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Anesth Analg 2002;94:954-958
© 2002 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

L-Arginine and Nitroglycerin Restore Hypercapnia-Induced Cerebral Vasodilation in Rabbits After its Attenuation by Ketamine

Kiyoshi Nagase, MD, Hiroki Iida, MD, and Shuji Dohi, MD

Department of Anesthesiology & Critical Care Medicine, Gifu University School of Medicine, Gifu City, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology & Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Although it has been reported that ketamine attenuates hypercapnia-induced cerebral vasodilation, the mechanism remains unknown. Because nitric oxide is involved in cerebral CO2 reactivity, we studied the effects of L-arginine and nitroglycerin on ketamine-mediated attenuation of vascular responses to hypercapnia. Under pentobarbital anesthesia, 16 rabbits underwent closed cranial window preparation. Hypercapnic challenges were repeated after IV saline, ketamine (10 mg/kg, followed by 20 mg · kg-1 · h-1), or ketamine plus either L-arginine (150 mg/kg, followed by 100 mg · kg-1 · h-1; n = 8) or nitroglycerin (5 µg · kg-1 · min-1 infusion; n = 8). Ketamine reduced hypercapnia-induced cerebral vasodilation (1.27%/mm Hg ± 0.45%/mm Hg [saline] versus 0.82%/mm Hg ± 0.53%/mm Hg [ketamine]: P < 0.05), but L-arginine restored reactivity (1.28%/mm Hg ± 0.73%/mm Hg: P < 0.05 versus ketamine), as did nitroglycerin (1.14%/mm Hg ± 0.73%/mm Hg [saline] versus 0.56%/mm Hg ± 0.63%/mm Hg [ketamine]: P < 0.05, and 1.15%/mm Hg ± 0.74%/mm Hg [ketamine plus nitroglycerin]: P < 0.05 versus ketamine). This indicates that ketamine attenuates cerebral CO2 reactivity, at least in part, via suppression of nitric oxide-cyclic guanosine monophosphate mechanisms in the cerebral vasculature.

IMPLICATIONS: The attenuation of cerebral vasodilation to hypercapnia seen under ketamine anesthesia is reversed by L-arginine or nitroglycerin infusion.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Because ketamine, a noncompetitive N-methyl-D-aspartate antagonist (1), has been reported to prevent cerebral deterioration after hypoxia/ ischemia (2), there is increased interest in its use in patients undergoing neurosurgical procedures. However, the effect of ketamine on the cerebral circulation remains a matter of debate. For example, there is evidence suggesting that ketamine does not increase cerebral blood flow but rather maintains it more or less constant, especially in anesthetized patients with controlled ventilation (3,4).

Understanding the effect of ketamine on hypercapnia-induced cerebral vasodilation is of particular interest because management of the PaCO2 is an important way of controlling cerebral blood flow and intracranial pressure in patients with a low intracranial elastance (5). We recently reported that ketamine attenuates hypercapnia-induced cerebral vasodilation in dogs anesthetized with either isoflurane or pentobarbital (4), although the underlying mechanism remains unclear.

Nitric oxide (NO), which in the brain is mainly produced by neuronal NO synthase (NOS), plays an important role in hypercapnia-induced cerebral vasodilation (6–9). Thus, we used L-arginine, a substrate for NO, and nitroglycerin, a NO donor, to determine whether increased NO availability would restore cerebral CO2 reactivity after its attenuation by ketamine. We used an in vivo preparation involving a closed cranial window in adult rabbits to evaluate the response of cerebral pial arterioles to hypercapnia.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experimental protocols were approved by our Institutional Committee for Animal Care. Experiments were performed on 24 rabbits weighing 2.0 to 2.5 kg using techniques described in detail elsewhere (4,10). Briefly, anesthesia was induced with pentobarbital sodium (30 mg/kg IV) and maintained with a continuous infusion at a rate of 4 mg · kg-1 · h-1 for the entire experiment. After tracheostomy, the lungs were mechanically ventilated with oxygen-enriched air (40%–50% oxygen). The tidal volume and respiratory rate were adjusted to maintain the PaCO2 at 35–40 mm Hg. Polyvinyl chloride catheters were placed in the left femoral vein and artery for the administration of drugs and fluid (20 mL/h), as well as for arterial blood pressure measurements and blood sampling. Rectal temperature was maintained at 38°C–39°C with the aid of a warm water-circulated blanket.

We used a closed cranial window to observe the pial microcirculation. Each anesthetized rabbit was placed in the sphinx position, the scalp retracted, the temporal muscle removed, and a hole 1 cm in diameter was made in the parietal bone. The dura and arachnoid membrane were cut. A ring fitted with a cover glass was secured over the hole with the aid of dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF) that was made up of: Na+ 156.5 mEq/L, K+ 2.95 mEq/L, Ca2+ 0.501 mEq/L, Cl- 138.7 mEq/L, Mg2+ 1.33 mEq/L, HCO3- 24.6 mEq/L, urea 40.2 mg/dL, and glucose 66.5 mg/dL. Its pH value was adjusted to 7.48, and it was bubbled with 5% CO2 in air at 38.5°C. The volume of fluid below the window was 0.2–0.3 mL. Two polyvinyl chloride catheters were inserted through the ring; one was attached to a reservoir bottle containing aCSF, which allowed adjustment of intrawindow pressure, and the other was used for drainage of aCSF. The temperature in the cranial window was monitored through a probe (Model 6510; Mallinckrodt Medical, St Louis, MO) placed inside the window and was maintained at 38°C–39°C.

Experiment 1
All experiments were performed in vivo using the following protocols: sixteen rabbits were allowed to recover from surgical procedures for at least 30 min. We then measured the pial arteriolar vasodilation elicited by hypercapnia after IV injection of saline 0.5 mL (control cerebral vasoreactivity). Next, we gave ketamine (Ketalar, Sankyo Pharmacy, Tokyo, Japan) IV (10 mg/kg bolus over 2 min, followed by a continuous infusion at 20 mg · kg-1 · h-1 until the end of the study period) and again measured the cerebral vasodilation elicited by CO2 30 min after the start of the ketamine infusion. Rabbits were randomly assigned to receive either L-arginine (Sigma Chemical Co, St Louis, MO) or nitroglycerin (Millisrol, Nihon Kayaku Pharmacy, Tokyo, Japan) (n = 8, each). In the L-arginine group, each rabbit received L-arginine (150 mg/kg bolus over 60 s, followed by a continuous infusion at 100 mg · kg-1 · h-1 IV), whereas the other group received nitroglycerin (5 µg · kg-1 · min-1 IV). In each animal, cerebral CO2 reactivity was reevaluated 30 min after the beginning of infusion. Each hypercapnic period (PaCO2 50–60 mm Hg) lasted 10 min and was achieved by adding CO2 to the inspired gas without changing mechanical ventilation variables. Pial arteriolar diameter, mean arterial blood pressure, heart rate, arterial blood gas tension, and arterial pH were measured before and after each intervention. At least 10 min was allowed after each intervention for the cerebral arterioles to return to baseline values before beginning the next intervention.

Experiment 2
In this experiment, we studied the effects of repeated exposure to CO2 on the cerebral circulation (as a time control) and the effects of L-arginine and nitroglycerin on cerebral CO2 reactivity. Animals were anesthetized with pentobarbital (as in Experiment 1) but did not receive ketamine. After instrumentation, four pentobarbital-anesthetized rabbits inhaled CO2 three times in the same manner as in Experiment 1 (an interval between inhalations of 10 min). Later, the effects of L-arginine and nitroglycerin on cerebral CO2 reactivity were evaluated.

In the other four rabbits, superfused aCSF was collected immediately after a 10-min CO2 exposure to measure nitrite (NO2-) and nitrate (NO3-) (stable oxidation products of NO) concentrations. This was done under saline, ketamine, and ketamine plus L-arginine in sequence (an interval between interventions of 15 min). We obtained 0.3 mL of aCSF during superinfusion at a rate of 6 mL/h, and drugs were given at the same doses and in the same manner as in Experiment 1. NO2- and NO3- were measured using high performance liquid chromatography.

In each experiment, the inner diameters of three arterioles (30–70 µm) were measured in each rabbit using a videomicrometer (Model VM-20; Flovel, Tokyo, Japan) attached to a microscope (Model OMK-1; Olympus, Tokyo, Japan) by an investigator blinded to the nature of the intervention. The data from each pial view were stored on videotape for later playback. The percentage changes in diameter recorded for individual arteriolar segments were averaged in each rabbit and used in the statistical analysis.

Values are given as mean ± SD. The CO2 reactivity of cerebral vessels was calculated by dividing the percentage change in pial arteriolar diameter (between the normocapnic and hypercapnic conditions) by the alteration in PaCO2 (units, percentage/mm Hg). We conducted a one-way factorial analysis of variance for repeated measures, followed by a Bonferroni/Dunn post hoc test to compare the CO2 reactivity of cerebral vessels within the L-Arginine and Nitroglycerin groups (Experiment 1), to compare the CO2 reactivity values obtained at different times (Experiment 2), and to compare NO2- and NO3- levels (Experiment 2). A P value <0.05 was regarded as statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Hemodynamic and physiologic values for the L-Arginine and Nitroglycerin groups are given in Tables 1 and 2, respectively. In each group, values for heart rate, mean arterial blood pressure, PaO2, and base excess were not different between normocapnia and hypercapnia, but the diameter of the pial arterioles and the arterial pH changed significantly with each hypercapnic challenge during each intervention.


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  		Table 1.  Hemodynamic and Physiologic Measurements in l-Arginine Group
 

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  		Table 2.  Hemodynamic and Physiologic Measurements in Nitroglycerin Group
 
In the L-Arginine group, ketamine did not change the diameter of pial arterioles (50.7 ± 9.9 µm before versus 50.5 ± 11.8 µm after ketamine). The cerebral vasodilation elicited by hypercapnia was smaller after ketamine than after saline (1.27%/mm Hg ± 0.45%/mm Hg [saline] versus 0.82%/mm Hg ± 0.53%/mm Hg [ketamine]: P < 0.05). Although L-arginine infusion did not change the resting diameter of pial arterioles (50.9 ± 14.3 µm before versus 50.4 ± 14.1 µm after L-arginine), it did restore cerebral CO2 reactivity to the level seen before ketamine (1.28%/mm Hg ± 0.73%/mm Hg; P < 0.05 versus after ketamine alone) (Figure 1).



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  		Figure 1. Carbon dioxide reactivity (percentage change in diameter per unit alteration in PaCO2) after IV saline, ketamine, and ketamine plus L-arginine. Values are mean ± SD, n = 8. *P < 0.05.

 
In the Nitroglycerin group, qualitatively similar results were obtained. Cerebral arteriolar diameter was 42.7 ± 13.6 µm before versus 47.6 ± 14.5 µm after ketamine (not significant). Again, ketamine attenuated hypercapnia-induced cerebral vasodilation (1.14%/mm Hg ± 0.73%/mm Hg [saline] versus 0.56%/mm Hg ± 0.63%/mm Hg [ketamine]: P < 0.05). Continuous infusion of nitroglycerin did not dilate cerebral pial arterioles (46.2 ± 16.3 µm versus 50.4 ± 15.3 µm) but restored the response to hypercapnia to the level seen after the saline administration (1.15%/mm Hg ± 0.74%/mm Hg; P < 0.05 versus after ketamine alone) (Figure 2).



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  		Figure 2. Carbon dioxide reactivity (percentage change in diameter per unit alteration in PaCO2) after IV saline, ketamine, and ketamine plus nitroglycerin. Values are mean ± SD, n = 8. *P < 0.05.

 
In Experiment 2, repeated episodes of hypercapnia as a time control for the effect of pentobarbital anesthesia (three times in each of four rabbits) revealed a consistent degree of cerebral CO2 reactivity (1.2%/mm Hg ± 0.5%/mm Hg, 1.3%/mm Hg ± 0.6%/mm Hg, and 1.4%/mm Hg ± 0.7%/mm Hg), and neither L-arginine nor nitroglycerin altered cerebral CO2 reactivity (1.5%/mm Hg ± 0.9%/mm Hg and 1.5%/mm Hg ± 0.8%/mm Hg, respectively). The baseline diameter of the pial arterioles studied in this experiment was 39.5 ± 18.1 µm.

In the other four rabbits, the NO2- content of the superfused aCSF obtained immediately after a 10-min episode of hypercapnia was less than the limit of detection in every sample. The NO3- content of the aCSF collected from the intracranial window after such hypercapnic episodes was similar among saline, ketamine, and ketamine plus L-arginine interventions (8.8 ± 3.2 µmol/L, 11.8 ± 5.9 µmol/L, and 8.8 ± 3.4 µmol/L, respectively).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study demonstrates that ketamine attenuates hypercapnia-induced cerebrovascular dilation under pentobarbital anesthesia in rabbits, and L-arginine and nitroglycerin restore it to the level seen before ketamine.

Neuronal NOS plays a major role in hypercapnia-induced cerebral vasodilation (5,7), whereas ketamine has been reported to reduce NO production. Galley et al. (11,12) reported that ketamine decreases brain NOS activity as well as NOS activity in human polymorphonuclear leukocytes in vitro. Ketamine is also reported to decrease the NO content in the rat cerebral cortex (13). Thus, we hypothesized that ketamine attenuated NO formation that occurs in response to hypercapnia because its attenuation of cerebral CO2 reactivity was reversed by coinfusion of L-arginine or nitroglycerin in the current study. However, some recent studies have questioned an inhibitory effect of ketamine on NO production (14,15). Lewis et al. (16) suggested that the discrepancy regarding the effect of ketamine on NO production is attributable to the differing doses of ketamine used. Indeed, the plasma ketamine concentration in in vitro studies, where an inhibitory effect of this agent on NO formation has been reported, was larger than plasma ketamine concentrations encountered in clinical anesthesia. The dose of ketamine used in the current study was chosen on the basis of previous studies. Pedraz et al. (17) reported that the plasma concentration of ketamine 30–90 min after a 10 mg/kg bolus IV administration in rabbits was 0.5–1.0 µg/mL, whereas Bjorkman et al. (18) reported that during continuous infusion of ketamine at 10 mg · kg-1 · h-1 in rabbits, the plasma concentration reached 0.3–0.8 µg/mL. Although we did not measure the plasma concentration of ketamine in the current study, our use of a 10 mg/kg bolus with an infusion of 20 mg · kg-1 · h-1 afterward would presumably have led to a plasma concentration in the region of 0.5–1.6 µg/mL, comparable to the concentrations encountered in clinical settings.

Ketamine has also been reported to inhibit N-methyl-D-aspartate-mediated cyclic guanosine monophosphate production (19), which mediates or modulates hypercapnia-induced cerebral vasodilation, suggesting its possible involvement in the effect of ketamine on cerebral CO2 reactivity. We reported that IV ketamine 1 or 5 mg/kg attenuates cerebral CO2 reactivity in dogs (4). In the current study, we measured the NO2- and NO3- content of superfused aCSF after CO2 inhalation during each of three interventions (under saline, ketamine, and ketamine plus L-arginine). Because we did not find any difference in the CO2-induced level of NO metabolites among three interventions, we have no direct evidence that ketamine inhibits NO formation. Other mechanisms, including inhibition of adenosine triphosphate-dependent potassium (KATP+) channels, may explain the results obtained in the present study, because ketamine has been reported to inhibit KATP+ channels (20), which in turn may be involved in hypercapnia-induced cerebral vasodilation (5,9,21). However, further studies are required to clarify the precise mechanism.

Our failure to observe a nitroglycerin-induced cerebral vasodilation requires some comment. Our finding that nitroglycerin 5 µg · kg-1 · min-1 had no impact on pial arteriolar diameters seems to be at odds with the concept that most NO donors dilate cerebral pial arterioles (9). However, a recent report by Csete et al. (22) demonstrated that 5 µg · kg-1 · min-1 of nitroglycerin IV did not change cerebral blood flow in rabbits. Although we do not know for certain why nitroglycerin failed to dilate cerebral pial arterioles, species differences or route of the administration may be relevant.

In contrast to our results, Sakai et al. (23), using a transcranial Doppler method, found that ketamine did not change the cerebral vascular reactivity to CO2 in humans (studied under propofol anesthesia). This discrepancy may be caused by the differences in species, basal anesthetic, dose of ketamine, or the method used to evaluate vascular reactivity. We chose pentobarbital as a basal anesthesia because it does not affect the NO content in the cerebral cortex (14,15) and maintains cerebral CO2 reactivity (24). Our previous studies also suggest that the response of the cerebral microcirculation to drugs and CO2 seem to be unaffected by pentobarbital (4,10). In addition, a previous study on isolated cerebral vessels demonstrated that pentobarbital has only a limited effect on cerebrovascular tone (25). However, at the present stage we cannot exclude the possibility that pentobarbital might have affected the cerebral microcirculation in some important way in our study.

We conclude that exogenous NO supplementation may play a role in the restoration of hypercapnia-induced cerebral vasodilation after its attenuation by ketamine. However, direct supporting evidence for the role of NO is lacking, and further studies will be required to confirm the mechanism.


   Acknowledgments
 
Supported, in part, by Grant-in-Aid for Scientific Research Nos. 11671489 and 13671570 from the Ministry of Education, Science, and Culture, Japan.


   References
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 

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Accepted for publication November 27, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press