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(Stroke. 1996;27:747-752.)
© 1996 American Heart Association, Inc.

Articles

Ketamine Antagonizes Nitric Oxide Release From Cerebral Cortex After Middle Cerebral Artery Ligation in Rats

Shinn-Zong Lin, MD, PhD; Ai-Lin Chiou, BS Yun Wang, MD, PhD

From the Departments of Neurosurgery (S.-Z.L.) and Pharmacology (A.-L.C., Y.W.), National Defense Medical Center, Taipei, Taiwan, Republic of China.

Correspondence to Yun Wang, MD, PhD, Department of Pharmacology, National Defense Medical Center, 18 Se-Yuan Rd, PO Box 90048-504, Taipei, Taiwan, 100 ROC. E-mail yun@ndmc1.ndmctsgh.edu.tw.

	Abstract

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Background and Purpose Ischemia or hypoxia activates N-methyl-D-aspartate (NMDA) receptors and results in nitric oxide (NO) production. The purpose of this study was to investigate whether an NMDA channel blocker can inhibit NO production during ischemia.

Methods Temporary cerebral ischemia was induced by middle cerebral artery ligation while common carotid arteries were clamped bilaterally for 40 minutes in urethane-anesthetized rats. Extracellular NO concentration in the cortex was recorded through Nafion- and porphyrine-coated carbon fiber electrodes. Ketamine, an NMDA channel blocker, was administered (50 mg/kg) intraperitoneally 15 minutes before the cerebral artery ligation.

Results During middle cerebral artery ligation, cortical NO was increased to its peak (18.76±3.36 nmol/L) in 7 minutes and then declined. The overflow of NO can be antagonized by pretreatment with ketamine, dizocilpine maleate (MK801), or N^G-nitro-L-arginine methyl ester (L-NAME). Local application of nitroprusside also induced NO production. However, this effect was not antagonized by ketamine.

Conclusions These findings demonstrated that NO release induced by short-term cerebral ischemia can be attenuated by pretreatment with NMDA antagonists.

Key Words: cerebral ischemia • ketamine • nitric oxide • N-methyl-D-aspartate • rats

	Introduction

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Nitric oxide has been found to be involved in ischemic brain injury.¹ NO is released during ischemia and reperfusion.^{2 3 4 5} Inhibition of NO synthesis reduces hypoxia- or ischemia-mediated tissue damage.^{6 7} Previous studies indicate that NMDA receptors are activated during ischemia or hypoxia.^{8 9} NO is thought to be a potent mediator of glutamatergic neurotoxicity during brain ischemia.¹⁰ We previously reported that ketamine, a commonly used anesthetic that inhibits the NMDA-activated cation channel, antagonized hypoxia-induced dopamine overflow in striatum.¹¹ There is still no direct evidence showing that elevation of NO during ischemic insults involves NMDA receptors or that such effect can be antagonized by an NMDA blocker such as ketamine.

In this study, we directly measured extracellular NO concentration with Nafion- and porphyrin-treated carbon fiber electrodes and in vivo chronoamperometric techniques. Our data suggested that ketamine can prevent the increase of NO release during MCA ligation.

	Materials and Methods

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Electrochemical Measurement of NO
Seventeen adult Sprague-Dawley rats were used for electrochemical detection of NO. Animals were anesthetized with urethane (1.25 g/kg IP), intubated, and placed in a stereotaxic frame. Body temperature was maintained at 37°C with an isothermal pad. The use of animals was in accordance with the National Institutes of Health guidelines.

The ligation of the right MCA and bilateral CCAs was performed using methods suggested by Chen et al.¹² The bilateral CCAs were identified and isolated through a ventral midline cervical incision. The CCAs were ligated with nontraumatic arterial clips. A craniotomy of about 2x2 mm² was made in the right squamosal bone. The right MCA was ligated with a 10-0 suture. The craniotomy was covered with gel foam.

In vivo chronoamperometric measurements of extracellular NO concentration were performed with a microcomputer-controlled apparatus (IVEC-10, Medical Systems Corp). The recordings were taken at the cerebral cortex (2.2 mm posterior to the bregma, 5.0 to 5.5 mm lateral to the midline, 0.9 mm below the cortical surface). Remote from this site, miniature Ag/AgCl reference electrodes were inserted into the left parietal cortex and cemented in place with dental acrylic. The working electrodes, which did not sense membrane potentials or respond to sodium or potassium fluxes,¹³ were made of two carbon fiber filaments (30 µm in diameter, Textron Co). The sensor was first coated with Nafion (5% solution, Aldrich Chemical Co) at 65°C to decrease the interference of ascorbic acid.¹⁴ The electrodes were then coated with 2 mmol/L TMPP-Ni in 0.1 mol/L NaOH, at 0.9 V for 15 minutes.¹⁵ The diameter of carbon fiber after coating was 30 µm. These electrodes were each tested for sensitivity and selectivity to NO in vitro. Calibration of NO (5 to 15 nmol/L) was made using 5 to 15 µmol/L SNAP in 0.1 mmol/L phosphated buffer, pH 7.4.¹⁶ Only electrodes showing selectivity of NO compared with ascorbic acid greater than 100 000:1 in vitro were used in the in vivo preparation. The NO current generated by application of oxidation potential of +0.9 V, relative to an Ag/AgCl reference electrode, was recorded in vivo continuously at a rate of 1 Hz. All in vivo signals were expressed as NO changes in nanomoles per liter using the in vitro calibration factors (Fig 1C).

View larger version (17K): [in this window] [in a new window]   Figure 1. Local application of NMDA induces NO production in the cerebral cortex. A, Administration of ascorbic acid (200 µmol/Lx150 nL) to the cortex does not induce an increase in oxidation current. B, However, application of NMDA (10 mmol/Lx25 nL) enhances NO production. C, The electrochemical sensor is calibrated in vitro using SNAP (5 to 15 µmol/L, pH 7.4) before the in vivo experiment; 1 µmol/L of SNAP is equivalent to 1 nmol/L NO. The y axis represents the function of oxidation current (µA)xtime (ms). The electrode is insensitive to ascorbic acid (250 µmol/L); however, the electrode shows a linear correlation between oxidation current and the changes in [NO] (r=.992).

The production and selectivity of NO were measured after microejection of nitroprusside, SNAP, or ascorbic acid into the cortical parenchyma. Nitroprusside (3 mmol/L, 75 to 150 nL), SNAP (10 µmol/L, 200 nL), or ascorbic acid (200 µmol/L, 50 to 200 nL) was locally applied through a micropipette. L-NAME was given intraventricularly (1 µg/µL, 10 µL per rat) 30 minutes before the vessel ligation, followed by local application of L-NAME (1 µg/µL, 192±8 nL). The working electrode and the micropipette were mounted together with sticky wax (Kerr Inc); tips were separated by 100 to 150 µm. Local application of nitroprusside from the micropipettes was performed by pressure ejection using a pneumatic pump (PPM-2, Medical Systems Corp). The ejected volume was monitored by recording the change in the fluid meniscus in the pipette before and after ejection with a dissection microscope.¹⁷

Histological Study
Six rats were used to study the topographical injury after vascular occlusion. The right MCA and CCAs were temporally ligated for 60 minutes to ensure the area of injury. Twenty-four hours after the ligation, these rats were killed and perfused intracardially with 0.9% saline. The brains were removed and immersed in cold saline for 5 minutes and sliced into 2-mm sections. The brain slices were incubated in a 2% TTC¹² saline at 37°C for 30 minutes and were then fixed in Histochoice medium (Amresco Inc) for 30 minutes. The volume of infarction was measured and summed by computerized planimetry (In Situ, LSR Ltd).

Chemicals
All drugs were dissolved in 0.9% saline. Ketamine hydrochloride (Ketalar; Parke-Davis Co) was given at a dose of 50 mg/kg IP. MK801 was administered at a dose of 2.5 mg/kg IP. TMPP-Ni was purchased from Porphyrin Products Inc. NMDA, MK801, SNAP, and L-NAME were purchased from RBI. TTC was purchased from Sigma Chemical Co.

	Results

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Previous experiments have shown that NO and ascorbic acid can be released during hypoxia and ischemia.^{18 19} To eliminate the interference of ascorbic acid, these NO sensors were coated with 5% Nafion. Only electrodes having high selectivity to NO in vitro were chosen for in vivo study. The selectivity of electrodes was also tested in vivo. We found that NO signals (2.67±0.75 nmol/L) can be detected during local application of SNAP (10 µmol/L, 200 nL, n=3) to the nonischemic cortex. However, application of 200 µmol/L ascorbic acid (135±25 nL) did not produce detectable oxidization current (n=5), suggesting that these sensors were selective to NO (Fig 1A). Previous studies indicated that NMDA can induce NO production. We found that these electrochemical sensors were able to detect NO production (15.8±3.3 nmol/L) induced by local application of a small volume of NMDA (10 mmol/L, 33±5 nL, n=6) to cortex (Fig 1B).

In 6 rats studied, we found that the extracellular NO concentration was increased by MCA ligation (Fig 2). During the ligation period, the basal NO level was gradually increased to an average±SEM of 18.76±3.36 nmol/L. The rise time, the period between the completion of vessel ligation and the peak of NO production, was 323.4±86.9 seconds. The half-life for NO decay was 980.0±90.4 seconds.

View larger version (28K): [in this window] [in a new window]   Figure 2. NO production induced by MCA ligation. A through D represent release of NO in four different animals. Occlusion of the MCA (arrows) induces NO production in cerebral cortex.

We previously reported that ketamine at a dose of 50 mg/kg antagonized hypoxia-induced dopamine release in the striatum without affecting blood pH, PO₂, or PCO₂.¹¹ In the present study, we pretreated 5 rats with ketamine (50 mg/kg IP) 15 minutes before the vessel ligation. The production of NO in the cortex after MCA ligation was antagonized by ketamine (Fig 3, A1 and A2). The average increase in NO concentration induced by ligation of the MCA was significantly diminished by the pretreatment with ketamine (1.44±0.84 nmol/L, n=5; P<.05, one-way ANOVA and Newman-Keuls test). In 3 rats, we also examined the interaction of ischemia-induced NO release with MK801, an NMDA channel blocker. We found that systemically administered MK801 (2.5 mg/kg IP) significantly antagonized NO production (1.57±1.21 nmol/L; P<.05, one-way ANOVA followed by Newman-Keuls post hoc test) during ischemic insults (Fig 3, B1 and B2, and Fig 5).

View larger version (16K): [in this window] [in a new window]   Figure 3. Systemic administration of ketamine or MK801 antagonizes NO production induced by MCA ligation. A1 and A2, NO release induced by ligation of the MCA (arrows) is greatly attenuated by the pretreatment with ketamine (50 mg/kg IP) in two animals. B1 and B2, Similarly, systemic application of MK801 (2.5 mg/kg IP) prevents the ischemia-induced NO production in the other two animals.

View larger version (20K): [in this window] [in a new window]   Figure 5. Ketamine, MK801, and L-NAME antagonize ischemia-induced NO release in cerebral cortex. The peak of NO overflow (mean±SEM) induced by MCA ligation is significantly attenuated by pretreatment with ketamine, MK801, or L-NAME compared with that in the control animals (*P<.05, one-way ANOVA followed by Newman-Keuls post hoc test).

We also found that the production of NO release during cerebral arterial ligation can be antagonized by pretreatment with L-NAME (Figs 4 and 5). Our preliminary study indicated that intraventricular application of L-NAME (1 µg/µL, 10 µL per rat) 30 minutes before vessel ligation, followed by local application of L-NAME (1 µg/µL, 192±8 nL), significantly attenuated NO production (5.71±2.44 nmol/L, n=3; P<.05, one-way ANOVA and Newman-Keuls test; Fig 5).

View larger version (21K): [in this window] [in a new window]   Figure 4. L-NAME attenuates NO production induced by MCA ligation. A1, Local application of ascorbic acid (200 µmol/Lx200 nL) to the cortex does not induce NO-like electrochemical current. A2, Pretreatment with L-NAME attenuates NO release evoked by the MCA ligation in the same animal. B and C represent the NO production induced by MCA ligation in the other two animals pretreated with L-NAME.

We found that NO can be generated (8.97±2.16 nmol/L) after local microejection of nitroprusside (3 mmol/L, 91±16 nL, n=11). The rise and decay times of NO induced by nitroprusside administration were less than 20 seconds. This nitroprusside-synthesized NO was not affected by ketamine, suggesting that the attenuation of NO production after ketamine was not attributable to the decreasing sensitivity of NO sensors.

We found that MCA ligation resulted in cortical infarction in 6 animals studied (Fig 6). The area of infarction was limited to the cortical area that corresponded to the placement of electrochemical sensors. The infarction volume was 77.7±8.2 mm³.

View larger version (101K): [in this window] [in a new window]   Figure 6. Cerebral cortical infarction after cerebral vascular ligation. The TTC staining method was used to delineate the infarction area in the cortex (white region). The area of infarction is limited to the cerebral cortex.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In the present study, we directly measured the extracellular NO concentration once per second, which afforded us a high degree of temporal resolution. Furthermore, because these sensors are made of two 30-µm carbon fibers, which are much smaller than those (200 µm) described in other studies,^{20 21} these electrodes are less traumatic to the brain tissue and have higher spatial resolution.²² These features enabled us to directly place the electrode in a small ischemic area in the cortex and measure NO concentration in real time.

A previous study suggested that quantities of NO in micromoles per liter may be released by MCA ligation.⁵ We found that ligation of the MCA can only induce NO release in the 20-nmol/L range, which is slightly higher than that seen in the global cerebral ischemia induced by hemorrhagic hypotension in cats.²¹ This difference may arise from several factors. (1) The tips of electrodes we used were relatively small and may be less traumatic to the cortex, resulting in less injury-induced NO release. (2) Using TTC staining techniques, we found that the ischemic area induced by direct vessel ligation in this study was limited to the cortex only. On the other hand, a much greater brain region, including cortex and basal ganglion, may be involved with use of intraluminal vascular occlusion.²³ (3) The tip of our electrochemical sensor was placed in the cortical area, ie, 0.9 mm below the cortical surface. The sensors used by Malinski and Taha¹⁵ were inserted 3 mm below the surface, which corresponds to basal ganglia. (4) Our electrodes have a very high selectivity to NO compared with ascorbic acid both in vitro and in vivo. It has been suggested that ascorbic acid may be released during hypoxia or ischemia.^{18 19} It is possible that the high surge of NO during ischemia in the previous study may have been contaminated with ascorbic acid.

Previous study indicated that NMDA receptors can be activated during ischemic or hypoxic insults. We reported that ketamine or MK801, an NMDA channel blocker, antagonized hypoxia-induced dopamine release in the striatum.¹¹ In the present study, we found that pretreatment with ketamine or MK801 antagonized ischemia-elicited NO production. In a preliminary study, we found that ketamine antagonized NMDA-mediated release of NO in the cortex (data not shown). Taken together, these data suggest that NO release induced by MCA occlusion may involve activation of NMDA receptors.

We found that NO release induced by MCA occlusion can be greatly suppressed by pretreatment with L-NAME, suggesting that the production of NO is mainly mediated through the activation of NO synthesis. On the other hand, the pretreatment with L-NAME did not abolish the NO production. The lack of complete abolition of NO production may be attributed to the limited distribution of L-NAME. Recent reports indicated that the carbon-14 radioactivity was not widely spread after intraventricular administration of [¹⁴C]L-nitroarginine, even in the hemisphere ipsilateral to the injection.²⁴

The physiological roles of NO production during occlusion of cerebral vessels are still not clear. The production of NO may be protective by virtue of its ability to induce cerebral vasodilation.²⁵ Inhibition of NO synthesis with N-nitro-L-arginine, a nonselective inhibitor of NO synthesis, increases the volume of focal ischemic infarction.²⁶ On the other hand, overproduction of NO may result in a greater infarction area. Animals treated with 7-nitroindazole, a selective inhibitor of neuronal NO synthase, showed a significant reduction of focal infarction after MCA occlusion.²⁷ A recent study indicated that the infarct volumes of mice deficient in neuronal NO synthase activity were significantly decreased compared with those in normal mice after MCA occlusion. However, after inhibition of endothelial NO synthesis, the other major NO synthesis type, the infarct size in the mutants became larger.²⁸ Taken together, these data indicate that neuronal NO production may exacerbate acute ischemic injury, whereas vascular NO protects after MCA occlusion. It has been reported that NO generated in response to activation of NMDA receptor in vivo is neuronally derived and not due to a direct vascular effect.²⁹ Inhibition of synthesis of the R1 subunit of the NMDA receptor by treatment with antisense oligodeoxynucleotides prevents the neurotoxicity elicited by NMDA and reduces the volume of focal ischemic infarction production by occlusion of the MCA.³⁰ Taken together, these data suggest that blocking NMDA receptors may limit injury during or after ischemic insults, possibly via inhibition of neuronal NO production.

In conclusion, our data suggest that short-term ischemia may activate NO release. We found that ketamine, an NMDA channel blocker, prevents NO release induced by acute ischemia in the cerebral cortex. It is possible that ketamine may be useful in the acute stage of ischemic attack or at least should be considered as an anesthetic agent for surgical patients with ischemic brain diseases.

	Selected Abbreviations and Acronyms

 

CCA = common carotid artery L-NAME = NG-nitro-L-arginine methyl ester MCA = middle cerebral artery MK801 = dizocilpine maleate TMPP-Ni = Ni meso-tetra(N-methyl-4-pyridyl)porphine tetra tosylate NMDA = N-methyl-D-aspartate NO = nitric oxide SNAP = S-nitroso-n-acetyl-dl-penicillamine TTC = triphenyltetrazolium chloride

	Acknowledgments

 
This work was supported by grants (NSC 85-2331-B016-075 and NSC 84-2331-B016-009) from the National Science Council, Republic of China.

Received August 14, 1995; revision received January 3, 1996; accepted January 11, 1996.

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