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Departments of Anesthesiology (W.O., H.C.H.), Neurology and Neuroscience (G.W.), and Pharmacology (H.C.H.), Weill Medical College of Cornell University, New York, New York
Received February 26, 2003; accepted April 24, 2003
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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). Considerable evidence indicates that potentiation of
GABAA receptors is involved in the facilitation of inhibitory
transmission by anesthetics (Yamakura et
al., 2001). General anesthetics also modulate other members of the
ligand-gated ion channel superfamily, including neuronal nicotinic
acetylcholine receptors and N-methyl-D-aspartate-type
glutamate receptors (Yamakura et al.,
2001). General anesthetics also affect voltage-gated
Na+, K+, and Ca2+ channels
(Topf et al., 2003), cell
signaling mechanisms such as protein kinase C
(Hemmings, 1998) and G
protein-coupled receptor pathways (Ishizawa
et al., 2002), vesicular exocytotic mechanisms
(van Swinderen et al., 1999),
and transmitter uptake mechanisms (Shahani
et al., 2002). The contributions of these and possibly other
targets to the synaptic actions of general anesthetics have not been clearly
defined.
Mounting electrophysiological evidence indicates that general anesthetics
depress excitatory synaptic transmission by presynaptic mechanisms
(MacIver et al., 1996;
Kirson et al., 1998;
Perouansky and Hemmings,
2003). At the neurochemical level, volatile anesthetics and
propofol inhibit depolarization-evoked glutamate release from isolated rat
cortical nerve terminals (Schlame and
Hemmings, 1995; Lingamaneni et
al., 2001). To investigate the possible ion channel targets for
these presynaptic actions, we used isolated rat neurohypophysial (NHP) nerve
terminals as a system amenable to patch-clamp electrophysiological analysis.
Nerve terminals from supraoptic and periventricular magnocellular neurons
terminate in the neurohypophysis and contain large dense-core synaptic
vesicles filled with oxytocin or arginine vasopressin. These nerve terminals
are of sufficient size (5–16 µm in diameter) for patch-clamp analysis
(Lemos and Nordmann, 1986).
Previous studies indicate that NHP nerve terminals express voltage-gated
Na+, K+, and Ca2+ channels, which
are involved in the control of nerve terminal excitability and peptide release
(Lemos and Nowycky, 1989;
Bielefeldt et al., 1992;
Lindau et al., 1992;
Turner and Stuenkel, 1998;
Wang et al., 1999). We now
report that the widely used general anesthetics isoflurane and propofol at
clinically relevant concentrations inhibit voltage-gated Na+
channels in isolated NHP nerve terminals.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Nerve Terminal Preparation. Experimental protocols were approved by
the Institutional Animal Care and Use Committee of Weill Medical College of
Cornell University. NHP terminals were prepared as described previously
(Wang et al., 1999) with minor
modifications. Male Sprague-Dawley rats were anesthetized with 80%
CO2, 20% O2 and decapitated; this technique avoids
hypoxemia and exposure to clinically used anesthetic drugs (H. C. Hemmings,
Jr., unpublished observations). The neurohypophysis was separated from pars
anterior and pars intermedia of the pituitary, and gently homogenized in a
solution containing 270 mM sucrose, 10 mM HEPES-Tris, and 0.01 mM K-EGTA, pH
7.25, using a 0.5-ml Teflon/glass homogenizer. The NHP homogenate was pipetted
into a plastic Petri dish (35 x 10 mm) and allowed to settle for 5 to 8
min. The Petri dish with dissociated NHP nerve terminals was placed onto the
stage of an ECLIPSE TE300 inverted microscope (Nikon, Melville, NY) equipped
with interference contrast optics (Hoffmann, Melville, NY) and super-fused
(2–3 ml/min) with Locke's solution consisting of 145 mM NaCl, 5 mM KCl,
2.2 mM CaCl2, 1 mM MgCl2, 10 mM Na-HEPES, and 15 mM
D-glucose, pH 7.30. Each preparation contained many structures less
than 3 µm in diameter, as well as a small number of terminals with
diameters of 5 to 16 µm. Terminals were identified by their bright
refraction, smooth spherical shape, and absence of a nucleus. Isolated NHP
terminals were readily distinguished from pars intermedia cells, which are
larger and nucleated. In the present study, we selected terminals of 5- to
10-µm diameter because of their relative abundance and space clamp
characteristics for Na+ current recording.
Electrophysiological Recording. Recording pipettes (tip diameter
<1 µm) were made from borosilicate glass capillaries (Drummond
Scientific, Broomall, PA) using a micropipette puller (Sutter Instruments,
Novato, CA) and fire polished (Narishige Microforge, Kyoto, Japan). The
perforated patch-clamp technique (Wang et
al., 1999) was used to record Na+ currents at room
temperature (23–25°C). Terminals with access resistances of <10
M
were selected for study. Pipettes were filled with a solution
containing amphotericin B (240–300 µg/ml) in 145 mM Cs-glutamate, 2
mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 5 mM
D-glucose, and 10 mM tetraethylammonium chloride, pH 7.25.
Capacitance and 60 to 80% series resistance were compensated. Whole-terminal
currents were sampled at 10 kHz and filtered at 1 to 3 kHz using an Axon 200B
amplifier and pClamp 8 software (Axon Instruments, Inc., Burlingame, CA).
Locke's solution perfused the chamber at 0.10 to 0.15 ml/min. Anesthetics were
introduced from glass syringes and applied locally to attached terminals at
0.05 ml/min through a 0.15-mm-diameter perfusion pipette (30–40 µm
away from patched terminals) using an ALA-VM8 pressurized perfusion system
(ALA Scientific, Westbury, NY). Isoflurane and propofol were diluted into
Locke's solution from stock solutions (10–12 mM isoflurane in Locke's
solution, prepared 12–24 h before experiments; or 10 mM propofol in
dimethyl sulfoxide). Concentrations of isoflurane or propofol in the recording
chamber were determined by local sampling of the perfusate at the site of the
recording pipette tip and analysis by gas chromatography
(Ratnakumari and Hemmings
1998) or high-performance liquid chromatography
(Lingamaneni et al., 2001),
respectively.
Data Analysis. IC50 values were obtained by least-squares
fitting of data to the Hill equation: Y = 1/(1 + 10[(log
IC50 - X) x nH]), where
X is the concentration, Y is the response, and
nH is the Hill slope. Activation curves were fitted to a
Boltzmann equation of the form G/Gmax = 1/[1 +
e(V1/2 - V)/k], where
G/Gmax is the normalized fractional conductance, Gmax is
the maximum conductance, V1/2 is the voltage for
half-maximal activation, and k is the slope factor. Na+
conductance (GNa) was calculated using the equation GNa
= INa/(Vt - Vr), where
INa is the peak Na+ current, Vt is
the test potential, and Vr is the Na+ reversal
potential (ENa = 67 mV). Steady-state inactivation curves were
fitted to a Boltzmann equation of the form I/Imax = 1/(1 +
e(V1/2 - V)/k), where
I/Imax is the normalized current, Imax is the
maximum current, V1/2 is the voltage of half-maximal
inactivation, and k is the slope factor. Data for INa
recovery from inactivation were fitted to a single exponential rising function
of the form I/Imax = 1 - A e(-t/
), where
I/Imax is the normalized current, A is the amplitude,
is the time constant for INa recovery, and t is the
interpulse interval. Data were analyzed using pClamp 8 (Axon Instruments,
Inc.), Prism 3.02 (GraphPad Software Inc., San Diego, CA) and SigmaPlot 6.0
(SPSS Science, Chicago, IL). Data are expressed as mean ± S.E.M.
Statistical significance was assessed by ANOVA or paired or unpaired
t test, as appropriate; p < 0.05 was considered
statistically significant.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Voltage-activated Na+ currents were blocked completely by 0.5
µM tetrodotoxin (Fig. 1).
INa amplitudes evoked from a holding potential of -90 mV
(conventionally used to fully activate Na+ current) were larger
compared with a holding potential of -70 mV (closer to physiological resting
potential) because fewer channels are in the inactivated state at -90 mV
(Ruben et al., 1992). At a
holding potential of -90 mV, mean peak INa amplitude was -1370
± 380 pA (n = 57); at a holding potential of -70 mV, mean peak
INa amplitude was -1090 ± 210 pA (n = 39).
Anesthetic Effects on Peak INa. Isoflurane and propofol inhibited INa in a reversible and dose-dependent manner (Fig. 2). Onset of inhibition of INa by isoflurane or propofol was rapid (less than 1 min of application) and rapidly reversed upon washing (within 1 min) using focal pipette perfusion of the patched terminals (data not shown). In the presence of 0.4 or 0.8 mM isoflurane, peak INa amplitude was reduced to 58 ± 2% (p < 0.01) and 39 ± 4% (p < 0.01) of control, respectively. In the presence of 2 or 5 µM propofol, peak INa amplitude was reduced to 75 ± 3% (p < 0.05) and 56 ± 5% (p < 0.01) of control, respectively (Fig. 2B).
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From a holding potential of -90 mV, peak INa activation was
elicited at -10 mV (Fig. 3A).
Low concentrations of either anesthetic had minimal effects on the
current-voltage (I-V) relationship, other than reductions in peak
INa amplitude. At holding potentials of -70 or -90 mV,
IC50 values for peak INa inhibition by isoflurane were
0.45 and 0.56 mM (Fig. 3B) with
Hill slopes of 1.7 and 1.8, respectively. At holding potentials of -70 or -90
mV, IC50 values for propofol were 4.1 and 6.0 µM (p
< 0.01) with Hill slopes of 1.6 and 1.8, respectively. These results
indicate slightly more potent inhibition of INa at physiological
resting membrane potential. The effects of both drugs were well fitted by the
Hill equation with efficacies of 100% inhibition. Both anesthetics were
effective at concentrations observed during clinical anesthesia: the
EC50 for general anesthesia for isoflurane is 0.35 mM
(Taheri et al., 1991) and for
propofol is 2.2 µM (Tonner et al.,
1992).
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Anesthetic Effects on INa Activation and Inactivation. The effects of anesthetics on the voltage dependence of Na+ channel activation are shown in Fig. 4. Isoflurane (0.8 mM) did not significantly alter the V1/2 of activation of Na+ conductance from holding potentials of -70 or -90 mV, consistent with no shift in the I-V curve (Fig. 3A). At a holding potential of -70 mV, 5 µM propofol produced a slight positive shift in the activation curve (p < 0.05, n = 5; Table 1), consistent with the small shift in the I-V curve apparent from -90 mV at 10 µM propofol (Fig. 3A). Both anesthetics slightly increased the slope factor (k) at -70 mV, and propofol also increased the slope factor at -90 mV.
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Steady-state inactivation curves for INa in the absence or presence of anesthetics were determined with standard two-pulse protocols (Figs. 5 and 6). Isoflurane (0.8 mM) produced a negative shift in the voltage dependence of inactivation with no effect on the slope factor (Table 1). Propofol (5 µM) produced a negative shift in the voltage dependence of inactivation and increased the slope factor (Table 1). Although not statistically significant, isoflurane and propofol had greater effects on inactivation curves when using a short (30 ms) compared with a long prepulse protocol (Fig. 6; Table 1). These observations are consistent with drug binding to and stabilization of the inactivated state of Na+ channels.
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Anesthetic Effects on INa Recovery from Inactivation. The kinetics of INa recovery from the inactivated state are crucial in regulating NHP terminal excitability and repetitive firing, and hence neuropeptide release. Inactivation was investigated using a standard two-pulse protocol with varying interpulse intervals from holding potentials of -70 or -90 mV (Fig. 7). INa recovery from inactivation was fitted by a single exponential function. Recovery was slower from a holding potential of -70 mV and was further slowed by application of isoflurane or propofol (Fig. 7; Table 2). Propofol had a greater effect on recovery from inactivation from a holding potential of -70 mV compared with -90 mV, whereas isoflurane had similar effects at either potential (Table 2). The slower rate of recovery from inactivation in the presence of propofol suggests slower dissociation of propofol from inactivated channels compared with isoflurane.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The actions of isoflurane and propofol on INa varied with
holding potential. The V1/2 of activation was shifted
slightly in a positive direction by propofol at a holding potential of -70 mV
(by 
5 mV), but isoflurane had no significant effect on
V1/2 of activation. The V1/2 of
inactivation was consistently shifted in a negative direction by both
isoflurane (-8 mV for 800-ms prepulse protocol; -14 mV for 30-ms prepulse
protocol) and propofol (-11 mV for 800-ms prepulse protocol; -14 mV for 30-ms
prepulse protocol). Both anesthetics also delayed recovery from inactivation.
These results suggest that anesthetics exert distinct effects on
Na+ channel gating, which may involve multiple target sites on
Na+ channels and/or on their modulators. Inhibition of
Na+ currents by isoflurane is caused by enhanced channel
inactivation, whereas inhibition by propofol can be attributed primarily to
enhanced inactivation with some contribution of less effective activation
apparent at higher concentrations. The greater effects of isoflurane and
propofol on inactivation after a short prepulse (30 ms), which induces mainly
fast inactivation, suggest that these general anesthetics primarily affect
fast inactivation, as do the local anesthetics
(Ragsdale et al., 1994). The
marked effects of isoflurane and propofol on channel inactivation are
consistent with greater anesthetic affinity for the inactivated state of the
channel, analogous to the actions of local anesthetics and anticonvulsants
(Catterall, 2002). The slowed
rate of recovery from inactivation may reflect either slow anesthetic
dissociation from the inactivated or resting state or slowed conversion of
channels from the inactivated to resting states.
The interaction between a drug and its receptor involves a specific intermolecular interaction that yields a sigmoidal concentration-effect response curve with a Hill slope related to the stoichiometry of the interaction. Despite efforts to obtain satisfactory space-clamp conditions for Na+ current recording using the perforated-patch method, atypically steep activation of Na+ current was observed in some recordings. Such imperfect voltage control would tend to increase the steepness of the concentration-effect curves, which would lead to artificially high Hill slope values. This limitation makes it difficult to infer the stoichiometry of the interaction of general anesthetics with the Na+ channel from Hill slope values alone. Thermodynamic parameters of the binding equilibrium of general anesthetics to Na+ channels could provide more detailed information on binding interactions. For example, the temperature dependence of binding of anesthetics could be analyzed using van't Hoff plots made by comparing IC50 values at various temperatures. However, such experiments in this preparation are limited by the instability of isolated nerve terminals at temperatures above 25°C.
Voltage-gated Na+ channels are hetero-oligomers composed of
, 
1, and 2 subunits. At least nine
different Na+ channel subunit isoforms have been cloned and
identified in human and rat: Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are expressed
in the central nervous system; Nav1.7, Nav1.8, and Nav1.9 are expressed in the
peripheral nervous system; and Nav1.4 and Nav1.5 are expressed in skeletal and
cardiac muscle, respectively (Goldin,
2002). The subunit alone is sufficient to produce
functional channels (Catterall,
2002); it contains four homologous domains, each containing six
transmembrane segments. Local anesthetics bind to receptor sites in segment S6
of domains III (Catterall,
2002) and IV (Ragsdale et al.,
1994; Catterall,
2002). The intracellular loop between domains III and IV may
function as the inactivation gate to mediate fast inactivation. Transmembrane
segment S6 in domain I also contributes to the local anesthetic binding site
(Yarov-Yarovoy et al., 2002).
Our findings that general anesthetics shift the steady-state inactivation
curve toward more negative membrane potentials and slow recovery from
inactivation support an interaction with the inactivated state of the
Na+ channel similar to that of local anesthetics. Whether general
anesthetics also interact with segment S6 will require further
investigation.
A voltage sensor characterized by a series of positively charged amino
acids in segment S4 is critically involved in Na+ channel
activation (Catterall, 2002;
Goldin et al., 2002). The actions of isoflurane on the voltage dependence of
activation were unremarkable, and the small effect of propofol was evident
only at a holding potential of -70 mV. In a previous report, volatile
anesthetics shifted the voltage dependence of both activation and steady-state
inactivation of cardiac Na+ currents toward more hyperpolarized
potentials (Weigt et al.,
1997). This may represent a subtle difference in anesthetic
actions on neuronal (Nav1.2, Nav1.3, and Nav1.6) versus cardiac (Nav1.5)
voltage-gated Na+ channels.
In an influential review, Franks and Lieb
(1994) concluded that effects
of general anesthetics on voltage-gated ion channels occurred only at
concentrations irrelevant to clinical anesthesia. This conclusion was based
largely on studies conducted in molluscan axons
(Haydon and Urban, 1983) and
has not been supported by more recent studies of mammalian Na+
channels. Thus, isoflurane (IC50 = 0.85 mM at -120 mV holding
potential; Rehberg et al.,
1996) and propofol (IC50 = 25.4 µM at -120 mV
holding potential; Rehberg and Duch,
1999) inhibited cloned rat brain (type IIa) Na+ channel
subunits (Nav1.2) heterologously expressed in Chinese hamster ovary
cells; both anesthetics also shifted the voltage dependence of inactivation in
a negative direction and delayed recovery from inactivation. The
IC50 values for inhibition of peak INa by isoflurane and
propofol in NHP terminals reported here are lower than those reported for the
isolated Nav1.2 subunit. These differences suggest possible effects of
specific Na+ channel isoforms, post-translational modification,
and/or the presence of auxiliary subunits on Na+ channel
sensitivity to anesthetics. For example, subunit coexpression increases
local anesthetic sensitivity of heterologously expressed rat Nav1.2
subunits (Bonhaus et al.,
1996).
We previously reported indirect neurochemical evidence that volatile
anesthetics and propofol inhibit presynaptic Na+ channels and
Na+ channel-dependent glutamate release in isolated rat
cerebrocortical nerve terminals (Schlame
and Hemmings, 1995;
Ratnakumari et al., 2000;
Lingamaneni et al., 2001;
Westphalen and Hemmings,
2003). Volatile anesthetics also inhibit voltage-gated
Na+ currents in isolated rat dorsal root ganglion neurons
(Ratnakumari et al., 2000). We
now provide direct evidence that isoflurane and propofol block voltage-gated
Na+ channels in nerve terminals at concentrations achieved
clinically during general anesthesia. In a study of nerve terminals isolated
from rat cerebral cortex, potency of isoflurane for inhibition of
veratridine-evoked glutamate release (IC50 = 0.41–0.50 mM)
was comparable with that for inhibition of NHP Na+ channels,
whereas propofol was more potent in inhibiting NHP Na+ channels
than glutamate release (IC50 = 11–18 µM;
Lingamaneni et al., 2001).
This difference may be caused by effects of Na+ channel
modification by veratridine, the presence of different Na+ channel
isoforms in cerebral cortex, and/or effects of different modulator proteins or
signaling pathways on sensitivity to isoflurane versus propofol.
Voltage-gated Na+ channels are essential to the generation and
propagation of action potentials
(Catterall, 2002) and for nerve
terminal depolarization leading to activation of voltage-gated
Ca2+ channels, Ca2+ entry, and
Ca2+-dependent neurotransmitter release from nerve
terminals (Tibbs et al.,
1989). Depolarization results in Na+ influx and
increases in [Na+]i in neurohypophysial nerve terminals
(Turner and Stuenkel, 1998),
which is also an important factor in the control of NHP peptide secretion
(Toescu and Nordmann, 1991).
Increases in [Na+]i can elicit
Ca2+-independent vasopressin release from NHP nerve
terminals (Stuenkel and Nordmann,
1993); this may be an important alternative pathway to the
Ca2+-dependent vesicular release pathway coupled to
voltage-gated Ca2+ channel activation
(Lee et al., 1992;
Lindau et al., 1992).
Inhibition of voltage-gated Na+ channels is predicted to inhibit
transmitter release by both pathways. Ethanol has been shown to inhibit
peptide release and voltage-gated Ca2+ channels in
isolated rat NHP terminals (Wang et al.,
1991). Our evidence suggests that general anesthetics exert a
direct inhibitory effect on NHP terminal excitability and presumably peptide
release. Future studies will investigate the effects of anesthetics on
Ca2+-dependent versus
Ca2+-independent peptide release and the possible
involvement of voltage-gated Ca2+ channels.
Inhibition of synaptic transmission by general anesthetics
(Wakasugi et al., 1999) may
result from depressed action potential firing
(Antkowiak, 1999) or nerve
terminal excitability caused by inhibition of presynaptic Na+
channels. Although the Na+ channel subtype(s) present in NHP nerve
terminals has not been identified, native channels seem to be somewhat more
sensitive to anesthetics than heterologously expressed rat brain Nav1.2
subunits. Magnocellular neurons in the supraoptic nucleus, which send
axons to the neurohypophysis, express both Nav1.2 and Nav1.6 (-II and
-Na6) and I and II subunits
(Tanaka et al., 1999), which
suggests that these isoforms may also be the isoforms present in NHP nerve
terminals.
Postsynaptic ligand-gated ion channels such as GABAA receptors
and/or N-methyl-D-aspartate receptors participate in the
actions of most general anesthetics
(Yamakura et al., 2001). The
presynaptic effects of general anesthetics on neurotransmitter release are
gaining recognition for their role in the synaptic actions of general
anesthetics (Richards, 1998;
Perouansky and Hemmings,
2003). Our data support previous findings that general anesthetics
influence synaptic transmission via presynaptic mechanisms, specifically via
inhibition of presynaptic voltage-gated Na+ channels through
enhanced inactivation.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: NHP, neurohypophysial; ANOVA, analysis of variance; I-V, current-voltage.
Address correspondence to: Dr. Hugh C Hemmings, Jr., Department of Anesthesiology, Box 50, LC-203, 525 E. 68th St., Weill Medical College of Cornell University, New York, NY 10021. E-mail: hchemmi{at}med.cornell.edu
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