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© 1999 International Anesthesia Research Society
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Abstract |
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We studied the effects of ketamine and propofol on two ligand-gated ion channels mediating fast synaptic transmission through sympathetic ganglia, neuronal nicotinic acetylcholine receptors (nAchRs), and P2X purinoceptors in a rat pheochromocytoma cell line PC12 using whole cell voltage clamp recording. Ketamine and propofol similarly inhibited the nicotine-induced inward current reversibly and dose-dependently at the membrane potential of -60 mV but had no effects on the adenosine triphosphate-induced current. Both anesthetics accelerated the current decay during agonist application, resulting in greater inhibition on the steady current than the peak current. The 50% inhibition concentration values for the steady current were lower than the clinically relevant concentrations for ketamine (2.8 ± 0.6 µM) and higher than those for propofol (5.4 ± 0.6 µM). Both anesthetics induced an addition of the fast component to the decay phase and an acceleration of the slow component, which suggests an open channel blockade or an enhancement of desensitization as a mechanism. The effects on closed channels seemed to be small because preincubation with the anesthetics did not significantly augment the block. Inhibition was voltage-independent at membrane potentials between -20 and -70 mV and was consistent with a noncompetitive block. Inhibition of the neuronal nAchR-mediated current may lead to the suppression of synaptic transmission in sympathetic ganglia by ketamine, but not by propofol, at the clinically relevant concentrations. However, these results are not consistent with changes in sympathetic nerve activities reported for animals or humans anesthetized with ketamine or propofol, which suggests effects from other systems, such as the central nervous system in vivo.
Implications: Ketamine (at smaller than clinically relevant concentrations) and propofol (at larger than clinically relevant concentrations) inhibited neuronal nicotinic acetylcholine receptor-mediated current in PC12 cells, which possess the receptors that resemble those in postganglionic sympathetic neurons. These findings are not consistent with in vivo experiments, which suggests that effects from other systems, such as the central nervous system, are of importance.
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Introduction |
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Neuronal nicotinic acetylcholine receptors (neuronal nAchRs) and P2X purinoceptors are ligand-gated ion channels widely distributed in central and peripheral neurons, including sympathetic ganglia (1–3). It is well established that neuronal nAchRs mediate fast synaptic transmission in autonomic ganglia (1). Adenosine triphosphate (ATP) or a related nucleotide has been considered to function as a neurotransmitter or a cotransmitter and to mediate fast synaptic transmission via P2X purinoceptors in some systems, including sympathetic ganglia (3). Therefore, evaluation of anesthetic effects on these receptors may help us to better understand their effects on the autonomic nervous system.
PC12 cells derived from rat pheochromocytoma express both neuronal nAchRs and P2X purinoceptors resembling those of postganglionic sympathetic neurons, but they lack GABAA receptors when untreated with nerve growth factors (4,5). We used PC12 cells as a model of postganglionic sympathetic neurons to study the effects of anesthetics on these ligand-gated ion channels mediating synaptic transmission in sympathetic ganglia, without influences from anesthetic actions on GABAA receptors. We have previously shown that thiopental inhibits the neuronal nAchR-mediated current, but little affects the P2X purinoceptor-mediated response in undifferentiated PC12 cells (6).
Ketamine and propofol are also widely used IV anesthetics that have opposite effects on sympathetic nerve activities. Ketamine stimulates, whereas propofol depresses, sympathetic nerve activities in whole animals and humans (7,8), and both anesthetics inhibit the nicotine-induced catecholamine release in adrenal medullary cells (9,10), which suggests inhibitory effects on neuronal nAchRs. However, no electrophysiological studies have characterized the effects of these anesthetics on neuronal nAchRs-mediated current in the autonomic nervous system. Additionally, no studies have investigated the effects of these anesthetics on P2X purinoceptors, despite their possible role in the sympathetic nervous system and for nociception.
In the present study, we compared the effects of these two anesthetics on the neuronal nAchR- and P2X purinoceptor-mediated current in undifferentiated PC12 cells using a conventional whole cell voltage clamp technique.
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Methods |
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PC12 cells were cultured as previously described (6). Cells were untreated with nerve growth factors. For the experiment, cells were plated on collagen and poly-L-lysine–coated cover slips and used after an additional 2- to 4-day culture.
Membrane currents were recorded by using a whole cell voltage clamp method (11) described previously (6). Cells on the cover slips were placed in a recording bath with an approximate volume of 1.5 mL and continuously perfused at the rate of 1–2 mL/min with a standard external solution containing (in mM): NaCl 140, KCl 5.4, CaCl2 1.8, MgCl2 1.0, N-2-hydroxy-ethylpiperazine-N'-2-ethanesulphonic acid (HEPES) 10, glucose 11.1 (pH adjusted to 7.4 with NaOH). Heat-polished patch pipettes had a tip resistance of 3–7 M
when filled with an intracellular solution containing (in mM): CsCl 150, HEPES 10, ethylene glycol-bis-(ß-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 5, ATP-Mg 2 (pH 7.3 with CsOH). Cells were voltage clamped at -60 mV with a patch clamp amplifier (CEZ 2400; Nihon Koden, Tokyo, Japan) unless otherwise stated. Whole cell currents were filtered at 0.2 kHz with a Bessel filter and digitized at 1 kHz. Data were stored and analyzed on a microcomputer using pCLAMP software and Axograph (Axon Instruments, Foster City, CA). All experiments were performed at room temperature (22–25°C).
Nicotine or ATP-Na2 30 µM in the external solution was applied to cells using a rapid application technique described as the "Y-tube " method (12). The tip of the Y-tube is positioned approximately 300 µm from the recorded cell. This method enables the complete exchange of the external solution surrounding the cell approximately 50–70 ms, as estimated by recording the liquid junction current produced at an open patch pipette. The agonists with or without the anesthetics were applied for 4 or 5 s, and each application was separated by 5 min. For preincubation with the anesthetic, the external solution containing the drugs was perfused at the rate of 5 mL/min for 5 min before rapid application. Cells were perfused with the plain external solution at the same rate for 5 min to wash the drugs from the bath after the measurement.
Drugs used in the current study were as follows: (-)-nicotine (Wako, Osaka, Japan), ATP-Na2, ATP-Mg, ketamine (Sigma, St. Louis, MO), and propofol (2,6-diisopropylphenol; 97% purity without vehicle; Aldrich Chemical, Milwaukee, WI). Ketamine was dissolved in distilled water to make a 30-mM stock solution and diluted with the external solution to the designated concentration. Propofol was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 50 mM for stock solution and diluted to the appropriate concentrations in the external solution. The commercial form of propofol (Diprivan® dissolved in Intralipid®; Zeneca, Osaka, Japan) was also used for comparison.
We measured the peak current and the steady current, which was defined as the average of the preceding 50 points at 4 s during agonist application. The response in the presence of ketamine or propofol was compared with the average of the elicited currents before and after anesthetic application. The same procedure was applied for the ATP-induced current.
Data are expressed as mean ± SEM. Statistical analysis was performed by using unpaired t-tests or analysis of variance followed by Dunnett's test to estimate the significance. P <0.05 was considered to be significant.
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Results |
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Nicotine 30 µM induced inward currents, which decayed rapidly reflecting receptor desensitization (5). The peak amplitudes varied greatly from cell to cell, from 50 to 400 pA, and tended to decline with repeated nicotine applications. When nicotine 30 µM was applied successively, the third response accounted for 72% ± 9% of the peak current and 66% ± 13% of the steady current of the first response (n = 7). Because the second response was very close to the average of the first and the third response—100% ± 3% for the peak current and 102% ± 6% for the steady current (n = 7)—the effects of ketamine or propofol were evaluated by comparison with the mean of the responses before and after the anesthetics.
In PC12 cells, ketamine (100 µM) or propofol (100 µM) alone elicited no significant ionic currents (n = 7 for both). DMSO (0.2%) also induced no current responses (n = 4). When ketamine and propofol were applied simultaneously with nicotine after preincubation, the current evoked by nicotine was reduced in the amplitudes with stronger effects on the steady current than on the peak current, and the current decay was accelerated (Fig. 1, A and B). The blockade of the nicotine current induced by ketamine and propofol was enhanced in a dose-dependent manner. The 50% inhibitory concentration (IC50) values for the peak and steady currents were 21.4 ± 1.9 and 2.8 ± 0.6 µM for ketamine and 46.6 ± 2.4 and 5.4 ± 0.6 µM for propofol, respectively (n = 5–7 each) (Fig. 1, C and D). The ratios of the postcontrol values after each anesthetic application to the precontrol values were not different from those of three successive nicotine applications, which indicates that the nicotine responses recovered fully from ketamine or propofol inhibition after the 5-min interval (data not shown). Diprivan® 30 µM reduced the peak and steady currents to 76.2% ± 5.2% and 13.3% ± 2.0% of control, respectively. The magnitudes of inhibition by Diprivan® were not significantly different from those by propofol dissolved in DMSO. DMSO did not affect the nicotine-induced current or the ATP-induced response at the concentrations equivalent to those associated with 30 and 100 µM propofol (data not shown).
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There was no change in the inhibition of peak and steady currents regardless of whether ketamine or propofol were preincubated.
The decay of the nicotine-induced inward current could be well fitted by single exponential functions with a mean time constant of 4.4 ± 0.6 s when 30 µM nicotine was used. The current traces in the presence of ketamine or propofol exhibited a double exponential decay (Fig. 1, A and B; middle panel). The time constant of the fast component (
f) was not greatly modified, but that of the slow component (s) was reduced with the increasing concentrations of both ketamine and propofol (Table 1). The changes in s were statistically significant at concentrations 
30 µM for both ketamine and propofol. Furthermore, the relative contributions of the fast decay component to the peak amplitude were increased with the increasing concentrations of both anesthetics (Table 1).
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The nicotine-induced current exhibited strong inward rectification and reversed around 0 mV, which is consistent with the previous reports (5). The current-voltage relationship in the presence of ketamine and propofol showed the same type of rectification without altering the reversal potential (Fig. 2, A and B). The magnitudes of inhibition were not different among the membrane potentials from -20 to -70 mV, which suggests that the inhibitions by ketamine and propofol were voltage-independent at these membrane potentials (n = 5 for each drug) (Fig. 2C).
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) at various holding potentials. The currents in the presence of the anesthetics were normalized to their corresponding control responses. Each point represents the mean ± SEM of five cells.When the doses of nicotine were increased to 100 or 300 µM, the magnitudes of depression of the steady current by both anesthetics and the peak current by propofol were not significantly different from those observed at the nicotine dose of 30 µM (n = 5 for each concentration) (Fig. 3). Inhibition of the peak current by ketamine was, however, significantly reduced in the experiment using 300 µM nicotine (Fig. 3).
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ATP 30 µM evoked slowly desensitizing inward currents at the membrane potential of -60 mV. Ketamine or propofol, when preperfused for 5 min and then coapplied with ATP 30 µM, did not affect the ATP-induced current at 30 or 100 µM (n = 4 each) (Fig. 4). Neither anesthetic induced remarkable changes in the current-voltage relationship of the ATP-induced current at the membrane potentials from -70 to 30 mV.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our results demonstrate that both ketamine and propofol cause a dose-dependent and reversible inhibition of the neuronal nAchR-mediated current but do not affect the P2X purinoceptor -mediated response in PC12 cells. The effects of ketamine and propofol on neuronal nAchRs were consistent with a noncompetitive block and exhibited a preferential inhibition of open channels. The inhibition by these anesthetics was voltage-independent at membrane potentials between -70 and -20 mV. These characteristics of the effects of ketamine and propofol are very similar to those of thiopental (6). When the binding of the anesthetics to serum proteins is considered, clinically relevant concentrations of unbound molecules are reportedly 4–7 µM for ketamine and 0.4–2 µM for propofol (13–16). The IC50 values for the inhibition of the steady current were well below the clinically relevant concentrations for ketamine and were 2.7–14 times higher than those for propofol.
The finding that a large concentration of propofol did not induce any current responses provides evidence that the PC12 cells studied lack functional GABAA receptors and that the observed effects on neuronal nAchRs were not contaminated with influences from activation of GABAA receptors. It is well known that PC12 cells express multiple subunits of neuronal nAchRs, including 
3, 5, 7, ß2, ß3, and ß4 subunits, and that they are often heterogeneous (17). Therefore, it is likely that the neuronal nAchRs studied in our experiment consisted of multiple classes of the receptors with different subunit combinations. However, it is also known that a single class of the receptor is usually dominant and accounts for most of the channel activities in single cells (18,19). We did not notice very great variability among cells in terms of sensitivity to the anesthetics and changes in current decay kinetics, which suggests that most of our results came from the putative dominant subtype of the receptors or multiple subtypes of the receptors with similar characteristics.
Both ketamine and propofol accelerated the current decay of the nicotine-induced current, which suggests an open channel blockade or an enhancement of desensitization as a mechanism. The exponential fitting of the current decay revealed that ketamine and propofol added the fast component to the slow decay phase of the control currents and increased the relative contribution of the fast component to the peak amplitude in a dose-dependent manner. Because the slow component may represent desensitization and the new fast component may correspond to the open channel block caused by the anesthetics (20), an open channel blockade may be one of the mechanisms. However, both anesthetics produced dose-dependent decreases of the time constant for the slow component without changing that for the fast component. This suggests an acceleration of desensitization as a major action. Our study could not differentiate between these two possibilities. Further studies with better time resolution and analysis of single-channel recordings are needed to clarify the exact mechanisms.
Preincubation of ketamine or propofol did not significantly increase the magnitude of inhibition compared with those without preincubation. Small effects of preincubation suggest that the anesthetics have little effect on closed channels and preferentially affect open channels (21). The small contribution of ketamine's effects on closed channels is not consistent with Scheller et al.'s (22) article, which describes the potent inhibition of closed channels of muscle nAchRs by concentrations of ketamine as low as 0.1 µM. Differences in subunit composition and time resolution of the measurements can account for this discrepancy, at least in part.
The inhibitory effects of the anesthetics were not diminished by the larger doses of nicotine, which is in accord with noncompetitive blockade, except for the inhibition of the peak current by ketamine. It is intriguing that 300 µM nicotine reduced ketamine's effect on the peak current, leaving the effect on the steady current unchanged. The peak current inhibition by ketamine, a part of which is caused by a block of closed channels, may involve different sites and mechanisms.
We found that three IV anesthetics—ketamine, propofol, and [in a previous study (6)] thiopental—have little effect on ATP-evoked current in PC12 cells, unlike neuronal nAchRs. Although we do not know whether the three anesthetics act on a common site or on distinct sites of nicotinic receptors, P2X purinoceptors lack the site(s) for these anesthetics' action, consistent with poor homology of amino acid sequences between these two receptors (23). Because P2X purinoceptors in PC12 cells resemble those of rat sympathetic ganglia (5), these results indicate that the IV anesthetics studied have little effect on the P2X purinoceptor-mediated response in sympathetic ganglia.
Ketamine strongly inhibited the ganglionic type of neuronal nAchRs at clinically relevant concentrations. This finding is not in accord with the observation that ketamine stimulates sympathetic nerve activities in intact animals and humans. Sympathomimetic action is reportedly mediated through effects on the central nervous system (7,24). In contrast, ketamine has been shown to depress renal sympathetic nerve activity in spinal cord-transected rats (24). This action may be related to the inhibition of nicotinic receptors described in the present study. It is likely that ketamine stimulates presynaptic nerve activities via its central effects and that very large concentrations of acetylcholine in the synaptic cleft caused by stimulation abolish the inhibitory effects of ketamine on the peak synaptic currents, as observed with the high concentration of nicotine in this study. Ketamine's inhibition on the ganglionic type of nicotinic receptors does not contribute to its clinical effects on the sympathetic nervous system, probably because inhibition of the peak synaptic current is more important in blocking synaptic transmission than in augmenting desensitization or the current decay. Although modulation of current decay kinetics by ketamine is obvious and potentially influences the shape of the synaptic current (25), its physiological significance seems to be small.
Propofol inhibits the sympathetic nervous system (8). However, it is unlikely that inhibition of neuronal nAchRs in sympathetic ganglia is responsible for this effect, because IC50 values for the peak current and the steady current are much higher than the clinically observed concentrations of unbound propofol. It seems that actions on other systems are responsible for the depression of sympathetic nerve activity observed clinically.
In conclusion, clinically relevant concentrations of ketamine, but not propofol, inhibit neuronal nAchRs in PC12 cells, which resemble those in postganglionic sympathetic neurons. However, these results are not consistent with changes in sympathetic nerve activities in vivo, which suggests that influences from other systems, such as the central nervous system, are more important in vivo.
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Acknowledgments |
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This work was supported by in part by grant-in-aid for scientific research (08671761 to TA and 08771216 to RF) from the Ministry of Education, Science and Culture, Japan.
The authors thank Fukuichiro Okumura, MD, PhD, for his review of this work and the manuscript.
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