(Stroke. 1995;26:282-289.)
© 1995 American Heart Association, Inc.
Articles |
NG-Nitro-L-Arginine Delays the Development of Brain Injury During Focal Ischemia in Rats
From the Neuroradiology Section, Department of Radiology, University of California, San Francisco.
Correspondence to Ewa Kozniewska, PhD, Warsaw's School of Medicine, Department of Clinical and Applied Physiology, Krakowskie Przedmiescie 26/28, 00-927 Warsaw, Poland.
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Abstract |
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Background and Purpose The present study was designed to determine the effect of nitro-L-arginine, the inhibitor of nitric oxide synthesis, on the evolution of cytotoxic brain edema during focal cerebral ischemia.
Methods Diffusion-weighted and contrast-enhanced, perfusion-sensitive magnetic resonance imaging was performed in anesthetized, mechanically ventilated rats at 30 minutes and 1, 2, and 3 hours after occlusion of the middle cerebral artery combined with coagulation of the basilar artery. At the onset of ischemia, the animals were infused intravenously with 0.5 mL of either 0.9% NaCl or nitro-L-arginine (30 mg/kg). The severity of cytotoxic edema was evaluated based on changes in the water apparent diffusion coefficient (ADC) derived from diffusion-weighted images. The size of the area affected by ischemia was evaluated 3 hours after occlusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining.
Results The percentage decrease of ADC in the striatum of rats pretreated with nitro-L-arginine was significantly smaller (P<.05) than in the control group at 30 minutes and 1 and 2 hours of ischemia. The ADC in the injured cortex of nitro-L-arginine–treated rats did not differ significantly from the ADC value measured in the contralateral cortex until 3 hours after the occlusion. However, at 3 hours of ischemia the percentage decrease of ADC in both the striatum and the cortex of either group of rats was similar. This transient attenuation of ADC drop during ischemia after nitro-L-arginine pretreatment occurred concurrently with a transient improvement of blood supply to the ischemic regions. The percentage of hemispheric area with abnormal TTC staining after 3 hours of ischemia did not differ between control and nitro-L-arginine–treated rats.
Conclusions Nitro-L-arginine delays the development of ischemic injury by retarding cytotoxic brain edema. This effect is, at least partially, mediated by an improvement in blood supply to the ischemic tissues.
Key Words: brain edema • cerebral ischemia, focal • magnetic resonance imaging • nitric oxide synthesis • rats
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Introduction |
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Nitric oxide (NO) is an important mediator in many physiological and pathological processes.1 Under physiological conditions it is produced in endothelial cells2 and discrete populations of neurons in the central nervous system and in the adrenal medulla.3 4 NO has been implicated in the regulation of blood pressure5 and flow through different tissues,6 7 including the brain.8 9 Apart from the inhibitory effect on vascular smooth muscle through the stimulation of cyclic GMP, it also regulates blood rheology by acting as an antiaggregation and antithrombotic factor.10 In the central nervous system, NO has been reported to function as a neurotransmitter. Its release in response to glutamate and stimulation of N-methyl-D-aspartate receptors has been demonstrated in the cerebellum, hippocampus, and striatum.11 12 13 14 15 Evidence that NO mediates the physiological effects of glutamate and that glutamate participates in the development of ischemic brain damage16 17 18 19 20 strongly suggests that NO is involved in mechanisms leading to neuronal injury. One such mechanism could be the generation of potent oxidants, peroxynitrite, and hydroxyl radicals,21 which have been reported to mediate ischemic brain injury.22 23 However, the vascular and rheological actions of NO seem to counteract rather than promote ischemia.
To date, results of studies on the effect of inhibition of NO synthesis on brain injury during ischemia have been inconclusive. Various investigators have demonstrated a decrease,24 25 an increase,26 27 or no change28 in infarct volume in animals pretreated with different NO inhibitors. In all of these studies, the extent of injury was evaluated postmortem between 4 and 24 hours after the insult using conventional histological methods.
The present study was designed to determine the effect of inhibition of NO on the early evolution of cerebral ischemia using sequential noninvasive high-speed magnetic resonance imaging (MRI).29 30 31
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Materials and Methods |
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Twenty-one adult male Sprague-Dawley rats weighing 240 to 280 g were used. The animals had free access to water and commercial chow pellet until the day of the experiment. They were anesthetized with chloral hydrate (36 mg/100 g body wt IP), paralyzed with pancuronium (0.05 mg/100 g body wt IV), and artificially ventilated with 30% O2 and 70% N2O. Femoral artery and ipsilateral femoral vein were cannulated to allow continuous measurements of mean arterial blood pressure and for arterial blood sampling for gasometric analysis (PaO2, PaCO2, pH), drug administrations, and supplementation of anesthesia.
Permanent focal cerebral ischemia was produced using a model of middle cerebral artery (MCA) intraluminal suture occlusion described by Zea Longa et al32 combined with a basilar artery coagulation to increase the reproducibility of the injury.33 Briefly, a midline skin incision was made on the anterior neck, the common carotid artery was exposed under the operating microscope, and the external and internal carotid arteries were identified. The clivus was exposed after the dissection of the surrounding muscles. After a small bone window (3-mm diameter) was opened in the clivus using a dental drill, the dura was cut with a 27-gauge needle. The basilar artery was carefully freed from the adjacent arachnoid membrane to avoid subarachnoid hemorrhage and perforator injury, electrocauterized, and cut with microscissors at the midpontine level. Next, the branches of the external carotid artery were coagulated at a level of carotid sinus. The pterygopalatine artery was then identified and ligated. To occlude the MCA, a 3.0 monofilament nylon suture with its tip rounded by flame heating was placed centripetally in the right external carotid artery, introduced into the internal carotid artery, and advanced intracranially approximately 17 mm from the bifurcation of the common carotid artery. Care was taken to avoid mechanical trauma to the carotid sinus innervation.
The rats with ischemia were divided into two groups according to the treatment performed at the time of occlusion. Group A (n=7) was injected with a vehicle (0.9% NaCl, 0.5 mL IV) and group B (n=7) with NG-nitro-L-arginine (30 mg/kg dissolved in 0.5 mL 0.9% NaCl, IV), which is a specific inhibitor of NO synthesis. Rats in both groups also received 150 U heparin IV (0.1 mL). In group B, blood pressure was controlled by blood withdrawal from the venous line to prevent its increase due to NO removal. An additional 7 rats (without ischemia) served as a control group for nitro-L-arginine. These rats underwent sham operation (exposure of the carotid arteries without occlusion and basilar artery without coagulation) and received intravenously the same dose of nitro-L-arginine and heparin as the animals with ischemia.
Immediately after surgery the rats were placed in the bore of the magnet for MRI. During the study they were kept normocapnic by appropriate adjustment of ventilatory parameters. PaO2 was kept close to 100 mm Hg. Body temperature was controlled and maintained around 37°C with a heating pad.
Diffusion-weighted and perfusion-sensitive high-speed echo planar MRI were performed 30 minutes and 1, 2, and 3 hours after the onset of ischemia and/or nitro-L-arginine administration using a 2-T Omega CSI system (Bruker Medical Systems) equipped with Acustar S-150 self-shielded gradients (20 G/cm, 15-cm inner diameter). The rats were positioned with their heads inside a 50-mm inner diameter radiofrequency excitation/detection coil. Preview spin/echo images were obtained to determine the optimal slice plane, which was chosen as a coronal section at approximately the level of the optic chiasm.
Stjeskal-Tanner diffusion-sensitizing gradients34 of strengths up to 11 G/cm were used to obtain 11 diffusion-weighted images with "b-values" in the range of 0 to 2440 s/mm2. All images were acquired with a 50-mm field of view, 3-mm slice thickness, and 128x128 matrix size. An echo time (TE) of 80 milliseconds and a total acquisition time of 82 milliseconds were used; eight averages were acquired per image with a 4-second repetition time (TR). Diffusion-weighted images were analyzed by pixel-by-pixel logarithmic regression analysis assuming an exponential loss of the signal (S), which depends on the product of the apparent diffusion coefficient (ADC) and the image b-value according to the equation S~exp(-bD), where D represents the ADC for water protons. Spatial ADC maps were constructed, from which ADC values were extracted for the anatomic regions of interest (ROIs). ROIs comprised the striatum and frontoparietal cortex of the injured hemisphere and the homologous contralateral region in the control hemisphere.
To study cerebral perfusion, high-speed,
T2*-sensitive echo planar imaging was performed using a
modification of the MBEST35 sequence. Echo planar
imaging was performed after intravenous injection of a short
(approximately 1 second) bolus of magnetic susceptibility contrast
agent (Sprodiamide injection, Nycomed Salutar Inc and Sanofi Winthrop;
0.25 mmol/kg)36 to obtain a series of 32 images acquired
at 1-second intervals. Variations in the integrated signal intensity
across the ROIs (the same as chosen for ADC analysis) during
transit of the contrast agent were transformed into plots of
R2* (the change in effective transverse relaxation rate)
versus time according to the relation
R2*(t)=-ln(St/S0)/TE, where
St is the signal intensity at time t, integrated over the
ROI, S0 is the precontrast baseline signal intensity, and
TE is the image echo time.
The quantity R2* appears to be directly proportional to
the regional concentration of magnetic susceptibility contrast
agent36 37 and thus allows construction of a
concentration-time curve that represents the transit of the
bolus of intravascular contrast agent through the tissue. There are two
measures that can be reliably extracted from the concentration-time
curves to characterize perfusion. One is the transit time of the
passage of the contrast bolus, which was estimated by measuring the
full width at half height (FWHH) of the concentration-time curve. The
reciprocal of the FWHH was used as an index of cerebral perfusion. This
method of relative quantification of cerebral perfusion was used to
demonstrate changes in the perfusion of the nonischemic part of the
brain due to nitro-L-arginine administration.
A second measure that can be extracted from the
concentration-time plot is the height of the curve at its maximum (peak
R2*). This measure represents the maximum
instantaneous amount of contrast agent that enters the ROI and is thus
related to the volume of blood delivered to this region. The peak
R2* was used to characterize perfusion deficit during
ischemia. The magnitude of the reduction in blood supply to the
ischemic regions was calculated for each ROI (the same ROI that was
used for the calculation of ADC value) as a ratio of the peak
R2* for the injured and intact hemisphere. This
normalization of peak R2* to the contralateral value
allows for the interinjection variation in the arterial form of the
bolus itself.
At the completion of the last MRI, the extent of injury was verified histologically with 2,3,5-triphenyltetrazolium chloride (TTC). The rats were perfused intracardially with 20 mL of 2% buffered TTC at 37°C to 38°C. The brains were removed and fixed in 4% formalin for 24 hours. Next they were scanned and analyzed with an image processing system to determine the size of the area of TTC-deficient staining as a percentage of the occluded hemisphere for each slice. In normal brain, TTC is converted by mitochondrial oxidative enzymes to a red formazan product, resulting in a deep red staining of brain parenchyma.38 Ischemia renders mitochondrial oxidative enzymes dysfunctional, resulting in a failure of TTC conversion to its red derivative and producing a pale area in the affected part of the brain.
Statistical analyses were performed using factorial or repeated-measures ANOVA where appropriate and post hoc Dunnett's t test. A two-tailed probability value of less than .05 was considered significant. All data are presented as mean±SEM.
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Hemodynamic parameters and blood gas analyses are presented in Table 1
. All animals were normocapnic, and
PaO2 values were within the range of 83 to
120 mm Hg. Mean arterial blood pressure was stable in both
nitro-L-arginine–treated and untreated (control) groups
but was significantly higher in the nitro-L-arginine
group 30 minutes (P<.01) and 60 minutes (P<.05)
after nitro-L-arginine administration.
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The decreased cerebral blood flow resulting from
nitro-L-arginine administration can be seen in the
significantly decreased cerebral perfusion index (reciprocal width of
R2* curve in the hemisphere contralateral to the
occluded MCA). In the group treated with
nitro-L-arginine, the cerebral perfusion index was 46%
lower (P<.05) in the striatum and 49% lower in the cortex
(P<.01) than in the corresponding regions of the untreated
control group (Table 2). This perfusion decrease was
accompanied by a decrease in ADC in the hemisphere contralateral to
occlusion in the nitro-L-arginine group compared with the
untreated control group. However, when nitro-L-arginine
was administered to sham-operated rats, although the cerebral perfusion
index decreased similarly, there was no significant ADC decrease (Table 3), suggesting that the ADC decrease is a consequence of
both locally reduced perfusion and ischemia in the alternate
hemisphere.
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MCA occlusion resulted in a decrease in peak R2* in the
hemisphere ipsilateral to the occlusion. This effect was more
pronounced in the end-arterial striatum than in the well-collateralized
cortical tissue. This observation was made in both
nitro-L-arginine–treated and untreated groups.
Expressed relative to the value in the contralateral striatum, peak
R2* in the ischemic striatum decreased to 20±4% 30
minutes after occlusion in the untreated control group. It remained
stable during the study at 23±5% (1 hour), 10±3% (2 hours), and
16±8% (3 hours). In the nitro-L-arginine–treated
group, the decrease in peak R2* was significantly
attenuated (P<.05) at 30 minutes, 1 hour, and 2 hours after
MCA occlusion (Fig 1, top). After 3 hours, however, the
peak R2* relative to the contralateral striatum was
24±5%, which was not significantly different from the untreated
control group.
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In the striatum of the untreated control group, the perfusion deficits
were accompanied by significant decreases in ADC of 30±1%
(P<.01) relative to the contralateral tissue after 30
minutes of occlusion. The ADC tended to decrease slowly over the course
of the 3-hour study (Fig 1
, bottom).
In the striatum of nitro-L-arginine–treated rats, the ADC decrease was attenuated. The ADC decrease was significantly less than that observed in the control group after 30 minutes (P<.01), 1 hour (P<.01), and 2 hours (P<.05). However, after 3 hours, there was not a significant difference in the ADC decrease in the group treated with nitro-L-arginine versus the control group.
Perfusion and ADC decreases were also observed in the cortex. However,
the perfusion variability resulting from collateral flow recruitment
rendered the observed tendencies statistically not significant (Fig 2,
top). Although a decreased ADC was observed in the
ischemic cortex of the untreated control group compared with the
contralateral hemisphere (P<.05) as soon as 30 minutes
after occlusion, no significant relative ADC reduction was observed in
the ischemic cortex of nitro-L-arginine–treated rats
until 3 hours after occlusion (Fig 2, bottom).
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The percentage of hemispheric area with abnormal TTC staining at 3
hours after occlusion was indistinguishable between consecutive slices
in both groups of animals (Fig 3). For the section most
similar to the imaged slice, the region of deficient TTC staining
corresponded well with the hyperintense region on diffusion-weighted
MRI.
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) and nitro-L-arginine–pretreated (
) rats.
It was evaluated as the percentage of hemispheric area in six
consecutive 1-mm-thick coronal sections. |
Discussion |
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The MRI techniques used in the present study enable noninvasive in vivo examination of the evolution of early cytotoxic brain edema together with direct visualization of relative changes in cerebral perfusion. Diffusion-weighted imaging is sensitive to translocation of water protons from the extracellular to intracellular space and has been shown to highlight regions of tissue injury within minutes after onset of ischemia.29 39 By comparison, conventional T2-weighted MRI is sensitive to net gain of water by tissues and does not demonstrate any changes until vasogenic edema develops.40 During focal ischemia, signal intensity changes seen on diffusion-weighted images seem to result from a failure of energy metabolism, which leads to an influx of Na+ and osmotically driven water into cells. This shift of water results in a net restriction of diffusion of water protons that yields hyperintensity on diffusion-weighted images, which is confined to the vascular territory of the compromised arterial vessels. Attenuation or exacerbation of this early phase of cytotoxic edema leads to graded changes in the ADC.
Fast, dynamic perfusion-sensitive MRI combined with the intravenous injection of paramagnetic contrast agent can be used to monitor a transient decrease in T2*-weighted signal intensity attributable to changes in cerebral perfusion state.29 Although the absolute value of cerebral blood flow cannot be determined from the concentration-time curve of the contrast passage through the brain, the perfusion index calculated as the reciprocal of the width of this curve (FWHH) seems to closely approximate cerebral blood flow. The changes in cerebral perfusion index observed after inhibition of NO synthesis in the present study parallel changes in cerebral blood flow observed earlier.8
The maximum height of the concentration-time curve of contrast passage
(peak R2*), on the other hand, reflects blood supply to
the ischemic part of the brain. Peak R2* is proportional
to the amount of contrast and thus to regional blood delivery. Such
combined perfusion/diffusion-sensitive MRI has been used previously in
our laboratory for dynamic evaluation of the evolution of focal brain
injury.29 31
Although a few other studies published in the literature have addressed the problem of the effect of NO inhibition on ischemic brain damage,24 25 26 27 28 we believe our present study is the first designed to observe the effect of NO synthase inhibition on the evolution of early ischemic changes in the same brain. Such a design seems to be important in view of the transient (up to 60 minutes) increase of NO outflow from rat brain during focal ischemia.41 42
The main finding of this study is that nitro-L-arginine
administration transiently attenuates the development of cytotoxic
brain edema during focal ischemia. The relative drop of ADC in the
striatum was significantly smaller in the group of animals pretreated
with an inhibitor of NO synthesis than in the control group during the
first 2 hours after the onset of ischemia. Similarly, the ADC in the
cortex of the occluded hemisphere did not decline in comparison to that
in the contralateral one until 3 hours after occlusion in this group.
These results alone strongly suggest that NO participates in the early,
cytotoxic phase of ischemic changes during focal cerebral ischemia. The
mechanism by which inhibition of NO synthesis modulates the evolution
of cytotoxic swelling seems, however, to be at least partially related
to the improvement of blood supply to the ischemic region due to the
increase in arterial blood pressure following administration of
nitro-L-arginine. This is obvious for the striatum but
less evident for the cortex. The attenuation of the decrease in
relative ADC in the ischemic striatum in the group of rats pretreated
with nitro-L-arginine, in comparison to the control
group, paralleled the increase of blood supply to this region. The ADC
in the ischemic cortex of the rats pretreated with
nitro-L-arginine did not differ from that in the
homologous contralateral cortex during 2 hours of ischemia, suggesting
preservation of local fluid-electrolyte homeostasis. During this time
interval, however, the mean relative peak R2* of the
ischemic cortex in this group of rats tended to be greater than the
corresponding mean relative peak R2* of controls. The
differences were not statistically significant because of the large
variability within groups. The increased perfusion to the ischemic
striatum was most probably related to the moderate increase of blood
pressure observed in the group of animals pretreated with
nitro-L-arginine. In the model of ischemia used in this
study, the severity of ischemia depends on the level of systemic blood
pressure. Even if the increase of perfusion pressure at the level of
the cerebral microcirculation is less pronounced than the increase of
systemic blood pressure, an increase in blood flow to the ischemic
territory of the brain will result from the abolition of the normal
autoregulatory pressure-flow relationship during ischemia.
In the cortex, which due to collateralization is less sensitive to the occlusion, the disturbances of the autoregulatory pressure-flow relationship were not as consistent as in the striatum. Hence, the passive increase in perfusion was not significant. The delay in the relative decrease of ADC in the ischemic cortex in the group of rats pretreated with nitro-L-arginine, therefore, seems to be directly related to the inhibition of NO synthesis. The delay in the development of cytotoxic edema after administration of nitro-L-arginine represents the possibility of a therapeutic window for the application of other long-lasting agents.
Although we did not measure the effectiveness of NO synthesis inhibition in the present study, our results on the effect of nitro-L-arginine on cerebral perfusion index and mean arterial blood pressure in the ischemic as well as the nonischemic control group of animals demonstrate that NO synthesis is inhibited for at least 3 hours. These effects are NO specific, since administration of excess amounts of L-arginine but not D-arginine largely reverses the increase of arterial blood pressure and the decrease of cerebral blood supply resulting from nitro-L-arginine administration.43 Based on the results of Dwyer et al,44 we can assume that, in our study, brain NO synthesis activity was inhibited by at least 50%.
The fact that inhibition of NO synthesis delays, but does not prevent, ischemic brain changes suggests that NO is an important mediator of an early phase of cytotoxic brain edema during focal ischemia. Its participation in this process can easily be overlooked if one does not study the temporal evolution of ischemic changes. Dawson et al28 could not find histological evidence of brain protection 4 hours after permanent MCA occlusion in rats pretreated with NO inhibitor. In that study, they used 30 mg/kg IV L-arginine methyl ester, the active form of which is nitro-L-arginine (used in our study). According to the recently published result of Carreau et al,45 nitro-L-arginine seems to be more effective against brain damage during focal cerebral ischemia when administered in lower doses than the 30 mg/kg used in our study. Thus, there is a possibility that if a lower dose had been used in our experimental model of ischemia, we would have been able to see more effective inhibition of the cytotoxic brain swelling.
In the present study, area of injury was estimated based on TTC staining. We are aware, however, that deficient TTC staining does not necessarily represent irreversibly damaged tissue.46 In our case, TTC was used rather as a marker for tissue with metabolic abnormality, since we were interested in the development of early cytotoxic changes. It should be stressed, however, that in each case there was good agreement between the area of TTC-deficient staining on the section identified as closest to the MRI slice and the area of hyperintensity on diffusion-weighted MR images (3 hours after occlusion). According to the data published by Minematsu et al47 in a similar model of focal cerebral ischemia in rats, diffusion-weighted imaging results obtained at 3 hours after occlusion were confirmed with TTC at 24 hours after occlusion.
Administration of nitro-L-arginine, which provided short-term protection for ischemic tissues, had the opposite effect on the contralateral nonischemic tissue. The perfusion index in this contralateral hemisphere was 46% to 49% lower in the group of rats pretreated with nitro-L-arginine than in the control group. Furthermore, the ADC in the contralateral hemisphere in the nitro-L-arginine–treated animals was also decreased from baseline. This drop in ADC did not seem to be a direct consequence of decreased perfusion alone, since in sham-operated rats treated with the same dose of nitro-L-arginine, there was no change in ADC despite a similar drop in perfusion index. Thus ADC decreased in the nonischemic tissue after nitro-L-arginine administration only in the presence of contralateral ischemia. It seems that the ischemic region affects the nonischemic one, making it more susceptible to effects of blood flow deficiency. Whether this is a specific effect of nitro-L-arginine and NO inhibition remains to be established. Nevertheless, the nonischemic hemisphere appears to be metabolically normal, according to TTC staining.38 Our present results do not give a clear insight into this interesting phenomenon.
In our study, systemic arterial blood pressure remained elevated after nitro-L-arginine despite an attempt to lower it by induced hemorrhage. This apparent resistance to hemorrhage suggests an enhanced reflex regulation of cardiovascular tone. Such an explanation is in agreement with the reported increase in sympathetic outflow after inhibition of NO synthesis48 and is supported by the observation that inhibition of NO synthesis restores arterial pressure in hemorrhaged rats.49
In summary, nitro-L-arginine was found to delay the development of ischemic injury by retarding cytotoxic brain edema. The mechanism of this transient attenuation of ischemic damage depends, at least partially, on an improvement in blood supply to the ischemic tissue.
Received November 8, 1993; revision received August 12, 1994; accepted October 6, 1994.
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