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Anesth Analg 2006;102:806-810
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000195547.35721.ff

ANESTHETIC PHARMACOLOGY

Ketamine Attenuates Sympathetic Activity Through Mechanisms not Mediated by N-Methyl-d-Aspartate Receptors in the Isolated Spinal Cord of Neonatal Rats

Chiu-Ming Ho, MD, PhD*, and Chun-Kuei Su, PhD{dagger}

*Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University; {dagger}Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

Address correspondence and reprint requests to Chiu-Ming Ho, MD, PhD, Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shihpai Rd, Taipei 112, Taiwan. Address e-mail to cmho{at}vghtpe.gov.tw.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Ketamine is believed to have sympathomimetic effects, although the central mechanism remains unclear. Using an in vitro splanchnic nerve-spinal cord preparation from neonatal rats, our previous investigations have demonstrated that tonic sympathetic activity is spontaneously generated from the thoracic spinal cord. We designed this study to investigate whether applications of ketamine to the cord would augment sympathetic activity and whether this action was dependent on N-methyl-d-aspartate receptors. Bath application of ketamine significantly reduced sympathetic activity in a concentration-dependent manner. Ketamine in 10, 20, 40, 80, and 120 µM reduced the sympathetic activity to 82.6% ± 4.4% (P < 0.05), 61.7% ± 5.1%, 42.8% ± 4.2%, 24.9% ± 4.4%, and 9.2% ± 2.7% of the control value, respectively (P < 0.01, n = 8 for each test). The 50% inhibitory concentration of ketamine on sympathetic activity was 32 µM. Pretreatment with DL-2-amino-5-phosphonovaleric acid, a selective competitive N-methyl-d-aspartate receptor antagonist, did not alter ketamine-induced depression of sympathetic activity. These results suggest that ketamine reduces sympathetic activity by mechanisms that are independent of N-methyl-d-aspartate receptor activity.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ketamine is a widely used anesthetic that has been in clinical practice for 40 yr. It is the only IV anesthetic that induces a general increase in arterial blood pressure and heart rate (1). Because of its sympathomimetic effects, the direct actions of ketamine on central sympathetic outflow are of particular interest. However, there are controversial observations about the effects of ketamine on sympathetic activity. In both animals and humans, administration of ketamine has been reported to have no effect (2,3), decrease (4,5), increase (6,7), and even to induce a biphasic effect on sympathetic activity (8,9). One possible reason for these discrepant observations was that the experimental results were obtained under in vivo conditions. Obvious disadvantages accompanying in vivo observations include lack of precise concentrations of ketamine in the extracellular medium, differences in basal anesthesia, ventilatory status, variations of hemodynamic conditions, and existence of autonomic balance. To overcome those disadvantages in exploring drug effects on sympathetic activity, our laboratory developed an in vitro splanchnic nerve-spinal cord preparation from neonatal rats (10,11).

With the advent of the in vitro experimental model, our previous investigations have demonstrated that tonic sympathetic activity is spontaneously generated from the thoracic spinal cord (11). The generation of sympathetic activity from the spinal cord requires Ca2+-dependent synaptic transmission and is mainly driven by the activity of several amino acid neurotransmitters, including glycine, {gamma}-aminobutyric acid, and glutamate (12). Ketamine, by acting on N-methyl-d-aspartate (NMDA)-type glutamate receptors, produces analgesia (1). In the present studies, we first investigated the effects of ketamine on spinally generated sympathetic activity. Second, we clarified whether the ketamine-induced effects were dependent on NMDA receptors.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Institutional Animal Care and Use Committee of Taipei Veterans General Hospital approved this study. Neonatal Sprague-Dawley rats (postnatal days 1–4) were used. We performed 66 individual experiments including nonviable cords and incomplete experiments. The general procedures for preparation of a thoracic spinal cord have been previously described (10–13). Briefly, neural tissue extending from T1 to T12 spinal segments was immersed in oxygenated 10°C artificial cerebrospinal fluid (aCSF) (in mM: 128 NaCl, 3 KCl, 1.5 CaCl2, 1.0 MgSO4, 24 NaHCO3, 0.5 NaH2PO4, 30 D-glucose, and 3 ascorbate) equilibrated with 95% O2–5% CO2. The dorsal parts of the vertebrae encasing the cord were removed to allow for better perfusion, and the ventral parts of the vertebrae were left intact to preserve sympathetic efferent pathways. Splanchnic nerves were identified by tracing the nerves that exited from the sympathetic chain and innervated the celiac ganglion, located adjacent to the adrenal gland. The distal ends of the splanchnic nerves were cut at a level proximal to the celiac ganglion. A suction electrode was then placed on the proximal end of the whole bundle splanchnic nerve to record sympathetic activity. During experiments, this splanchnic nerve-thoracic spinal cord preparation was kept in a bath chamber that contained 30 mL freshly oxygenated aCSF and was maintained at 24.5°C ± 1°C. Incubating at this temperature, the cord was able to generate a stable sympathetic nerve activity (10,11).

Neural signals recorded from splanchnic sympathetic activity were amplified, filtered (band pass: 0.1–1 kHz; DAM50, World Precision Instruments, Sarasota, FL), and stored in a PCM-tape recorder (Neuro-Corder DR-886, Neuro Data, New York, NY) for off-line analysis. The envelope of sympathetic activity was acquired by a leaky integrator (discharging time constant, 15 ms) to better reveal the slow rhythmic oscillation of sympathetic activity. A time-based integrator (Gould 13-4615-70; Gould, Cleveland, OH) with a resetting time of 5 s was used to measure total sympathetic activity. At the end of each experiment, the background noise level of sympathetic activity was determined by integrating noise signals after increasing KCl concentration in the bath solution (final concentration, 100 mM) to obtain a depolarizing blockade of neural activity (13). True neural signals were obtained by subtracting recorded signals from background noise.

Ketamine (Ketalar) was purchased from Pfizer (Taipei, Taiwan); NMDA (a selective NMDA receptor agonist), and DL-2-amino-5-phosphonovaleric acid (AP-5, a selective competitive NMDA receptor antagonist) were purchased from Sigma Chemical (St. Louis, MO). To prepare concentrated solutions, drugs were dissolved in water (in mM: 10 ketamine, 5 NMDA, 20 AP-5). Concentrated solutions were stored at –20°C and thawed at room temperature before application. A final concentration of drugs in the micromolar range was achieved by adding an aliquot of concentrated solution directly into the bath chamber. After ketamine application, a period of 15 min was allowed for equilibrium. The concentration-response tests of ketamine (in µM: 10, 20, 40, 80, or 120) were conducted by cumulatively increasing drug concentrations in the bath solution. To explore whether ketamine-induced effects on sympathetic activity were dependent on NMDA receptors, the preparation was pretreated with 50 µM AP-5 for 15 min before 50 µM ketamine was added to the bath solution. In a series of experiments, we clarified if 50 µM AP-5 was sufficient to block NMDA receptors by examining the excitatory effects of 20 µM NMDA on sympathetic activity in the absence or presence of AP-5.

To pool data from individual experiments and eliminate the inevitable variation of electrical recording conditions that may affect absolute amplitude of neural signals, the height of time-based integration of sympathetic activity under control conditions was taken as 100% activity. The averages of neural signals in a 10-min period before drug application were used as controls. Drug effects on integration of sympathetic activity amplitude were then calculated as percent changes from control activity. The effectiveness of drugs on changing sympathetic activity in a concentration-dependent manner was evaluated first by analysis of variance followed by post hoc multiple comparison, using adjusted Student's t-tests with P values corrected by Bonferroni procedure (SPSS for Windows version 12; SPSS Inc, Chicago, IL). The data used for calculating the concentration of ketamine required to achieve 50% maximal effects were analyzed with Origin version 4.1 (Origin Labs, Northampton, MA) and fit with a sigmoidal Boltzman function, y = A2 + (A1 – A2)/{1 + EXP[(x – x0)/dx]}, where A1 and A2 were the upper and lower asymptotes, respectively, x0 was the half-maximal response, and dx was the width. In practice, sympathetic activity before ketamine application (100% activity) was set as a fixed asymptote for A1. A P value <0.05 was considered significant. All values are presented as means ± sem unless otherwise indicated.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Figure 1 shows that bath applications of ketamine (10–120 µM) reduced sympathetic activity in a concentration-dependent manner. Ketamine-induced reduction of sympathetic activity was reversible after washout. Figure 2 summarizes the effects on total sympathetic activity induced by applications of ketamine. At a concentration as small as 10 µM, ketamine significantly reduced sympathetic activity to 82.6% ± 4.4% of control activity (P < 0.05; n = 8). As ketamine concentration increased from 10 to 120 µM, sympathetic activity decreased further. In the presence of 120 µM ketamine, only 9.2% ± 2.7% of control sympathetic activity remained (P < 0.01; n = 8). The 50% inhibitory concentration (IC50) of ketamine on sympathetic activity was 32 µM.


Figure 121
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  		Figure 1. Original traces show ketamine-induced reduction of sympathetic activity. A, Fast traces of the envelope of sympathetic activity show a reduced oscillation of sympathetic activity after ketamine (10 µM or 120 µM). Note that reduction of sympathetic activity by ketamine was reversible. The background noise of sympathetic activity recording was determined after adding 100 mM KCl to the bath solution. B, Slow traces show the time course of the reduction of sympathetic activity after cumulatively increasing the concentration of ketamine in the bath solution. Arrowheads indicate the timing of drug applications. The quantitative analysis of changes of sympathetic activity was based on the changes of total sympathetic activity.

 

Figure 221
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  		Figure 2. Ketamine reduces total sympathetic activity in a concentration-dependent manner. For each group, data (means ± sem) were obtained from averaging responses of 8 experiments. Asterisks represent significant difference from control. *P < 0.05; **P < 0.01.

 

The presence of functional NMDA receptors in the cord was verified by applications of the receptor agonist, NMDA. Bath applications of 20 µM NMDA significantly increased sympathetic activity to 285.4% ± 38.8% of control activity (P < 0.01); (n = 8). The antagonistic effect of AP-5 on NMDA-induced increase of sympathetic activity was tested. Bath applications of 50 µM AP-5 alone did not alter sympathetic activity (Fig. 3) (n = 8). In the presence of 50 µM AP-5, 20 µM NMDA did not cause an apparent change in sympathetic activity (102.2% ± 9.4% of control activity; n = 8). We further examined whether or not AP-5 would affect ketamine-induced depression of sympathetic activity. In the presence of 50 µM AP-5 in the bath solution, applications of 50 µM ketamine significantly reduced sympathetic activity to 38.7% ± 4.7% of control activity (Fig. 3) (P < 0.01; n = 8).


Figure 321
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  		Figure 3. Lack of effects elicited by AP-5 preteatment on ketamine-induced reduction of sympathetic activity. A, Fast traces of the envelope of sympathetic activity. Application of 50 µM AP-5 did not alter sympathetic activity. A further application of 50 µM ketamine in presence of 50 µM AP-5 reduced sympathetic activity. The reduction of sympathetic activity by ketamine was reversible. B, Summed effects on total sympathetic activity induced by AP-5 or AP-5 plus ketamine. Data (mean ± sem) were obtained from averaging responses of 8 experiments. **P < 0.01 represents significant difference from control.

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We did not find a sympathomimetic effect elicited by ketamine applications to an in vitro splanchnic nerve-spinal cord preparation from neonatal rats. On the contrary, applications of ketamine reduced the spinally generated sympathetic activity in a concentration-dependent manner. This ketamine-induced depression of sympathetic activity was not altered by pretreatment with AP-5. Therefore, ketamine reduced central sympathetic activity through mechanisms that were independent of NMDA receptor activity.

A primary question surrounding an in vitro study is whether the observation occurs at clinically relevant concentrations. Plasma concentrations of ketamine in the surgical setting are typically in the range of 20 to 60 µM (14,15). As the protein-bound fraction is 12% (16), the free plasma concentration of ketamine was around 18 to 53 µM. In rats, the plasma concentration of ketamine that produced general anesthesia was approximately 50 µM (17). In the present study, the minimum concentration of ketamine that effectively reduced sympathetic activity was 10 µM; the IC50 of ketamine on sympathetic activity was 32 µM (7.6 µg/mL). This suggests that our finding of ketamine-induced reduction in sympathetic activity occurs at clinically relevant concentrations. Our data show that ketamine depressed central sympathetic outflow. Therefore, the circulatory stimulation by ketamine, as unraveled by the sympathomimetic effects, might be attributable to neuronal inhibition of norepinephrine reuptake at adrenergic nerve endings (18,19), as well as inhibition of parasympathetic outflow (20,21).

Although the major analgesic effect of ketamine is thought to be mediated by NMDA receptors in a noncompetitive mode (1), the precise mechanism responsible for ketamine-induced depression of central sympathetic outflow is unclear. In this study, we have excluded a direct involvement of NMDA receptors in ketamine-induced reduction of sympathetic activity. Ketamine blocks NMDA receptor in a use-dependent mode (exerts its effects primarily after the channel of NMDA receptor has been opened) that is dependent on the presence of agonist (22). In contrast, AP-5 acts on the glutamate transmitter recognition site of NMDA receptors, preventing receptor activation by competing with agonist for the transmitter-binding site (22). We tested the involvement of NMDA receptors in ketamine-induced sympathetic depression by pre-incubating the nerve-cord preparation with 50 µM AP-5. AP-5 at a concentration of 50 µM was sufficient to block NMDA receptors in the current preparation, as it has been shown in other isolated spinal cord preparations of neonatal rats (23,24). In addition, this result showed that application of 50 µM AP-5 alone did not alter the spontaneously generated sympathetic activity. The current finding is in agreement with our previous attempts to block broad-spectrum ionotropic glutamate receptors by kynurenate (a nonselective antagonist of NMDA and non-NMDA receptors); we did not observe a simple reduction of sympathetic activity induced by kynurenate as it was caused by ketamine in the current study (12). Our previous study suggested that NMDA receptors might not be an important component in the spontaneously generated sympathetic activity in newborn rat spinal cord. The spinal cord contains a powerful cholinergic system (possibly interneurons) that can influence sympathetic preganglionic neurons (25). Considering the targets of ketamine actions at the clinical concentrations, it is possible that ketamine may affect activities of neuronal nicotinic acetylcholine receptors (26), muscarinic acetylcholine receptors (27), or both. This possibility should be clarified in future studies.

In comparison with the other in vivo studies (2–9), the present study using an in vitro preparation enables us to analyze drug-induced effects with precise control of drug concentrations in the extracellular medium and under anesthetic-free and muscle relaxant-free conditions. Because the nutrition or oxygen supply in this nerve-cord preparation has bypassed blood circulation, indirect influences resulting from changes in hemodynamic conditions can also be excluded. We used neonatal rats in the current preparation; synaptic connections might not have been mature. However, in our previous studies, bath application of baclofen ({gamma}–aminobutyric acidB receptor agonist) (28) or adenosine analog (N6-cyclopentyladenosine) (13) to this nerve-cord preparation simulated the regimens that used intrathecal baclofen (29) or adenosine analog (30) producing sympathoinhibitory effects in adult rats. All these findings suggest that the current preparations can be a useful model to explore the drug effects at the spinal level. Although this preparation presents technical advantages, extrapolation of results to the intact and adult animal should always be made with a degree of caution.

In conclusion, we have presented evidence indicating that ketamine at concentrations relevant to clinical anesthesia can reduce central sympathetic outflow at the level of the spinal cord. This ketamine-induced reduction of central sympathetic activity does not work via a blockade of NMDA receptors.

The authors thank Ms. Yi-Wen Cheng, Ms. Shu-Chun Peng, and Mr. Guo-Wei Tarng for their skillful technical assistance.


   Footnotes
 
Supported, in part, by grants from National Science Council of the Republic of China (NSC 93-2314-B-075-081).

Accepted for publication October 4, 2005.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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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 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press