| JOURNAL HOME | CME HOME | THIS MONTH | PAST ISSUES | ETOC | COLLECTIONS |
| AUTHORS | REVIEWERS | EDITORIAL BOARD | FEEDBACK | RSS | HELP |
 
|
|
|
||
|
|
Anesth Analg 2003;97:96-103 © 2003 International Anesthesia Research Society
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Because inhibition of voltage-dependent Ca2+ channels can be a mechanism underlying general anesthesia, we examined sensitivities to propofol and halothane in mice lacking the R-type (Cav2.3) channel widely expressed in neurons. Sleep time after propofol injection (26 mg/kg IV) and halothane MACRR and MAC (50% effective concentrations for the loss of the righting reflex and for the tail pinch/withdrawal response, respectively) were determined. Significantly shorter propofol-induced sleep time (291.6 ± 16.8 s versus 344.4 ± 12.1 s) and larger halothane MACRR (1.11% ± 0.04% versus 0.98% ± 0.03%) were observed in Cav2.3 channel knockouts (Cav2.3-/-) than in wild-type (Cav2.3+/+) litter mates. To investigate the basis of the decreased anesthetic sensitivities in vivo, field excitatory postsynaptic potentials and population spikes (PSs) were recorded from Schaffer collateral CA1 synapses in hippocampal slices. Propofol (10–30 µM) inhibited PSs by potentiating
-aminobutyric acid-ergic inhibition, and this potentiation was markedly smaller at 30 µM in Cav2.3-/- mice, possibly accounting for the decreased propofol sensitivity in vivo. Halothane (1.4%–2.2%) inhibited field excitatory postsynaptic potentials similarly in both genotypes, whereas 1%–2% halothane depressed PSs more in Cav2.3-/- mice, suggesting the postsynaptic role of the R-type channel in the propagation of excitation and other mechanisms underlying the increased halothane MACRR in Cav2.3-/- mice. IMPLICATIONS: Because inhibition of neuronal Ca2+ currents can be a mechanism underlying general anesthesia, we examined anesthetic sensitivities in mice lacking the R-type (Cav2.3) Ca2+ channels both in vivo and in hippocampal slices. Decreased sensitivities in mutant mice imply a possibility that agents blocking this channel may increase the requirements of anesthetics/hypnotics.
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Accumulating evidence has suggested that anesthetics act on ion channels and receptors on the neuronal cell membrane and alter synaptic transmission in the central nervous system (CNS) (1–3). Recent studies on mice with a targeted mutation also support the importance of several ion channels and receptors in mediating general anesthesia in vivo (4–6). Voltage-dependent Ca2+ channels (VDCCs) expressed on neuronal membranes control various cellular functions, including excitability of the soma-dendrites and neurotransmitter release from nerve endings (7), whereas general anesthetics at clinically relevant concentrations inhibit various types of Ca2+ currents (8–12). Therefore, inhibition of VDCCs is considered to be a plausible candidate for anesthetic mechanisms.
VDCCs are classified into six distinct types—L-, N-, P-, Q-, R-, and T-types—on the basis of their pharmacological and electrophysiological properties (7). They are heteromultimeric protein complexes composed of 
1, 2-
, ß, and subunits, and the 1 subunit contains an ion-conducting pore, voltage sensor, gating machinery, and drug-binding sites, determining the type of VDCC (7). Among the currently identified 10 different 1 subunits (1A–I and 1S), the 1E (Cav2.3) subunit is considered to contribute to the R-type VDCC (7). Like other Cav2-class VDCCs, the Cav2.3 channel is widely and predominantly expressed in the brain (7) and has been inhibited by various anesthetics (11,12). This channel is suggested to participate in neurotransmitter release (13) and propagation of somatodendritic excitation (14), yet clinical information regarding the role of the Cav2.3 channel in mediating the actions of anesthetics has been lacking, partly because of the limited availability of specific blockers. To clarify the role of the Cav2.3 channel in the neuronal activities on which anesthetics exert their effects in intact animals, we investigated the sensitivities to propofol and halothane in mice lacking the Cav2.3 channel in vivo as well as in vitro by using hippocampal slice preparation.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All the animal experiments were approved by the Animal Care Committee of Tokyo Medical and Dental University. Homozygous mutant mice lacking the Cav2.3 subunit of the VDCC (Cav2.3-/-), heterozygous mutant mice (Cav2.3+/-), and wild-type mice (Cav2.3+/+) were created as described previously (15). These mice were viable and fertile, and their gross behaviors appeared to be normal (15,16). Behavioral responses to acute mechanical, thermal, and chemical pain were similar among the genotypes (15). Mice of both sexes were used at the age of 9–32 wk for behavioral studies and at the age of 4–10 wk for in vitro experiments. All the behavioral studies were performed by a single examiner who was blinded to the genotypes of the mice. Mice were kept warm by a heat lamp before and throughout the behavioral experiments to avoid hypothermia during anesthesia.
Lipid emulsion containing 10 mg/mL of propofol (Diprivan®; AstraZeneca, London, UK) was used in the behavioral study and was diluted in artificial cerebrospinal fluid (aCSF) for the field recordings. Intralipid® (vehicle of propofol; Fresenius Kabi AB, Uppsala, Sweden), alone did not affect field responses at equivalent concentrations. During behavioral experiments with halothane (Takeda Chemical Industries, Osaka, Japan), the concentration (vol%) in an anesthetic box was continuously monitored by a gas analyzer (AM-1; Acoma, Tokyo, Japan). In the field recordings, aCSF in a plastic bottle (volume, 300 mL) was saturated with halothane vaporized in 95% oxygen/5% CO2 at the flow rate of 0.5 L/min for 10 min before administration. Concentration of halothane in the gas phase in the bottle was monitored by the gas analyzer. Vaporized halothane was also blown onto the surface of aCSF in the recording chamber to minimize the escape of halothane from the slice perfusate.
Sleep time induced by propofol was assessed in almost the same way as previously described (17). Briefly, mice (n = 26, 29, and 22 for Cav2.3+/+, Cav2.3+/-, and Cav2.3-/-, respectively) were injected with propofol (26 mg/kg) via a tail vein, and sleep time, defined as the duration for which the righting reflex was lost, was measured. The righting reflex was defined as regaining the upright position when mice were placed on their backs.
Two modified MAC values for halothane were determined: 50% effective concentration (EC50) for the loss of the righting reflex (MACRR) as a surrogate measure for hypnosis (18) and EC50 for the loss of the tail pinch/withdrawal response (MAC) as a surrogate measure for immobilization (19). Mice (n = 26, 24, and 22 for Cav2.3+/+, Cav2.3+/-, and Cav2.3-/-, respectively) were individually put into the air-tight box (approximately 2 L in volume), where each mouse was able to move freely. Halothane (0.6%) vaporized in oxygen was administered into the box at 2 L/min for 30 min. Then the mouse was gently located on its back in the box, and the righting reflex was monitored for up to 15 s. Subsequently, the middle third of the tail was clamped with an alligator clip to observe the withdrawal movement of the head, limbs, and body for up to 1 min. The concentration of halothane was increased stepwise by a 0.2% increment for 15 min until both of the reflexes were lost. MAC values were calculated by averaging the two concentrations at which mice either lost or finally exhibited the reflex. Rectal temperature was measured with a temperature probe (TR-100; Fine Science Tools Inc., North Vancouver, BC, Canada) before and after each experiment. At the end of the MAC experiments, mice (n = 6, 6, and 5 for Cav2.3+/+, Cav2.3+/-, and Cav2.3-/-, respectively) were removed from the box and made to breathe the same gas composition via a face mask, and the heart was punctured percutaneously with a 26-gauge needle to collect arterial blood gas samples.
In another group of mice (n = 6 each for Cav2.3+/+ and Cav2.3-/-), blood pressure and pulse rate were measured from the tail artery with a noninvasive device (BP-98A; Softron, Tokyo, Japan), with body temperature maintained at 37°C. The measurements were performed before and at each end of series of halothane administration (0.5%, 1%, 1.5%, and 2%; 15 min each). Three consecutive values measured at 1-min intervals were averaged. These systemic variables were not measured in the propofol experiment because of its short duration of action.
Cav2.3+/+ and Cav2.3-/- mice were intraperitoneally injected with pentobarbital sodium (Abbott Laboratories, North Chicago, IL) at 50 mg/kg and decapitated. The brain was quickly removed, and transverse hippocampal slices (thickness, 400 µm) were sectioned in ice-cold aCSF, which contained (mM) 137 NaCl, 2.5 KCl, 21 NaHCO3, 0.58 NaH2PO4, 2.5 CaCl2, 1.2 MgCl2, and 10 glucose, and was bubbled with 95% oxygen/5% CO2. A cut was made between the CA1 and CA3 region of the hippocampus. The slices were placed in an interface chamber for recovery for at least 2 h (25°C–26°C).
Two types of field responses, field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs), in the hippocampal CA1 region were recorded to examine the actions of anesthetics in vitro. The fEPSPs (n = 7 and 9 for propofol; n = 7 each for halothane for Cav2.3+/+ and Cav2.3-/- mice, respectively) were recorded from the stratum radiatum (a dendritic layer of CA1), whereas PSs (n = 8 each for propofol; n = 8 and 7 for halothane for Cav2.3+/+ and Cav2.3-/- mice, respectively) were recorded from the stratum pyramidale (the somatic layer of CA1). Square-wave single pulses or paired pulses (50-ms interpulse interval) of 200 µs duration and 60–150 µA intensity were delivered to the Schaffer collateral-commissural fibers every 15 s to evoke fEPSPs or PSs, respectively. Four consecutive field responses were averaged. The magnitude of fEPSPs was evaluated from the slope at an initial falling phase of the dendritic recordings, whereas that of PSs was evaluated from the peak amplitude of the negative spike of the somatic recordings. The effective volume of a recording chamber was approximately 0.4 mL, and each slice was perfused with aCSF at a flow rate of 3 mL/min at 28°C.
Anesthetics at 2 concentrations were applied for 15 min each in a dose-cumulative manner: propofol 10 and 100 µM and halothane 1.4% and 2.2% for fEPSPs and propofol 10 and 30 µM and halothane 1.0% and 2.0% for PSs. After recovery was obtained by washout of anesthetics for at least 15 min, the same protocols were repeated by perfusing aCSF containing an antagonist of the -aminobutyric acid type A (GABAA) receptor, bicuculline (10 µM; Sigma, St. Louis, MO). Bicuculline was also added to aCSF throughout the recordings of fEPSPs.
All results are expressed as mean ± SEM. Group differences were evaluated by the Tukey-Kramer test for nonparametric multiple comparisons. Comparisons between two groups were evaluated by Student’s t-test. Differences at P < 0.05 were considered to be statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sleep time after IV injection of propofol was significantly shorter in Cav2.3-/- mice than in Cav2.3+/+ mice (291.6 ± 16.8 s versus 344.4 ± 12.1 s; P = 0.007; Fig. 1A). MACRR for halothane was larger in Cav2.3-/- mice than in Cav2.3+/+ mice (1.11% ± 0.04% versus 0.98% ± 0.03%; P = 0.026; Fig. 1B, left), whereas MAC for halothane did not differ significantly between genotypes (Fig. 1B, right).
|
Effects of the halothane exposure on systemic variables are summarized in Table 1. Rectal temperature was maintained and hypercapnic/metabolic acidosis was found after halothane MAC was determined in three genotypes. During halothane exposure, blood pressure and heart rate decreased similarly in Cav2.3+/+ and Cav2.3-/- mice in a concentration-dependent manner. No significant differences between Cav2.3-/- and Cav2.3+/+ mice were observed in regard to all these variables.
|
The basal input-output relationship between presynaptic fiber-volley and fEPSP at the Schaffer collateral-CA1 synapses was not altered in the Cav2.3-/- mice (data not shown); this is consistent with our previous study (16). Halothane, at clinical concentrations, inhibited fEPSPs reversibly and concentration dependently, but no significant differences were observed between the two genotypes (Fig. 2, A and B). However, propofol, even at the larger concentration (100 µM), minimally affected fEPSPs both in Cav2.3-/- and in Cav2.3+/+ mice (Fig. 2C).
|
We further investigated the effects of propofol and halothane on PSs recorded from the stratum pyramidale in the hippocampal CA1 region. The averaged control PS amplitudes did not differ significantly between Cav2.3-/- and Cav2.3+/+ mice (1.86 ± 0.25 mV versus 2.53 ± 0.42 mV at 80 µA intensity), and the addition of bicuculline enhanced them similarly both in Cav2.3-/- and Cav2.3+/+ mice (47.8% ± 16.1% versus 40.8% ± 17.3% increase at 80 µA intensity). Propofol decreased the amplitude of PSs in response to the second of the paired-pulse stimulation (PS2) dose dependently (Fig. 3A), and the relative inhibition compared with the control PS2 amplitude was significantly smaller in Cav2.3-/- mice than in Cav2.3+/+ mice at 30 µM propofol (43.6% ± 7.0% versus 67.6% ± 8.4%; P = 0.046; Fig. 3B, left). PSs in response to the first of the paired-pulse stimulation (PS1) were also modestly inhibited by propofol, but there was no significant difference between the genotypes (data not shown). Bicuculline almost completely antagonized this inhibitory effect of propofol on PS1 and PS2 (Fig. 3B, right, for PS2).
|
The effect of halothane on PSs was assessed by PS1 amplitudes because, unlike propofol, halothane markedly inhibited PS1 amplitudes, whereas it modestly inhibited PS2. The representative PS1 traces under bicuculline administration are shown in Figure 4A. Regardless of bicuculline action, clinical concentrations of halothane inhibited PS1 amplitudes concentration dependently (Fig. 4B), and in the presence of bicuculline, the inhibitory effects of halothane at both 1% and 2% were significantly more in Cav2.3-/- mice compared with those in Cav2.3+/+ mice (P = 0.016 and 0.009 at 1% and 2% halothane, respectively; Fig. 4B, right).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
We demonstrated decreased sensitivities to the hypnotic actions of propofol and halothane in Cav2.3-/- mice. These findings were unexpected because the blockade of VDCCs by Ca2+ antagonists has been found to augment the potency of volatile and IV anesthetics in vivo (20,21). Systemic conditions such as hypothermia, hypoxia, hypercapnia, metabolic acidosis, and hypotension affect anesthetic sensitivity (19). These conditions did not differ significantly between Cav2.3-/- and Cav2.3+/+ mice, suggesting that the decreased sensitivities to propofol and halothane in Cav2.3-/- mice were derived not from alterations in vital conditions, but, presumably, from those in the CNS function in the mutant mice.
General anesthetics are thought to exert their actions in the CNS by reducing membrane excitability, depressing excitatory synaptic transmission, potentiating inhibitory transmission, or a combination of these (3) in an drug-specific manner (22,23). To examine the basis of the decreased anesthetic sensitivities in vivo in Cav2.3-/- mice, we then focused on the excitatory synaptic transmission within the Schaffer collateral-CA1 synapses in hippocampal slices. Because of its well defined neuronal circuitry and synaptic physiology, the hippocampal slice preparation has been widely used in investigating the effects of anesthetics on synaptic transmission (24). Moreover, we have previously found intense expression of the Cav2.3 channel in the hippocampus in mice (16,25). However, we found no significant differences in the control fEPSPs and in the depression of fEPSPs by halothane between Cav2.3-/- and Cav2.3+/+ mice, suggesting that deletion of the Cav2.3 channel did not affect the basal excitatory synaptic transmission and the depressing action of halothane on the excitatory synapses. Consistent with a previous report (26), propofol hardly depressed fEPSPs, even with the larger concentration than expected to be clinically relevant.
In the hippocampal CA1 neuronal circuit, monosynaptic Schaffer collateral-CA1 excitatory transmission elicits action potential generation in the CA1 pyramidal neurons, which is modulated by GABAergic interneurons. Previous studies have shown PS recordings from the somatic layer of the CA1 pyramidal neurons to be useful in examining the effects of various anesthetics on both inhibitory and excitatory pathways (22,26,27). In particular, by application of appropriate interpulse intervals of the paired-pulse stimulation, IV anesthetics such as propofol have markedly inhibited PS2 via potentiation of recurrent feed-forward inhibition elicited by the first paired pulse (22,26). This depression of PS2 is antagonized by several GABAA receptor antagonists (22,26). In this study, 10–30 µM propofol depressed PS2, which was almost completely antagonized by bicuculline, and the depression of PS2 at 30 µM was significantly smaller in Cav2.3-/- mice than in Cav2.3+/+ mice. These findings indicate that the potentiating effect of propofol on the inhibitory neuronal activities in the hippocampal CA1 was blunted by the deletion of the Cav2.3 channel.
We evaluated the depressing effect of halothane on PSs by PS1 because it did not depress PS2 as much as PS1, most likely because of the influence of paired-pulse facilitation (27). Halothane depressed PSs more in Cav2.3-/- mice in the presence of bicuculline, indicating that the depression of excitatory neuronal activities by halothane was accelerated in the neuronal circuitry lacking the Cav2.3 channel. Although we have previously reported the intimate link between the Cav2.3 channel and inhibitory neuronal function in a model of ischemic neuronal injury by using a hippocampal slice preparation (25), this channel also participates in excitatory neuronal activities in the hippocampus. Notably, although halothane similarly depressed fEPSPs recorded from the dendritic layer in both genotypes of mice, it depressed PSs recorded from the somatic layer more in Cav2.3-/- mice. Thus, the deletion of the Cav2.3 channel likely affected sensitivity to halothane in the process of generating action potentials in postsynaptic neurons, but not in that of presynaptic glutamate release.
How do our electrophysiological findings in vitro correlate with the decreased behavioral sensitivities to propofol and halothane? Because propofol is believed to exert its anesthetic action mainly through activation of the inhibitory transmission (22,28), the decreased potentiating effect of propofol on the inhibitory pathway in the hippocampal CA1 possibly accounts for the decreased propofol-induced sleep time in Cav2.3-/- mice. A pharmacologically relevant free aqueous concentration of propofol was estimated to be 0.4 µM on the basis of the blood concentration in humans, a blood/plasma partition coefficient, and a rate of protein binding (2). However, concentrations that enhance GABAA receptors/Cl- currents in whole-cell recordings were reported to be larger than that (approximately 1–15 µM) (29–31). This inconsistency may be explained partly by the considerably larger concentration of propofol in the brain than in plasma or blood (32). Moreover, in previous studies using the acute slice preparation, concentrations that potentiated GABAergic transmission appeared to be even larger (varying from 7 to 5000 µM) (22,26,28). It may be expected that in slice preparations, the concentration of propofol within the slice tissue may decline in accordance with the distance from the surface because of its protein binding or other factors in the process of diffusing, and, thus, concentrations around the recording sites within the tissue can be smaller than those of the perfusate. Thus, the actual concentration of propofol around neurons where we recorded PSs while perfusing 10–30 µM propofol might be relevant to that achieved in the in vivo propofol administration.
In contrast, the increased depressing effect of halothane on the excitatory neuronal activities in vitro does not account for the increased MACRR for halothane in Cav2.3-/- mice. Although halothane is considered to exert its anesthetic action both through the potentiation of the inhibitory pathway and the depression of the excitatory pathway (22,33), we could not clearly delineate the potentiating effect of halothane on the inhibitory neuronal activities in the method we applied. It is noteworthy that, in our study, blockade of GABAergic inhibition by bicuculline clearly enhanced the differences between the genotypes to the statistically significant level in PS recordings (Fig. 4B; left versus right panel). This fact may imply that the effect of halothane on the depression of PSs via GABAergic transmission was smaller in Cav2.3-/- mice than in Cav2.3+/+ mice. If this is the case, in the knockout mice, the decreased sensitivity to halothane in the inhibitory pathway might overcome the increased sensitivity in the excitatory pathway in mediating the effect of this anesthetic on the righting reflex. In addition, although the hippocampus was shown to be an important anatomical site that correlates with anesthetic sensitivities assessed by the loss of the righting reflex (34), multiple sites in the CNS may also interact and mediate behavioral end-points of volatile anesthetics (34,35). Thus, halothane, like propofol, may exert its effect on the righting reflex essentially via its influence on the inhibitory pathway, despite the depression of excitatory neuronal activities observed at clinical concentrations in the hippocampus.
In summary, this study demonstrated that hypnotic sensitivities to propofol and halothane, assessed by the loss of the righting reflex, were significantly decreased in mice lacking the Cav2.3 channel. Our electrophysiological findings further indicate that deletion of this channel decreases the potentiating effect of propofol on inhibitory neuronal activities, whereas it augments the depressing effect of halothane on excitatory ones in the process of action potential firing. We suggest that the Cav2.3 channel is involved in both the inhibitory and excitatory neuronal activities on which propofol and halothane exert their actions, although their actions on the righting reflex may be mediated preferentially through the inhibitory pathway. This study also implies that drugs that have the property of blocking the R-type Ca2+ current potentially counteract anesthetics that mediate hypnotic action mainly through the inhibitory pathway. Further studies focusing on the role of other neuronal VDCCs in general anesthesia would clarify the specific role of each channel in mediating anesthetic actions in the CNS.
|
Acknowledgments |
|---|
The authors thank Mutsumi Kondoh and Masae Tamura (Department of Pharmacology and Neurobiology, Tokyo Medical and Dental University) for technical assistance, Drs. Kuninori Yokoyama (Department of Anesthesiology) and Makoto Osanai (Department of Pharmacology and Neurobiology) for technical advice, and Dr. Francis Chee (Department of Pharmacology and Neurobiology) for critically reading the manuscript.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci 1999; 55: 1278–303.[Web of Science][Medline]
- Franks NP, Lieb WR. Molecular and cellular mechanisms of general anaesthesia. Nature 1994; 367: 607–14.[Medline]
- Pocock G, Richards CD. Excitatory and inhibitory synaptic mechanisms in anaesthesia. Br J Anaesth 1993; 71: 134–47.
[Free Full Text] - Lakhlani PP, MacMillan LB, Guo TZ, et al. Substitution of a mutant alpha2a-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci U S A 1997; 94: 9950–5.
[Abstract/Free Full Text] - Quinlan JJ, Homanics GE, Firestone LL. Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology 1998; 88: 775–80.[Web of Science][Medline]
- Joo DT, Gong D, Sonner JM, et al. Blockade of AMPA receptors and volatile anesthetics: reduced anesthetic requirements in GluR2 null mutant mice for loss of the righting reflex and antinociception but not minimum alveolar concentration. Anesthesiology 2001; 94: 478–88.[Web of Science][Medline]
- Catterall WA. Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 2000; 16: 521–55.[Web of Science][Medline]
- Study RE. Isoflurane inhibits multiple voltage-gated calcium currents in hippocampal pyramidal neurons. Anesthesiology 1994; 81: 104–16.[Web of Science][Medline]
- Todorovic SM, Lingle CJ. Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents. J Neurophysiol 1998; 79: 240–52.
[Abstract/Free Full Text] - Kameyama K, Aono K, Kitamura K. Isoflurane inhibits neuronal Ca2+ channels through enhancement of current inactivation. Br J Anaesth 1999; 82: 402–11.
[Abstract/Free Full Text] - Kamatchi GL, Chan CK, Snutch T, et al. Volatile anesthetic inhibition of neuronal Ca channel currents expressed in Xenopus oocytes. Brain Res 1999; 831: 85–96.[Web of Science][Medline]
- Nakashima YM, Todorovic SM, Covey DF, Lingle CJ. The anesthetic steroid (+)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile blocks N-, Q-, and R-type, but not L- and P-type, high voltage-activated Ca2+ current in hippocampal and dorsal root ganglion neurons of the rat. Mol Pharmacol 1998; 54: 559–68.
[Abstract/Free Full Text] - Wu LG, Borst JG, Sakmann B. R-type Ca2+ currents evoke transmitter release at a rat central synapse. Proc Natl Acad Sci U S A 1998; 95: 4720–5.
[Abstract/Free Full Text] - Kavalali ET, Zhuo M, Bito H, Tsien RW. Dendritic Ca2+ channels characterized by recordings from isolated hippocampal dendritic segments. Neuron 1997; 18: 651–63.[Web of Science][Medline]
- Saegusa H, Kurihara T, Zong S, et al. Altered pain responses in mice lacking 1E subunit of the voltage-dependent Ca2+ channel. Proc Natl Acad Sci U S A 2000; 97: 6132–7.
[Abstract/Free Full Text] - Kubota M, Murakoshi T, Saegusa H, et al. Intact LTP and fear memory but impaired spatial memory in mice lacking Cav2.3 (IE) channel. Biochem Biophys Res Commun 2001; 282: 242–8.[Web of Science][Medline]
- Glen JB. Animal studies of the anaesthetic activity of ICI 35 868. Br J Anaesth 1980; 52: 731–42.
[Abstract/Free Full Text] - Quinlan JJ, Jin K, Gallaher EJ, et al. Halothane sensitivity in replicate mouse lines selected for diazepam sensitivity or resistance. Anesth Analg 1994; 79: 927–32.
[Abstract/Free Full Text] - Quasha AL, Eger EI II, Tinker JH. Determination and applications of MAC. Anesthesiology 1980; 53: 315–34.[Web of Science][Medline]
- Maze M, Mason DM Jr, Kates RE. Verapamil decreases MAC for halothane in dogs. Anesthesiology 1983; 59: 327–9.[Web of Science][Medline]
- Dolin SJ, Little HJ. Augmentation by calcium channel antagonists of general anaesthetic potency in mice. Br J Pharmacol 1986; 88: 909–14.[Web of Science][Medline]
- Wakasugi M, Hirota K, Roth SH, Ito Y. The effects of general anesthetics on excitatory and inhibitory synaptic transmission in area CA1 of the rat hippocampus in vitro. Anesth Analg 1999; 88: 676–80.
[Abstract/Free Full Text] - de Sousa SL, Dickinson R, Lieb WR, Franks NP. Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000; 92: 1055–66.[Web of Science][Medline]
- Kendig JJ, MacIver MB, Roth SH. Anesthetic actions in the hippocampal formation. Ann N Y Acad Sci 1991; 625: 37–53.[Web of Science][Medline]
- Toriyama H, Wang L, Saegusa H, et al. Role of Cav2.3 (1E) Ca2+ channel in ischemic neuronal injury. Neuroreport 2002; 13: 261–5.[Web of Science][Medline]
- Albertson TE, Walby WF, Stark LG, Joy RM. The effect of propofol on CA1 pyramidal cell excitability and GABAA-mediated inhibition in the rat hippocampal slice. Life Sci 1996; 58: 2397–407.[Web of Science][Medline]
- Maclver MB, Mikulec AA, Amagasu SM, Monroe FA. Volatile anesthetics depress glutamate transmission via presynaptic actions. Anesthesiology 1996; 85: 823–34.[Web of Science][Medline]
- Collins GG. Effects of the anaesthetic 2,6-diisopropylphenol on synaptic transmission in the rat olfactory cortex slice. Br J Pharmacol 1988; 95: 939–49.[Web of Science][Medline]
- Hales TG, Lambert JJ. The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones. Br J Pharmacol 1991; 104: 619–28.[Web of Science][Medline]
- Orser BA, Wang LY, Pennefather PS, MacDonald JF. Propofol modulates activation and desensitization of GABAA receptors in cultured murine hippocampal neurons. J Neurosci 1994; 14: 7747–60.[Abstract]
- Krasowski MD, O’Shea SM, Rick CE, et al. Alpha subunit isoform influences GABA(A) receptor modulation by propofol. Neuropharmacology 1997; 36: 941–9.[Web of Science][Medline]
- Shyr MH, Tsai TH, Tan PP, et al. Concentration and regional distribution of propofol in brain and spinal cord during propofol anesthesia in the rat. Neurosci Lett 1995; 184: 212–5.[Web of Science][Medline]
- Wakamori M, Ikemoto Y, Akaike N. Effects of two volatile anesthetics and a volatile convulsant on the excitatory and inhibitory amino acid responses in dissociated CNS neurons of the rat. J Neurophysiol 1991; 66: 2014–21.
[Abstract/Free Full Text] - Ma J, Shen B, Stewart LS, et al. The septohippocampal system participates in general anesthesia. J Neurosci 2002; 22: RC200.
[Abstract/Free Full Text] - Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993; 79: 1244–9.[Web of Science][Medline]
This article has been cited by other articles:
|
|
 |
|
  S.-W. Ying and P. A. Goldstein Propofol-Block of SK Channels in Reticular Thalamic Neurons Enhances GABAergic Inhibition in Relay Neurons J Neurophysiol, April 1, 2005; 93(4): 1935 - 1948. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Nagele, L. B. Metz, and C. M. Crowder Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans PNAS, June 8, 2004; 101(23): 8791 - 8796. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
