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© 1999 International Anesthesia Research Society
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Abstract |
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Little is known about the role of nitric oxide in the pathophysiology of spinal cord ischemia. We evaluated the effects of nitric oxide synthase (NOS) inhibition by NG-nitro-L-arginine-methyl ester (L-NAME) in rabbits whose abdominal aorta was occluded for 20 min (Experiment 1) or 25 min (Experiment 2). In Experiment 1, the L-NAME group (n = 6) received 3 mg/kg IV L-NAME, followed by an IV infusion of 3 mg · kg-1 · h-1 until 6 h after reperfusion. Ischemia was induced 20 min after the start of L-NAME. The phenylephrine group (n = 6) received phenylephrine to maintain comparable blood pressure. The control group (n = 6) received saline. In Experiment 2, L-NAME (3 mg/kg IV L-NAME, followed by an IV infusion of 3 mg · kg-1 · h-1 until 6 h after reperfusion) and phenylephrine groups (n = 6 each) were studied. Ischemia was induced 100 min after the start of L-NAME. Forty-eight hours after reperfusion, hindlimb motor function and histopathology of the spinal cord were examined. In Experiment 1, L-NAME and phenylephrine both improved neurologic outcome, with higher intraischemic blood pressures than saline. In Experiment 2, L-NAME worsened the neurologic and histopathologic outcome compared with phenylephrine. Attenuation of damage by L-NAME in Experiment 1 may be attributable to an intraischemic blood pressure increase. The worse outcome with L-NAME in Experiment 2 suggests that NOS inhibition exacerbates ischemic spinal cord damage.
Implications: Nonselective inhibition of nitric oxide synthase activity has aggravating effects on the neurologic and histopathologic outcome after transient spinal cord ischemia.
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Introduction |
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Several studies have shown that nitric oxide (NO) may be involved in the pathophysiology of cerebral ischemia (1–3). An increase in NO production may be neuroprotective by increasing organ blood flow by vasodilation and/or inhibition of platelet aggregation (1–4). NO can also down-regulate N-methyl-D-aspartate receptors (5) and may provide neuroprotective effects. However, free radical-mediated neuronal damage by NO has also been proposed (5). The final outcome after ischemia may be determined by the net effects of these actions of NO.
For spinal cord ischemia, there have been only limited reports investigating the role of NO (6,7). Marsala et al. (6) have demonstrated that spinal cord gray matter layers rich in nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase-positive neurons (laminae I-III and X) are refractory to transient ischemia in rabbits. Although nitric oxide synthase (NOS) is not the only enzyme that has NADPH diaphorase activity, the results indicate that NO may act to protect against ischemic damage. Nemoto et al. (7) have reported that an inhibition of NOS by NG-monomethyl-L-arginine (L-NMMA) accelerates the recovery of polysynaptic reflex potentials after transient spinal cord ischemia in cats. However, the relevance of NOS inhibition to neurologic outcome after spinal cord ischemia has not been investigated.
We designed the present study to determine whether preischemic administration of NG-nitro-L-arginine-methyl ester (L-NAME) influences neurologic and histopathologic outcome after transient spinal cord ischemia. Because the administration of L-NAME to rabbits was found to increase systemic blood pressure in a preliminary study, the effect of L-NAME was compared with that of phenylephrine, which produced comparable increases in blood pressure during ischemia.
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Methods |
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This experiment was reviewed and approved by our institutional ethics committee. We used 30 New Zealand White rabbits weighing 2.6 ± 0.1 (mean ± SD) kg.
Surgical preparation, monitoring of physiological variables and segmental spinal cord evoked potential (SSCEP), transient ischemic insult and reperfusion, postischemic care, neurologic assessment, and histologic evaluation are the same as in our previous reports (8,9) and are briefly described below.
The rabbits were anesthetized with 1%–2% halothane in oxygen and mechanically ventilated through an endotracheal tube. Lactated Ringer's solution was administered at a rate of 4 mL · kg-1 · h-1 through an ear vein catheter. After skin infiltration with 0.25% bupivacaine, PE-60 catheters were inserted into both femoral arteries. The right femoral catheter was advanced 3 cm into the abdominal aorta while the other was advanced 17 cm. Before catheter insertion, heparin 400 U was administered IV.
In the right lateral decubitus position, a flank skin incision (4–5 cm) parallel to the spine was made at the 12th costal level on the left side. The PE-60 catheter was placed around the aorta retroperitoneally, immediately distal to the left renal artery. An occluder tube (16F rubber tube) was then tunneled into the skin for later occlusion of the aorta to produce spinal cord ischemia. The left sciatic nerve was exposed through a small skin incision made at the left thigh, and bipolar electrodes were placed around the nerve. Esophageal and paravertebral muscle temperatures were monitored. The paravertebral muscle temperature was maintained at approximately 38°C with a heating lamp and warming pad. After surgery, the end-tidal halothane concentration was maintained at 1% in all groups.
In Experiment 1, animals were randomly assigned to either the L-NAME, phenylephrine, or control group (n = 6 each). The L-NAME group received a 3-mg/kg IV bolus of L-NAME (dissolved in saline) over 10 min, followed by an IV infusion of 3 mg · kg-1 · h-1 until 6 h after reperfusion. The phenylephrine group received an IV bolus and an IV infusion of phenylephrine (1–5 µg · kg-1 · min-1) dissolved in saline to maintain a proximal mean arterial pressure (MAP) during the ischemic period comparable to that in the L-NAME group. The control group received a volume of saline equal to that in the L-NAME group. All animals were subjected to 20 min of spinal cord ischemia. In the L-NAME group, ischemia was begun 20 min after the onset of L-NAME administration.
In Experiment 2, we increased the ischemic duration and started the administration of L-NAME 100 min before ischemia. Twelve rabbits were assigned to one of two groups: L-NAME or phenylephrine (n = 6 each). The L-NAME group received a 3-mg/kg IV bolus of L-NAME (dissolved in saline) over 10 min, followed by an IV infusion of 3 mg · kg-1 · h-1 until 6 h after reperfusion. The phenylephrine group received an IV bolus and an IV infusion of phenylephrine to maintain proximal MAP during ischemia comparable to that in the L-NAME group.
To confirm the presence of spinal cord ischemia, SSCEP was monitored. The left sciatic nerve was stimulated with square-wave pulses of 0.1 ms duration and 0.6 mA intensity delivered at 3 Hz. SSCEPs were recorded before ischemia and every 2 min during ischemia using a Neuropack Four (Model MEB-5304; Nihon Kohden, Tokyo, Japan). Recording was performed in a bipolar fashion from the needle electrodes, which were inserted into the midline interspinous ligament so that they were in contact with the lamina at L4 and L5. Fifty repetitions were averaged. The typical recording of SSCEP from L4-5 and L5-6 demonstrates two positive waves and four negative waves (N1-N4). We measured amplitudes of N3 as representative for the postsynaptic component (10).
In both experiments, heparin 400 U was again administered IV immediately before aortic occlusion. Spinal cord ischemia was produced by pulling the PE-60 catheter and clamping an occluder tube for 20 or 25 min. At the end of the 20- or 25-min period of ischemia, reperfusion of the spinal cord was established by removal of the occluder tube and PE catheter. Immediately after release of the aortic ligature, satisfactory pulsatile distal aortic pressure was observed. In the phenylephrine group, the phenylephrine infusion was discontinued at the end of the ischemic period. The arterial catheters were removed 30 min after reperfusion. Halothane (0.5%–1%) was administered until all the wounds were closed with sutures.
After extubation of the trachea, animals were allowed to recover in a warmed plastic box that contained supplemental oxygen for 6 h. L-NAME or saline was administered IV for 6 h after reperfusion. Cephazolin (30 mg/kg IM) was administered once daily. Bladder contents were expressed manually as required.
At 6, 12, 24, and 48 h after reperfusion, the rabbits were neurologically assessed by an observer unaware of the treatment group using the 5-point grading scale proposed by Drummond and Moore (11): 4 = normal motor function; 3 = ability to draw legs under body and hop, but not normally; 2 = some lower extremity function with good antigravity strength but inability to draw legs under body; 1 = poor lower extremity motor function, weak antigravity movement only; 0 = paraplegic with no lower extremity function.
After the neurologic deficit scoring at 48 h, the animals were reanesthetized with 4% halothane in oxygen. Transcardiac perfusion and fixation were performed. Coronal sections of the spinal cord (L5 level) were cut at a thickness of 8 µm and stained with hematoxylin and eosin. Neuronal injury was evaluated at a magnification of x400 by an observer unaware of the treatment groups. Ischemic neurons were identified by cytoplasmic eosinophilia with loss of Nissl substance and by the presence of pyknotic homogenous nuclei. In each slice, normal neurons in the anterior spinal cord (anterior to a line drawn through the central canal perpendicular to the vertical axis) were counted. In rabbits not subjected to ischemia in our laboratory, the number of normal neurons ranged from approximately 70 to 100 in the anterior lumbar spinal cord. We previously demonstrated that there is a good correlation between the neurologic deficit scoring system and the number of normal neurons in the anterior spinal cord (8,9).
Physiologic variables were analyzed by using repeated-measures analysis of variance. Where differences were identified, one-way analysis of variance with Scheffé's post hoc test was performed. The time required for the amplitudes of N3 to decrease to 50% of the preischemic values, hindlimb motor function, and number of normal neurons in the anterior spinal cord were analyzed by using the Kruskal-Wallis test, followed by the Mann-Whitney U-test. P < 0.05 was considered statistically significant. Parametric data are presented as mean ± SD.
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Results |
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Experiment 1
Physiologic variables for Experiment 1 are shown in Table 1. Proximal MAP values during ischemia in the L-NAME and phenylephrine groups were significantly higher than those in the control group. Distal MAP values after reperfusion in the L-NAME group were significantly higher than those in the phenylephrine group. Heart rate during ischemia was significantly lower in the L-NAME and phenylephrine groups than in the control group. There were no significant differences among the groups for esophageal and paravertebral muscle temperatures, pH, arterial oxygen partial pressure, arterial carbon dioxide partial pressure, plasma glucose, or hematocrit. All animals survived until the final neurologic scoring (48 h after reperfusion). The final neurologic status in the L-NAME and phenylephrine groups was better than that in the control group (L-NAME versus control P = 0.0105, phenylephrine versus control P = 0.0017) (Fig. 1, left). Animals in the phenylephrine group were all neurologically normal 48 h after reperfusion. There was no significant difference in the final neurologic status between the L-NAME and phenylephrine groups. The average times required for the amplitude of N3 waves in SSCEPs to decrease by 50% during ischemia are shown in Table 2. The time required for the N3 wave to decrease by 50% was significantly longer in the L-NAME and phenylephrine groups than in the control group. One animal in the control group that had a neurologic deficit score of 3 was excluded from histopathologic examination because of a technical problem during perfusion-fixation. There seemed to be more normal neurons in the anterior spinal cord in the L-NAME and phenylephrine groups than in the control group (Fig. 2, left), but the difference did not reach statistical significance (P = 0.066).
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Experiment 2
The physiologic variables in Experiment 2 are shown in Table 3. There was no significant difference in any variable. All animals survived until the final neurologic scoring. The final neurologic status in the L-NAME group was worse than that in the phenylephrine group (P = 0.015) (Fig. 1, right). The average times required for the amplitude of N3 waves in SSCEPs to decrease by 50% during ischemia are shown in Table 2. The time required for the N3 wave to decrease by 50% was significantly shorter in the L-NAME group than in the phenylephrine group. One animal in the phenylephrine group (neurologic deficit score 4) and one in the L-NAME group (neurologic deficit score 0) were excluded from histopathologic examination because of a technical problem during perfusion-fixation. Nevertheless, there were significantly fewer normal neurons in the anterior spinal cord in the L-NAME group than in the phenylephrine group (P = 0.044) (Fig. 2, right).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our principal findings are: 1) L-NAME and phenylephrine, which increase intraischemic blood pressure, improve neurologic outcome after 20 minutes of spinal cord ischemia compared with saline and 2) after 25 minutes of ischemia and possibly a greater and more stable inhibition of NOS, L-NAME worsens the neurologic and histopathologic outcome, compared with phenylephrine, with a comparable blood pressure increase.
In spinal cord ischemia, the role of NO is largely unexplored. Marsala et al. (6) have demonstrated that spinal cord gray matter layers rich in NADPH diaphorase-positive neurons (laminae I-III and X) are refractory to 40 minutes of ischemia in rabbits. Although NOS is not the only enzyme that has NADPH-diaphorase activity, they speculated that regional synthesis of NO and its vasodilatory effect during ischemia may account for the observed selective resistance of these spinal cord neurons to transient ischemia. Nemoto et al. (7) have investigated the effects of NOS inhibition by L-NMMA on the recovery of polysynaptic reflex potentials and regional blood flow measured by a laser Doppler method in transient spinal cord ischemia in cats. They produced repeated 10-minutes episodes of ischemia with an interval of 120 minutes. L-NMMA was administered before the second ischemic episode. The recovery of polysynaptic reflex potentials after the second ischemic episode was accelerated compared with that after the first ischemic episode (its own control) in the L-NMMA group. Nemoto et al.'s (7) study may be inconsistent with Marsala et al.'s (6) study. However, in Nemoto et al.'s (7) study, polysynaptic reflex potentials disappeared during the first ischemic episode but partially remained during the second ischemic episode in the L-NMMA group. It is likely that ischemic insult was attenuated with L-NMMA administration. There is a report showing that NOS inhibition decreases spinal cord blood flow (12). However, in Nemoto et al.'s (7) study, L-NMMA did not decrease spinal cord blood flow before ischemia, with a MAP increase from 81 ± 3 to 118 ± 10 mm Hg. Although they did not report intraischemic blood pressure, regional blood flow during ischemia might have increased through collaterals. Indeed, regional blood flow in the spinal cord was 20% ± 4% (mean ± SE) of the control value during the first ischemic episode and 29% ± 7% during the second ischemic episode, although the difference was not statistically significant (7).
In the present study, neurologic outcome in both the L-NAME and phenylephrine groups was significantly better with higher proximal MAP during ischemia than in the control group in Experiment 1. The time required for the N3 wave in the SSCEPs to decrease by 50% was significantly longer in the L-NAME and phenylephrine groups than in the control group. These results are compatible with those in Nemoto et al.'s study (7). The occlusion of the aorta just distal to the origin of the left renal artery decreases blood flow to 5%–10% of control in the lower lumbar segments (13). In the rabbit, spinal cord blood flow in the caudal portion is segmentally supplied from the abdominal aorta with poor collaterals between segments. However, the results in the phenylephrine group suggest that the increase of proximal blood pressure during ischemia may have maintained better residual blood flow in the ischemic region and improved the neurologic outcome. The dosing pattern of L-NAME in Experiment 1 may have had the same effect.
The animals in the L-NAME and phenylephrine groups in Experiment 1 (20-minute ischemia) had comparable and better outcomes than those in the control group. It was difficult to determine whether the better neurologic outcome in the L-NAME group was attributable to an increase in the intraischemic blood pressure or to decreased neurotoxic effects of NO. Because all animals in the phenylephrine group in Experiment 1 were neurologically normal after 20-minute ischemia, we thought that no difference could be detected in the outcome even if L-NAME provided neuroprotective effects. Therefore, expecting that some animals in the phenylephrine group would show neurologic deficits, we increased the ischemic duration in Experiment 2 to determine more clearly whether L-NAME is neuroprotective (or neurotoxic) to the ischemic spinal cord. To achieve a greater and more stable inhibition of NOS, we also started the administration of L-NAME 100 minutes before the onset of ischemia in Experiment 2, because a report published after the completion of Experiment 1 suggested that >30 minutes was required to reach a stable level of NOS inhibition by L-NAME (14). The neurologic and histopathologic outcome in the L-NAME group was significantly worse than that in the phenylephrine group. The time required for the N3 wave amplitude in SSCEPs in the L-NAME group to decrease by 50% was also significantly shorter than that in the phenylephrine group. The results from SSCEPs suggest that functional disturbances occurred earlier in the L-NAME group than in the phenylephrine group. There is good evidence that NO may play a key role in maintaining blood flow in the spinal cord (15,16). Chronic ingestion of L-NAME in the hypertensive rat results in central nervous system damage, with the incidence of lesions being significantly higher in the spinal cord than in the brain (15). The injection of L-NAME into the normal spinal cord has also been shown to result in neuronal damage, this damaging effect being blocked by L-arginine and inversely related to spinal levels of NOS activity (16). In this context, the dosing pattern of L-NAME in Experiment 2 might have resulted in a greater inhibition of NOS, leading to a greater vasoconstriction of the spinal cord. The greater vasoconstriction caused by L-NAME may have outweighed the increase in residual blood flow during ischemia through collaterals by a blood pressure increase.
We did not measure NOS activity in this study. Based on an article by Traystman et al. (14), the dosing pattern of L-NAME in Experiment 1 may have mainly inhibited endothelial NOS, whereas neuronal NOS may also have been inhibited, although not completely, in Experiment 2. Therefore, the worsened outcome in the L-NAME group in Experiment 2 could be alternatively explained by a decreased direct neuroprotective role of NO. Further studies are required to evaluate this issue.
In summary, in spinal cord ischemia produced by occlusion of the abdominal aorta, an increase in the proximal blood pressure by phenylephrine significantly attenuated ischemic insult. Although L-NAME attenuated the spinal cord injury produced by 20 minutes of ischemia compared with saline, this effect may be due to the increase in blood pressure produced by L-NAME. With 25 minutes of ischemia and, possibly, a greater and more stable inhibition of NOS, L-NAME was associated with an exacerbation of neurologic injury compared with a blood pressure-matched phenylephrine group. These data suggest that nonselective inhibition of NOS activity has aggravating effects on the neurologic and histopathologic outcome after transient spinal cord ischemia.
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Acknowledgments |
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This work was supported in part by the Ministry of Education, Science, Sports, and Culture Grant 05454423 (to TS).
We thank Dr. Mark H. Zornow for his advice in preparing this manuscript.
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Footnotes |
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Presented in part at the 17th International Symposium on Cerebral Blood Flow and Metabolism, Cologne, Germany, July 2–6, 1995.
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References |
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- Lipton SA, Choi Y-B, Pan Z-H, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626–32.[Medline]
- Marsala J, Kluchova D, Marsala M. Spinal cord gray matter layers rich in NADPH diaphorase-positive neurons are refractory to ischemia-reperfusion-induced injury a histochemical and silver impregnation study in rabbit. Exp Neurol 1997;145:165–79.[Web of Science][Medline]
- Nemoto T, Sekikawa T, Suzuki T, et al. Inhibition of nitric oxide synthesis accelerates the recovery of polysynaptic reflex potentials after transient spinal cord ischemia in cats. Schmiedebergs Arch Pharmacol 1997;355:447–51.
- Matsumoto M, Iida Y, Sakabe T, et al. Mild and moderate hypothermia provide better protection than a burst-suppression dose of thiopental against ischemic spinal cord injury in rabbits. Anesthesiology 1997;86:1120–7.[Web of Science][Medline]
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Wakamatsu H, Matsumoto M, Nakakimura K, et al. The effects of moderate hypothermia and intrathecal tetracaine on glutamate concentrations of intrathecal dialysate and neurologic and histopathologic outcome in transient spinal cord ischemia in rabbits. Anesth Analg 1999;88:56–62.
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