameter of cerebral arterioles returned to baseline. Application of acetylcholine was then repeated 60 and 120 minutes after injection of either vehicle (10 mL/kg IP peanut oil; n=8) or 7-NI (50 mg/kg IP; n=8). This series of experiments was performed to determine whether responses of cerebral arterioles to acetylcholine are similar in the presence of vehicle and 7-NI.
Activity of Brain NO Synthase
NO and L-citrulline are formed
stoichiometrically by NO synthase from
L-arginine.19 Thus, enzyme activity was
determined as the rate of conversion of
[14C]L-arginine (New England Nuclear) to
[14C]L-citrulline.19 After
the last measurement of vessel diameter (120 minutes after injection of
vehicle or 7-NI), a sample of the cerebrum was obtained and used for
determination of enzyme activity in vitro following methods described
previously.20 21 Brain tissue was frozen in liquid
nitrogen and stored at -70°C until used. Tissue samples were
homogenized in 20 vol (wt/vol) of ice-cold buffer (50
mmol/L Tris, 2 mmol EDTA, pH 7.4) and centrifuged at
10 000g for 15 minutes at 4°C.
Enzyme activity was assayed at 20°C in duplicate with the use of the supernatant. The reaction was initiated by combining 25 µL of brain supernatant to 100 µL of a mixture containing 3 µmol/L [14C]L-arginine, 1 mmol NADPH, and 1 mmol/L CaCl2. The reaction was terminated after 15 minutes by adding 1.8 mL of stop buffer (30 mmol/L HEPES and 3 mmol/L EDTA, pH 5.2). Samples were applied to a 0.5-mL Dowex resin column (Sigma 50X-400, Na+ form) to remove [14C]L-arginine. The columns were then washed with 1 mL of water, and [14C]L-citrulline was quantified in the flow-through fraction with the use of a scintillation counter. Enzyme activity was expressed as picomoles per milligram protein per minute. The concentration of [14C]L-citrulline was calculated after we subtracted the blank value, which represents nonspecific radioactivity in the absence of enzyme activity.
To assess that the measured citrulline production was due to activity of constitutive NO synthase (calcium-dependent NO synthase), parallel samples were processed in the absence of calcium and in the presence of a potent inhibitor of activity of NO synthase (L-NAME, 1 mmol/L). Activity of brain NO synthase was decreased by more than 99% when measured in the absence of calcium. Production of L-citrulline was also reduced by more than 99% by 1 mmol/L L-NAME. Because enzyme activity was calcium dependent and essentially abolished by L-NAME, production of L-citrulline measured in these experiments was presumably due to activity of constitutive NO synthase. Protein concentrations of the samples were measured with the use of the Bradford assay (Bio-Rad).
Statistical Analysis
For comparison of change in vessel diameter under control
conditions and 60 and 120 minutes after administration of either
vehicle or 7-NI, statistical analysis was performed with the
use of ANOVA. Unpaired t tests were used to compare values
for activity of NO synthase in vehicle- and 7-NI–treated animals. All
values are expressed as mean±SE. A value of P<.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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NMDA produced concentration-related dilatation of cerebral arterioles that was reproducible at 60 and 120 minutes in the presence of vehicle (Fig 1
). Baseline diameters of
cerebral arterioles were 92±7, 89±8, and 83±8 µm under control
conditions and 60 and 120 minutes after injection of vehicle.
Arterial pressure was 79±2 mm Hg under control conditions
and was not affected by injection of vehicle (arterial
pressures were 79±1 and 77±1 mm Hg 60 and 120 minutes after injection
of vehicle, respectively).
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Dilatation of cerebral arterioles in response to NMDA (100 and 300
µmol/L) was inhibited by 30% to 40% 60 and 120 minutes after
administration of 7-NI (50 mg/kg) (Fig 2;
P<.05 for both concentrations; n=10). Baseline diameters of
cerebral arterioles were 90±6, 89±6, and 82±7 µm under control
conditions and 60 and 120 minutes after injection of 7-NI. This
reduction in baseline diameter after injection of 7-NI was not
different from the reduction seen 120 minutes after administration of
vehicle (decrease in diameter of 9% versus 10%). Arterial
pressure was 77±1 mm Hg under control conditions in this group of
rabbits and was not affected by injection of 7-NI (arterial
pressures were 77±1 and 76±1 mm Hg 60 and 120 minutes after injection
of 7-NI, respectively) (Fig 3).
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In contrast to effects on responses to NMDA, vasodilatation in response
to acetylcholine (1 and 10 µmol/L) was similar in animals injected
with vehicle and 7-NI. At 120 minutes after injection, cerebral
arterioles dilated by 17±5% and 47±7% in the presence of vehicle
and 21±4% and 46±5% in the presence of 7-NI (50 mg/kg) (Fig 3
). These responses were not statistically different
(P>.05).
Two hours after administration of 7-NI (50 mg/kg) or vehicle, activity
of brain NO synthase (measured by conversion of
L-arginine to L-citrulline) in animals
that received 7-NI was reduced by 33% compared with animals that
received vehicle (24±1 versus 16±3 pmol/min per milligram protein;
n=7; P<.05) (Fig 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The major finding in this study is that administration of 7-NI reduced activity of brain NO synthase and inhibited dilatation of cerebral arterioles in response to NMDA. Vasodilatation in response to acetylcholine was not different in vehicle- and 7-NI–treated animals, suggesting that 7-NI did not alter activity of endothelial NO synthase. These findings support the concept that dilatation of cerebral arterioles in response to NMDA is mediated by neuronal NO synthase.
Responses to NMDA
Local application of glutamate, NMDA, and kainate produces
dilatation of cerebral arterioles that is dependent on
production of NO.6 7 8 9 10 11 22 Neurons in culture are
known to produce NO in response to these stimuli,1 2 3 4 5 which
is compatible with the hypothesis that neuronal production of
NO mediates responses to excitatory amino acids in vivo. Because
inhibitors of NO synthase, such as L-NNA, that have been
used previously exert effects on all known isoforms of NO synthase
(macrophage or immunologic, endothelial, and
neuronal isoforms),19 it has not been possible to identify
neurons as the source of NO, based solely on the use of these
inhibitors.
7-NI is a recently described inhibitor of NO synthase that appears to be relatively selective for the neuronal isoform of NO synthase.12 13 14 15 In vivo, 7-NI has been found to inhibit activity of brain NO synthase.13 16 18 In the present study we examined effects of 7-NI on activity of brain NO synthase and dilatation of cerebral arterioles in response to NMDA. 7-NI inhibited both vasodilatation and activity of NO synthase by approximately 30% to 40%. Studies using immunocytochemistry23 and a murine model that reportedly lacks the gene for the neuronal isoform of NO synthase24 both suggest that the majority of NO synthase activity in brain is present in neurons. When enzyme activity is measured in cortical tissue, as in the present study, activity of NO synthase probably reflects changes occurring primarily in neurons.
The present findings support the hypothesis that dilatation of cerebral arterioles in response to NMDA is dependent on production of NO by neuronal NO synthase. The effects of 7-NI on both enzyme activity and vascular responses were significant but moderate in magnitude (activity of brain NO synthase was inhibited by one third). This observation is generally consistent with a previous study that reported that the same dose of 7-NI inhibited activity of brain NO synthase by approximately 50%.16 A higher concentration of 7-NI produced no additional inhibition.16 L-NNA produced greater inhibition of cerebral vasodilatation in response to NMDA in previous studies7 10 than was observed in the present study using 7-NI. This difference probably relates to the fact that L-NNA produced greater inhibition of brain NO synthase10 than 7-NI.
Responses to Acetylcholine
The major conclusion of the present study, that vasodilatation
of brain in response to NMDA is mediated by neuronal NO synthase, is
based on the assumption that 7-NI is a selective inhibitor
of neuronal NO synthase. This assumption appears valid for several
reasons. Inhibitors of endothelial NO
synthase increase arterial pressure when given systemically
and inhibit dilatation of cerebral vessels in response to
acetylcholine.7 25 Although 7-NI inhibited activity of
brain NO synthase, it did not increase arterial pressure or
inhibit dilatation of cerebral arterioles in response to acetylcholine.
Thus, inhibitory effects of 7-NI on responses to NMDA
appear to be selective. If 7-NI affected NO synthase in
endothelium in these experiments, one would have
expected arterial pressure to increase and to have observed
inhibition of vasodilatation in response to acetylcholine. Dilatation
of cerebral arterioles in response to acetylcholine is
endothelium dependent26 and reduced
substantially by other inhibitors of NO synthase such as
L-NNA, which are not selective for one isoform type.7 26
Our findings that 7-NI does not affect arterial pressure
and cerebral vasodilatation to acetylcholine are consistent
with a recent study.16
In previous studies, inhibition of NO synthase using L-NAME or L-NNA produced constriction of cerebral vessels and reductions in cerebral blood flow.7 25 26 The findings that 7-NI inhibits activity of brain NO synthase but does not alter the diameter of cerebral arterioles (present study and Reference 16) suggest that NO, which influences the basal tone of cerebral vessels, is endothelium derived.
Some data suggest that 7-NI may inhibit inducible NO synthase under some conditions.27 In the present study, because dilatation of cerebral arterioles in response to NMDA is receptor mediated and occurs rapidly, it is very unlikely that activity of inducible NO synthase is involved.
In summary, several recent findings suggest that activation of glutamate receptors produces local vasodilatation in brain that is mediated, at least in part, by NO.7 10 22 25 28 29 30 The present study supports this concept and provides new evidence that activation of neuronal NO synthase mediates vasodilatation in response to NMDA.7 26 31
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institutes of Health grants HL-38901, NS-24621, and GM-08442 and by Grants-in-Aid from the American Heart Association (95014510 and IA-94-GS-29). Dr Faraci is an Established Investigator of the American Heart Association. The authors thank Keith Breese and Kristen Orgren for technical assistance and Dr Donald Heistad for critical review of the manuscript.
Received May 22, 1995; revision received July 5, 1995; accepted July 12, 1995.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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