(Stroke. 1997;28:2259-2265.)
© 1997 American Heart Association, Inc.
Articles |
Neither L-Arginine nor L-NAME Affects Neurological Outcome After Global Ischemia in Cats
From the Departments of Anesthesiology and Critical Care Medicine and Neurology and Pathology, The Johns Hopkins Medical Institutions, Baltimore, Md.
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Abstract |
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Background and Purpose We attempted to determine whether N
-nitro-L-arginine methyl ester
(L-NAME) would improve neurological outcome and whether
L-arginine (L-ARG) would worsen neurological outcome
after transient global ischemia. Methods Halothane-anesthetized cats (n=6 for each group) were treated with intravenous saline, L-NAME (5 mg/kg or 10 mg/kg), or L-arginine (300 mg/kg) 30 minutes before 10 minutes of ischemia (temporary ligation of the left subclavian and brachiocephalic arteries with hemorrhagic hypotension to 50 mm Hg). At 30 minutes of reperfusion, cats in the L-ARG group were administered an additional 300 mg/kg dose of intravenous L-arginine.
Results Time (mean±SE) to isoelectric electroencephalography was similar among groups (saline, 26±11 seconds; L-NAME–5, 15±4 seconds; L-NAME–10, 36±27 seconds; and L-ARG, 22±7 seconds). At 72 hours, reperfusion pathological injury was severe and neurological deficit score (mean, range) was similar among groups (saline, 38 [11 to 70]; L-NAME–5, 52 [40 to 73]; L-NAME–10, 47 [23 to 70]; and L-ARG, 40 [0 to 79]).
Conclusions Nitric oxide is not important in the mechanism of brain injury after global ischemia in cats.
Key Words: cerebral ischemia, global • neuroprotection • nitric oxide • neuronal death • cats
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Introduction |
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Many studies1 2 have found that NO is an important mediator of brain injury after focal cerebral ischemia and reperfusion. For example, inhibition of neuronal NOS with either a low dose of a nonspecific NOS inhibitor3 4 or a specific neuronal NOS inhibitor5 6 decreases ischemia-induced infarct volume. Likewise, neurological injury that results from transient focal ischemia is less in neuronal NOS– deficient mice compared with wild-type mice.7
In the setting of global ischemia, NO appears to be partially involved in the mechanism of postischemic hyperemia.8 In addition, even during the period of delayed hypoperfusion there is continued production of NO that affects cerebrovascular tone.9 10 Mice deficient in neuronal NOS have less neuronal injury in CA1 hippocampus after 5 or 10 minutes of global ischemia.11 However, the inhibition of NOS after transient forebrain ischemia in gerbils12 and rats13 fails to provide neuroprotection in hippocampus. In an attempt to resolve this controversy regarding the role of NO in brain injury after ischemia, we tested whether the administration of the nonspecific NOS inhibitor L-NAME would improve neurological outcome and whether L-arginine (by increasing the production of NO) would worsen neurolog- ical injury produced by transient global cerebral ischemia in the cat.
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Materials and Methods |
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The study was conducted in accordance with the National Institutes of Health's Guidelines for the Use of Experimental Animals, and the protocols were approved by the Institutional Animal Care and Use Committee.
Halothane-anesthetized (1.5 to 2.0%) male cats weighing 2.8 to 5.8 kg (n=45) were prepared with controlled ventilation via an endotracheal tube to maintain PaCO2 at 35±5 mm Hg. Oxygen was added to the inspiratory limb of the vaporizer to maintain PaO2 greater than 90 mm Hg. Antibiotic prophylaxis was with cefazolin (25 mg/kg, IM); before and immediately after surgery and every 8 hours for 24 hours. Esophageal temperature was maintained at 38.0±0.5°C throughout the surgical procedures using a heat lamp.
All surgical techniques were performed using sterile techniques. The left femoral artery was cannulated to measure MABP, glucose, PaO2, PaCO2, and pH. The left femoral vein was cannulated for the administration of fluids and drugs. After cannulation the left femoral wound was closed, and both catheters were tunneled through subcutaneous tissue and exteriorized in the posterior midthorax. The right femoral artery and vein were cannulated for use only during the period of ischemia.
Through a left thoracotomy, ligatures were loosely placed around the brachiocephalic trunk and the left subclavian artery. Bifrontal needle electrodes were placed for subsequent monitoring of the EEG during ischemia. The ground electrode and electrocardiogram electrodes were placed in the forepaws.
Arterial blood pressure was continuously monitored during the experimental preparation, ischemia, and the first 30 minutes of reperfusion. Arterial pH, PaCO2, PaO2, hemoglobin, and blood glucose concentration were measured as previously described.14
Before the onset of ischemia, cats in the 10-minute ischemia protocol were randomly assigned to one of four groups: saline (10 mL), L-NAME–5 (5 mg/kg), L-NAME–10 (10 mg/kg), or L-ARG (300 mg/kg). After the results from the first cohort had been obtained, a second, smaller cohort was designed to test the efficacy of L-NAME–10 in cats exposed to a shorter duration of ischemia (5 minutes). In the second cohort, cats were randomly assigned to one of two groups: saline (10 mL) or L-NAME–10. All groups received their drugs in a volume of 10 mL over 10 minutes by continuous intravenous infusion, 30 minutes before the onset of ischemia. In the L-ARG group, cats received a second dose at 30 minutes of reperfusion.
One minute before the onset of ischemia, inspired halothane concentration was lowered to 0.5%. Cerebral ischemia was produced by tightening the ligatures around the brachiocephalic trunk and left subclavian artery and inducing hypotension to a MABP of 50 mm Hg. MABP was lowered by withdrawal of blood into heparinized syringes. We have previously demonstrated that this protocol produces dense ischemia throughout the brain.8 9 10 15 Rapid onset of an isoelectric EEG was taken as evidence of adequate ischemia. After 10 minutes (cohort 1) or 5 minutes (cohort 2) of ischemia, reperfusion occurred by removing the ligatures and reinfusing shed blood. Inspired halothane concentration was returned to preischemic values within 5 minutes of reperfusion. All wounds were infiltrated with 0.25% bupivacaine before closure. A chest tube was placed in the pleural space to reestablish negative intrapleural pressure after chest wound closure. The chest tube was removed before emergence from anesthesia in all cats. All cats were treated with 0.2 mg/kg morphine sulfate intravenously as a single bolus injection before emergence from anesthesia.
Halothane was discontinued after all wounds were closed (at approximately 45 minutes of reperfusion). The trachea was extubated within 30 minutes of stopping halothane in all cats. Criteria for extubation included the presence of spontaneous ventilation with end-tidal CO2 of less than 45 mm Hg, the ability to hold head up unsupported, the ability to cough to endotracheal tube suctioning, and the ability to blink to eyelash stimulation.
All cats received intensive care nursing throughout the period of reperfusion. Nutrition was provide by gavage feeding (Clinical Care Feline Liquid Diet; Tet-Ag Inc). All physiological variables and neurological deficit scores16 17 were recorded at 48 and 72 hours of reperfusion by observers (A.B. and D.F.H.) who were blinded to treatment group. The maximum overall neurological deficit score possible was 100. The neurological deficit score was based on level of consciousness (maximum 15 for comatose), respirations (maximum 5 for abnormal), cranial nerve function (maximum 14 for none), motor tone and motor response (maximum 16 for abnormal tone and absent motor response in all four extremities), behavioral reactions (maximum of 20 for absence of wheelbarrowing, extensor postural thrust, front and rear extremity placing, feeding and cleaning), and gait (maximum of 30 for no purposeful movement).
At 72 hours of reperfusion, cats were reanesthetized with pentobarbital (20 to 30 mg/kg, IV), intubated, ventilated, and then perfused intra-aortically with ice-cold phosphate-buffered saline (10 mmol/L, pH 7.4) followed by cold 4% paraformaldehyde prepared in phosphate-buffered saline. After perfusion, the brain was allowed to fix in situ for an additional 2 hours before it was removed from the skull and then immersed in fixative. All brains were cut and sampled systematically for neuropathological evaluation. The hippocampus was sampled coronally at anterior and middle levels, and the cerebellum was sampled midsagittally and parasagittally, including the vermis and anterior and posterior lobules. These samples were paraffin-processed, sectioned (10 µm), and stained with hematoxylin and eosin. Regional neuronal damage was quantified nonstereologically (ie, profile counting) by light microscopy at x1000 magnification for hippocampus and x200 magnification for cerebellum. Two sections from each region were evaluated. The criteria for neuronal damage were eosinophilic cytoplasm and proximal dendrites, cytoplasmic microvacuolation, nuclear pyknosis, and cellular shrinkage. The percentage of damaged neurons was estimated in each section from six nonoverlapping, contiguous microscopic fields within the stratum pyramidale of dorsal CA1 and within the Purkinje cell layer of random folia in the anterior and posterior lobules of cerebellum (equal numbers of measurements were determined from crowns and sulcal depths of cerebellar folia). In dorsal hippocampus, the medial most part of CA1 was evaluated consistently in each cat. This approach was used so that measurements could be made always within the same subregion of CA1, to avoid the bias of sampling from only patchy areas of damage in stratum pyramidale that may occur throughout CA1. Only neurons with visible nuclei (normal or pyknotic) were counted so that perikaryal fragments were not counted. In each field, neurons were counted throughout the depth of the section within the z axis. In general, in each microscopic field, 6 to 33 neurons were counted in CA1, and 2 to 25 Purkinje cells were counted in cerebellar cortex. For each microscopic field, the fraction of neurons with ischemic cytopathology was determined (ie, the percent neuronal damage). Measurements of percent neuronal damage from all fields from each region were averaged to determine a regional value for each cat. Two cats acted as sham-operated controls.
Seven cats were excluded from the protocol before histological evaluation. One cat in the L-ARG group had residual EEG activity during the period of ischemia. The other six cats died before 72 hours of reperfusion (1 placebo cat; 1 L-NAME–5 cat; 2 L-NAME–10 cats; 2 L-ARG cats).
Values are expressed as mean±SE. ANOVA was used to assess parametric data over time (repeated measures) and between groups. Post hoc analysis was performed with the Newman-Keuls test. Neurological deficit score was compared among the placebo group and treatment groups with the Mann-Whitney test. Statistical differences were considered significant at P<.05.
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Results |
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There were no significant differences for physiological variables among the experimental groups in the 10-minute protocol (Table 1
) or between groups in the 5-minute
protocol (Table 2). In the 10-minute
protocol, treatment with L-NAME before the onset of ischemia
increased MABP in both groups (Fig 1).
Likewise, L-NAME was associated with an increase in MABP in the
5-minute protocol (68±5 to 86±6 mm Hg). The volume of
hemorrhage required to lower MABP to 50 mm Hg during
ischemia was greater in the L-NAME–10 group (210±29
mL) than the L-ARG group (147±21 mL) but was similar in the other
groups (saline, 168±13 mL; L-NAME–5, 168±37 mL). During
ischemia, the time to achieve an isoelectric EEG was not
different among groups in the 10-minute protocol (saline, 26±10
seconds; L-NAME–5, 15±4 seconds; L-NAME–10, 35±25 seconds; and
L-ARG, 22±6 seconds) or between groups in the 5-minute protocol
(saline, 13±2; L-NAME–10, 17±3 sec). Esophageal temperature
increased during reperfusion (in the unanesthetized state)
compared with the anesthetized state (before and during
ischemia). However, there were no differences among groups over
time. However, when saline-treated animals exposed to either 5 or 10
minutes of ischemia were compared, the longer duration of
ischemia was associated with higher esophageal temperature at
24 (5-minute, 38.6±0.2°C; 10-minute, 39.6±0.2°C), 48, and 72
hours of reperfusion (Tables 1 and 2).
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Neurological injury was severe in all groups exposed to 10 minutes of
ischemia and less severe in cats exposed to 5 minutes of
ischemia. There was no effect of drug treatment in
percent-injured neurons in CA1 hippocampus or cerebellar Purkinje cells
(Fig 2) regardless of ischemic
duration (5 or 10 minutes). Likewise, drug treatment did not affect
neurological outcome regardless of ischemic duration (Fig 3). However, in the 10-minute protocol
the amount of abnormal tone in the groups treated with either dose of
L-NAME was greater than the group treated with saline.
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Discussion |
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This study demonstrates that the inhibition of NOS or the administration of L-arginine to increase NO production does not affect the intensity of ischemic insult (time to EEG silence during occlusion) or neurological outcome (neurological and neuropathological examination) in a model of transient global ischemia in the cat. Ten minutes of global cerebral ischemia produces severe neurological injury in the cat as measured either by standard neuropathology or by evaluation of the neurological examination. Although control cats exposed to 5 minutes of global ischemia demonstrated less histological injury than those exposed to 10 minutes of ischemia, treatment with L-NAME was not associated with therapeutic or detrimental effects. Therefore, our data do not support the hypothesis that NO is an important mediator of brain injury during transient global ischemia in the cat.
In pilot experiments we assessed the effect of varying the duration of ischemia on neurological injury. Initially we chose 10-minute ischemia duration as a model that would be clinically relevant and cause significant brain injury but not cause acute death. Drug-induced worsening of neurological deficit in this model would have likely produced animals that could not be weaned from mechanical ventilation or that would have died before 72 hours recovery. In 10-minute protocol there was no difference among groups in the number of cats that died before 72 hours of reperfusion. We excluded these animals from the data analysis rather than obtaining neuronal injury and neurological deficit scores for end points other than 72 hours. In the 5-minute protocol neurological injury was less than that observed in the 10-minute protocol, leaving adequate opportunity to observe a worsening of neurological injury by L-NAME if it were to occur.
The high dose of L-NAME was chosen on the basis of the therapeutic efficacy of this dose in the setting of focal ischemia.4 18 We also evaluated a lower dose of L-NAME to address the possibility that the 10 mg/kg dose may be detrimental because of an alteration in postischemic blood flow.8 9 10 Previously, we have found 10 mg/kg L-NAME to produce near maximal inhibition of brain NOS activity in the cat.4 19 Although the burst of NO production appears to occur during the period of ischemia and immediate reperfusion,20 21 it is possible that a different dosing scheme for L-NAME would have provided for therapeutic efficacy.22
In the cat, L-arginine has been shown to mitigate the protective role of L-NAME in the setting of transient focal ischemia.4 We speculate that L-arginine treatment could ameliorate ischemic injury by improving postischemic blood flow or that it may worsen ischemic injury by making more NO available to react with oxygen radicals to form more toxic radicals. We did not measure the effect of L-arginine on NOS activity in this model. However, Salter et al23 demonstrated that intraperitoneal administration of 150 or 300 mg/kg of L-arginine to rats caused a substantial increase in brain NOS activity. These authors speculated that the mechanism for an increase in brain NOS activity by systemic administration of L-arginine, despite an apparent excess amount of L-arginine in whole brain samples, was preferential use of L-arginine by glial cells rather than in NOS-containing neurons or because the Km of neuronal NOS in vivo is much different than that determined in vitro. In addition, although L-arginine treatment ameliorates brain injury in spontaneously hypertensive rats exposed to focal ischemia by a mechanism that involves improving blood flow to the area of ischemia,24 25 26 its role in global ischemia has not been previously evaluated. It is possible that the lack of effect for L-arginine in this model of global ischemia in worsening neurological outcome is due to the diffuse and intense vasodilation that already exists in the brain during the period of ischemia and early reperfusion.
The histopathological data presented in this study are variable. This is one of the weaknesses of this model, but one that makes it more clinically relevant than those models that evaluate drug efficacy in genetically identical mice or rats. Certainly similar (or greater) variability would be expected in stroke in humans. However, even with this degree of variability, the fact that we were able to demonstrate a difference in the amount of injury in cats subjected to 5 minutes rather than 10 minutes of ischemia suggests (but does not prove) that we could determine whether L-arginine or L-NAME caused an important reduction in neurological injury in cats exposed to 10 minutes of ischemia and whether L-NAME caused an important increase in injury in cats exposed to 5 minutes of ischemia. However, the utility of the model would have been even more convincing if it had been shown that another pharmacological treatment was effective in modulating ischemic damage, while L-NAME treatment was not. On the contrary, behavioral testing appears to be an insensitive indicator of histopathological improvement or worsening, since the improved histopathological findings in the group exposed to 5 minutes of ischemia were not associated with a significantly improved neurological examination.
Even small increases in temperature during global ischemia cause significant worsening of neurological deficits.27 In the current study, esophageal temperature during ischemia was maintained normothermic in all groups. However, temperature was increased in all groups during the late stages of reperfusion, without any differences among groups exposed to the same duration of ischemia. However, body temperature was higher after 24 hours of reperfusion in control cats exposed to 10 minutes compared with 5 minutes of global ischemia. It is possible that this increase in temperature, which occurred after the period of ischemia, may be part of the cause of the severe neurological injury.28 The mechanism for the increased body temperature postischemia is unclear. All cats were provided with perioperative antibiotics to prevent infectious disease complications. It is possible that the increase in temperature was a result of the severe brain injury, with hypothalamic dysfunction rather the etiology of the severe brain injury. When all groups are combined, our data demonstrated no correlation between temperature at 48 or 72 hours and neurological deficit score at 72 hours. However, there was a significant correlation (r=.41; P=.03) between temperature at 72 hours and percent-injured Purkinje cells in the cerebellum but not in the CA1 hippocampus.
During ischemia we used halothane as the anesthetic in order to facilitate a rapid emergence from anesthesia after all the wounds were closed and infiltrated with bupivicaine. We believe that there is no ideal anesthetic to use in animal models of cerebral ischemia. Most of the anesthetics have been demonstrated to affect ischemic tolerance. Likewise, most of the anesthetics have been demonstrated to alter activity of NOS in the brain. We have demonstrated29 that halothane (like other anesthetics) decreases NOS activity in whole rat brain homogenates in vitro. However, in vivo we have also demonstrated that halothane and isoflurane increase cerebral blood flow by a mechanism that can be inhibited by intravenous administration of L-NAME.30 31 More recently, Rengasamy et al32 33 demonstrated that inhalational anesthetics do not alter neuronal NOS activity. However, in the presence of N-methyl-D-aspartate, isoflurane caused further stimulation of neuronal NOS, but this did not occur with halothane. Because excitatory amino acids are known to increase during ischemia, these new data33 support the hypothesis that halothane, unlike isoflurane, has little effect itself on NOS activity during ischemia.
In conclusion, intravenous administration of either L-NAME or L-arginine does not affect the intensity of ischemic insult (time to EEG silence during occlusion) or neurological outcome (neurological and neuropathological examinations) in a model of transient global ischemia in cat. Ten minutes of global cerebral ischemia produces severe neurological injury in the cat as measured by either conventional neuropathology or evaluation of the neurological examination. Five minutes of ischemia is associated with less neurological damage than 10 minutes, but the amount of damage is not affected by pretreatment with L-NAME. This model of global cerebral ischemia may produce neurological injury by a mechanism that does not involve NO.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by US Public Health Service National Institutes of Health grant NS20020. Dr Bhardwaj is supported in part by the American Heart Association Clinician Scientist Award and the Richard S. Ross Clinician-Scientist Award from the Johns Hopkins University School of Medicine. The authors thank Ying Wu, Dawn Spicer, and Ann Price for their excellent technical assistance.
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Footnotes |
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Reprint requests to Jeffrey R. Kirsch, MD, Department of Anesthesiology and Critical Care Medicine, 600 North Wolfe St, Blalock 1410, Baltimore, MD 21287-4963.
Received April 24, 1997; revision received July 8, 1997; accepted July 18, 1997.
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