Sodium Channels As Targets for Volatile Anesthetics

View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 30 March 2012 provided by PubMed Central doi: 10.3389/fphar.2012.00050 Sodium channels as targets for volatile anesthetics

Karl F. Herold 1 and Hugh C. Hemmings Jr.1,2*

1 Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA 2 Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA

Edited by: The molecular mechanisms of modern inhaled anesthetics are still poorly understood Mohamed Chahine, Laval University, although they are widely used in clinical settings. Considerable evidence supports effects Canada on membrane proteins including ligand- and voltage-gated ion channels of excitable cells. Reviewed by: + Xander H. T.Wehrens, Baylor College Na channels are crucial to action potential initiation and propagation, and represent poten- of Medicine, USA tial targets for volatile anesthetic effects on central nervous system depression. Inhibition Clemens Möller, of presynaptic Na+ channels leads to reduced neurotransmitter release at the synapse Albstadt-Sigmaringen University, and could therefore contribute to the mechanisms by which volatile anesthetics produce Germany their characteristic end points: amnesia, unconsciousness, and immobility. Early studies *Correspondence: + Hugh C. Hemmings Jr., Departments on crayﬁsh and squid giant axon showed inhibition of Na currents by volatile anesthetics of Anesthesiology and Pharmacology, at high concentrations. Subsequent studies using native neuronal preparations and het- Weill Cornell Medical College, Box-50, erologous expression systems with various mammalian Na+ channel isoforms implicated LC-203, 1300 York Avenue, New York, inhibition of presynaptic Na+ channels in anesthetic actions at clinical concentrations. NY 10065, USA. + e-mail: [email protected] Volatile anesthetics reduce peak Na current (INa) and shift the voltage of half-maximal steady-state inactivation (h∞) toward more negative potentials, thus stabilizing the fast- inactivated state. Furthermore recovery from fast-inactivation is slowed, together with enhanced use-dependent block during pulse train protocols. These effects can depress presynaptic excitability, depolarization and Ca2+ entry, and ultimately reduce transmitter release. This reduction in transmitter release is more potent for glutamatergic compared to GABAergic terminals. Involvement of Na+ channel inhibition in mediating the immobility caused by volatile anesthetics has been demonstrated in animal studies, in which intrathecal infusion of the Na+ channel blocker tetrodotoxin increases volatile anesthetic potency, whereas infusion of the Na+ channels agonist veratridine reduces anesthetic potency. These studies indicate that inhibition of presynaptic Na+ channels by volatile anesthetics is involved in mediating some of their effects.

Keywords: sodium channels, volatile anesthetics, presynaptic, anesthetic mechanism

BACKGROUND biochemical level (Franks and Lieb, 1994). Animal studies showed It has been over 160 years since the use of diethyl ether as a general that volatile anesthetics produce their immobilizing effects pri- anesthetic was publicly demonstrated, yet our mechanistic under- marily by actions on the spinal cord (Antognini and Schwartz, standing of these vitally important drugs lags far behind that of 1993; Rampil et al., 1993), whereas unconsciousness and amnesia most other major drug classes. Most modern inhaled anesthetics involve actions at supra-spinal centers (Eger et al., 2008). Mem- are derivatives of ether, and over the years have been developed to brane proteins including ion channels have been implicated as have improved pharmacokinetics, but they are still plagued by a key mediators of the depressive effects of anesthetics on neuronal lack of specificity with significant cardiovascular and respiratory function. Many potential targets have been identified, and it has side effects. It remains unclear how these drugs produce general become clear that anesthetics act at multiple distinct targets in the anesthesia, a pharmacologically induced coma characterized by central nervous system to produce the various component effects amnesia, unconsciousness, and immobility in response to painful of the anesthetic state (multi-site hypothesis). stimuli (Hemmings et al., 2005b). Studies into their molecular mechanisms in the 1960s, which have their origins in the Meyer– MECHANISMS OF GENERAL ANESTHETIC EFFECTS ON THE Overton correlation of anesthetic potency with lipophilicity from CENTRAL NERVOUS SYSTEM 1900, led to a lipid-based theory involving a unitary mechanism The idea of general anesthetics acting both on excitatory and of non-specific actions on the lipid bilayer (Meyer, 1899; Overton, inhibitory synaptic transmission has lead to many studies point- 1901). ing out the complexity of anesthetic mechanisms (Rudolph and With technical advances in biochemistry and biophysics, spe- Antkowiak, 2004; Hemmings et al., 2005b; Franks, 2006). Gen- cific targets were studied and identified. Pioneering studies showed eral anesthetics, including both volatile and intravenous anesthet- that anesthetic interactions with proteins themselves,not necessar- ics, enhance synaptic inhibition via postsynaptic γ-aminobutyric ily involving lipid interactions, could explain anesthetic effects at a acid type A (GABAA) receptor modulation (Nicoll et al., 1975;

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Zimmerman et al., 1994). More recent studies also point out the importance of extrasynaptic GABAA receptors as a target of anesthetics by potentiating tonic inhibitory currents (Orser, 2006; Rau et al., 2009) and by enhancing the release of GABA by a presynaptic increase in miniature inhibitory postsynaptic current (mIPSC) frequency (Nishikawa and MacIver, 2001). Depression of excitatory transmission by presynaptic effects is another target of anesthetic action (Perouansky et al., 1995; Maclver et al., 1996; Ouanonou et al., 1999; Wakasugi et al., 1999). Both volatile and intravenous anesthetics reduce excitatory postsynaptic potentials (EPSPs) in neurons, an effect most likely due to presynaptic mechanisms (Weakly, 1969; Richards and White, 1975; Kullmann et al., 1989; Berg-Johnsen and Langmoen, 1992). Recent evidence suggests that inhibition of glutamatergic synaptic transmission through N -methyl-d-aspartate (NMDA)-type glutamate receptor blockade by inhaled anesthetics might also contribute to depres- FIGURE1|Schematic of the effects of anesthetics on cell membrane sion of excitatory transmission (Dickinson et al., 2007; Haseneder and Na+ channels. In the absence of the drug. (A) Na+ channels initiate et al., 2008). and propagate electrical signals, i.e., action potentials. (B) The anesthetic + It is now evident that ligand-gated ion channels are major tar- was believed to affect Na channels by partitioning and interacting with the membrane. This process called lipid fluidification altered the cell membrane gets for general anesthetics (Franks and Lieb, 1994). Both inhibi- and subsequently distorted the channel protein leading to block of channel tion of excitatory NMDA receptors and potentiation of inhibitory function (Seeman, 1974). GABAA and glycine receptors have come under scrutiny as important targets for both intravenous and inhaled anesthetic effects on synaptic transmission (Franks, 2006). These receptors are found anesthetics on Na+ and K+ currents in the crayfish or squid giant + throughout the central nervous system and are major transducers axon showed inhibition of peak Na (I Na) current and effects on of excitatory and inhibitory neurotransmitter signaling. channel recovery, but in these preparations inhibition occurred Second-messenger regulated protein phosphorylation of Na+ at relatively high concentrations (Bean et al., 1981; Haydon and channels has been implicated as another possible target of volatile Simon, 1988). Subsequent studies examined the effects of various anesthetics. Halothane increases both purified (Hemmings and volatile anesthetics on mammalian brain derived Na+ channels Adamo, 1994) and endogenous (Hemmings and Adamo, 1996) heterologously expressed in mammalian cell lines (Rehberg et al., + brain protein kinase C (PKC) activity. Phosphorylation of Na 1996). Inhibition of peak I Na due to stabilization of the inac- channels by PKC and PKA reduces Na+ channel activity by altering tivated state of Na+ channels was evident as a hyperpolarizing channel kinetics, for example by slowing inactivation, and is there- “left-shift”in steady-state (or h∞) inactivation. These experiments fore an important component of neuromodulation (Cantrell and were among the first to demonstrate inhibition of neuronal Na+ Catterall, 2001). It is possible that some of the inhibitory effects of channels by volatile anesthetics. The sensitivity of Na+ channels to volatile anesthetics on Na+ channel activity are mediated through clinically relevant concentrations of volatile anesthetics was con- PKC phosphorylation. firmed in various in vitro expression systems and was subsequently More recent studies have extended the range of likely anes- extended to more physiologically relevant neuronal preparations. thetic targets to include neuronal nicotinic acetylcholine receptors Electrophysiological recordings performed in isolated rat neu- + (Flood et al., 1997), two pore domain K2P channels and K leak rohypophysial nerve terminals, an experimentally accessible nerve channels (Patel and Honore, 2001; Sirois et al., 2002), and presy- terminal preparation, showed that clinically relevant concentra- + + naptic voltage-gated Na channels. This review considers Na tions of isoflurane inhibited peak I Na in nerve terminals in a channels as targets for the effects of volatile anesthetics (inhaled concentration- and voltage-dependent manner (Ouyang et al., alkane and ether derivatives). 2003; Figure 2A, upper panel). Similar to heterologous expression systems, a left-shift in the voltage-dependence of steady-state PRESYNAPTIC Na+ CHANNELS AS ANESTHETIC TARGETS inactivation demonstrated stabilization of the fast-inactivated Na+ channels play a crucial role in cell-to-cell communication, as state. These results support the hypothesis that volatile anesthet- they are involved in initiating and propagating action potentials ics depress excitatory synaptic transmission by inhibiting presy- in excitable cells throughout the nervous system (Hodgkin and naptic voltage-gated Na+ channels. In addition, in the rat neu- Huxley, 1952). Early reports in the 1970s associated the effects of rohypophysial nerve terminal preparation, isoflurane inhibited volatile anesthetics on lipid bilayer properties to alterations of cer- action potential amplitude and increased action potential half- tain membrane bound ion channels, in particular voltage-gated width (Ouyang and Hemmings, 2005; Figure 2A, lower panel). Na+ channels (Figure 1). The underlying current mediating the fast and rising depolarizing These reports were among the first to hypothesize a specific ion phase of the action potential is carried by tetrodotoxin (TTX)- channel (Na+ channels) as a potential target of volatile anesthetics, sensitive Na+ channels, which were inhibited by isoflurane using a though at that time no specific binding site or specific mecha- voltage-stimulus based on an averaged action potential. The effects nism could be identified. Early studies on the effects of general of non-immobilizers (structurally similar compounds without

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anesthetic properties) in rat dorsal root ganglion neurons showed of nociceptive sensory neurons are the (main) origin of neuro- that compound F3, an anesthetic fluorinated cyclobutane, inhib- pathic and inflammatory pain signals (Dib-Hajj et al., 2010), but ited Na+ channels similar to the effects of conventional volatile the pro- or anti-nociceptive effects of volatile anesthetics are not anesthetics,but the non-anesthetic (non-immobilizer) fluorinated clearly defined. It is evident that these nociceptive neurons carry cyclobutane F6 had only minimal effects (Ratnakumari et al.,2000; a distinct selection of Na+ channel subtypes related to pain sig- + Figure 4A). These findings support the role of Na channels as naling (e.g., Nav1.7, Nav1.8, Nav1.9; see review Dib-Hajj et al., molecular targets for volatile anesthetic action. 2010). Subsequently, Nav1.8 expressed in mammalian neuronal Studies investigating subtype-specific effects of volatile anes- cells revealed concentration- and voltage-dependent inhibition of thetics revealed small, but potentially significant, differences in Nav1.8 by clinically relevant concentrations of isoflurane similar isoflurane potency with IC50 values ranging from 0.45 to 0.7 mM to other subtypes (Herold et al., 2009; Figure 3A, upper panel). (at V h −70 mV) on Nav1.2, Nav1.4, Nav1.5 expressed in Chinese This demonstrates the importance of choosing a suitable expres- hamster ovary cells (Ouyang and Hemmings, 2007). Despite the sion system for pharmacological studies of ion channels. In this small potency differences, there were differences between isoforms case the neuronal cell line ND7/23, a hybrid cell line between in recovery from fast-inactivation tested by a double-pulse pro- rat dorsal root ganglion neurons and mouse neuroblastoma cells, tocol. The effect of isoflurane on channel recovery was greatest may have provided auxiliary β-subunits or other neuron-specific in Nav1.2, a major brain isoform (Figure 2B). Another study in signaling pathways that are important for inhibition by anesthet- which subtypes Nav1.2, Nav1.4, Nav1.6, and TTX-resistant Nav1.8 ics. A comparative study showing the effects of several different were expressed (with and without β1 subunit co-expression) in volatile anesthetics on heterologously expressed Na+ channels in Xenopus oocytes also revealed that Nav1.2, Nav1.4, Nav1.6 were mammalian cells revealed that desflurane, a highly fluorinated sensitive to isoflurane, whereas the TTX-resistant subtype Nav1.8, inhaled anesthetic, had the strongest effect on peak I Na inhibi- which is highly expressed in dorsal root ganglion nociceptive neu- tion, but all agents in this class were effective at clinically relevant rons, was insensitive (Shiraishi and Harris, 2004). Nerve terminals concentrations (Ouyang et al., 2009; Figure 3B). In contrast, the

FIGURE 2 | Volatile anesthetics inhibit Na+ channels in various heterologously expressed in mammalian cells. Recovery was assessed using expression systems. [(A), upper panel] Electrophysiological recordings of a two-pulse protocol with a 30-ms conditioning pulse followed by a variable isolated rat neurohypophysial nerve terminals show a reversible block of Na+ recovery interval of up to 30 ms, and then a 5-ms test pulse to peak activation currents and [(A), lower panel] action potentials evoked by small current voltages. The time course of channel recovery from fast-inactivation was well injections at clinically relevant concentrations of isoﬂurane (Ouyang et al., ﬁtted by a monoexponential function [(B), left panels]. Representative current

2003; Ouyang and Hemmings, 2005). (B) Effects of isoﬂurane on channel traces for a holding potential (V h)of−100 mV are shown for all three subtypes recovery from fast-inactivation of three different Na+ channel isoforms [(B), right panels; Ouyang and Hemmings, 2007].

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FIGURE 3 | [(A), upper panel] Concentration-dependent inhibition of Isoﬂurane signiﬁcantly inhibited I Na from a V h of either −80 or −100 mV

tetrodotoxin-resistant (TTX-r) Nav1.8 by isoﬂurane. Current traces of (Ouyang et al., 2007). (B) Inhibition of Nav1.4 by equipotent

TTX-r Nav1.8 are shown in the absence or presence of two isoﬂurane concentrations of various inhaled anesthetics. Peak I Na were recorded

concentrations. Normalized peak I Na values for TTX-r Nav1.8 were ﬁtted from a holding potential of –80 mV by 25-ms test steps as shown in the

to the Hill equation to yield IC50 values and Hill slopes (Herold et al., inset. The effects of clinically equipotent concentrations of halothane, 2009). [(A), lower panel] Effects of isoflurane on NaChBac expressed in isoflurane, sevoflurane, enflurane, and desflurane are shown in these

HEK293 cells. Families of current traces are shown at two different representative traces. Desﬂurane had the greatest effect of peak I Na

holding potentials (V h) in the absence or presence of isoflurane. reduction. intravenous anesthetic propofol inhibits Na+ channels only at of the differential effects of these structurally different compounds supratherapeutic concentrations (Rehberg and Duch, 1999). has yet to be elucidated. Differences also exist in the potency of The prototypical halogenated ether isoflurane also inhibits volatile anesthetic inhibition of specific Na+ channel subtypes the prokaryotic voltage-gated Na+ channel of Bacillus halodurans (Ouyang et al., 2009), but again the mechanisms for these dif- (NaChBac; Ouyang et al., 2007; Figure 3A, lower panel). This was ferences have to be studied in more detail. Such differences might the first prokaryotic channel shown to be inhibited by an anes- underlie region-specific presynaptic effects of volatile anesthetics thetic, and demonstrates impressive evolutionary conservation of on neurotransmitter release (Westphalen et al., 2010, 2011). the mechanism responsible for this pharmacological effect.As with + mammalian channels, inhibition of peak I Na was concentration- Na CHANNEL INHIBITION LEADS TO INHIBITION OF and voltage-dependent, and was associated with a positive shift NEUROTRANSMITTER RELEASE BY ANESTHETICS in the voltage-dependence of activation and a negative shift in the A physiological consequence of presynaptic Na+ channel inhibi- voltage-dependence of steady-state fast-inactivation. Furthermore tion is depression of presynaptic action potential generation and use-dependent block occurred due to slowed recovery from inac- conduction. Considerable evidence indicates that volatile anes- tivation. Despite the evolutionary difference between prokaryotic thetics inhibit neurotransmitter release, and that this is due in and eukaryotic voltage-gated Na+ channels, the mechanisms by part to inhibition of presynaptic Na+ channels. Volatile anesthet- which volatile anesthetics act on the channel seem remarkably ics preferentially inhibit 4-aminopyridine (4AP)-evoked release similar. of glutamate compared to GABA from isolated rat cortical nerve Aromatic compounds such as fluorobenzene, hexafluoroben- terminals (Westphalen and Hemmings, 2006). Action potential- zene, and 1,2-difluorobenzene have been shown to inhibit Nav1.2a evoked depolarization and release can be pharmacologically mim- + + expressed in Xenopus oocytes. Inhibition of peak I Na as well icked by 4AP, a K channel blocker, while Na channel indepen- as a shift in the V1/2 of fast-inactivation occurs in an agent- dent release can be elicited by depolarization with elevated extra- dependent manner (Horishita et al., 2008). The exact mechanism cellular K+ (Tibbs et al., 1989). Using this approach, 4AP-evoked

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FIGURE 4 | Volatile anesthetics inhibit neurotransmitter release in Isoflurane inhibition of 4AP-evoked glutamate release from rat cortical nerve terminals. (A) Effects of the anesthetic compound F3 and the nerve terminals in the absence or presence of tetrodotoxin (TTX, 1 μM). non-immobilizer F6 on 4-aminopyridine- (4AP) evoked glutamate release The potency of isoflurane inhibition is much greater in the absence of the from cortical synaptosomes. The anesthetic cyclobutane F3 significantly Na+ channel blocker TTX indicating a strong involvement of Na+ channels inhibits glutamate release, whereas the non-anesthetic (non-immobilizer) in inhibition of neurotransmitter release by volatile anesthetics cyclobutane F6 shown no inhibitory effect (Ratnakumari et al., 2000). (B) (Westphalen et al., 2011). release is significantly more sensitive to inhibition by volatile anes- as immobilizers (Xing et al., 2003; Zhang et al., 2007). The role of thetics as compared to KCl-evoked release, supporting a role for Na+ channels in volatile anesthetic-mediated immobility is fur- blockade of presynaptic Na+ channels in the inhibitory effects of ther supported by the observation that intrathecal infusion of the the anesthetics (Schlame and Hemmings, 1995; Westphalen and Na+ channel activator veratridine, a plant neurotoxin that binds Hemmings, 2003). Interestingly, inhibition of glutamate release to site 2 and stabilizes the open state (Ulbricht, 1998), reduces occurs with about 50% greater potency than inhibition of GABA the potency of isoflurane (Zhang et al., 2008), while intrathecal release, consistent with pharmacologically relevant transmitter- infusion of TTX increases the potency of isoflurane, and reverses specific specializations in neurotransmitter release regulation, per- the effect of veratridine (Zhang et al., 2010). Taken together, these haps involving differential coupling to Na+ channels (Westphalen results indicate that inhibition of spinal voltage-gated Na+ chan- et al., 2010; Figure 4B). There is also evidence that volatile anes- nels by inhaled anesthetics is likely an important mechanism in thetics inhibit neurotransmitter release in a brain region-specific anesthetic immobility. manner (Westphalen et al., 2011), which suggests diversity in presynaptic Na+ channel subtype expression and/or coupling to NON-ANESTHETIC EFFECTS OF VOLATILE ANESTHETICS release (Westphalen et al., 2010). A major side effect of volatile anesthetics is cardiovascular depres- Further experiments have examined the effects of volatile anes- sion. Multiple ion channel types expressed in cardiomyocytes thetics on synaptic vesicle exocytosis, detected using fluorescence contribute to action potential conduction and myocardial contrac- imaging, in cultured rat hippocampal neurons. This preparation tility. Inhibition of L-type Ca2+ currents or voltage-gated transient allows electrical stimulation of release, and showed concentration- and sustained outward K+ currents by volatile anesthetics can lead dependent and reversible inhibition of action potential-evoked to reduced contractility and delayed repolarization with mismatch exocytosis by isoflurane. Involvement of presynaptic Na+ chan- of action potential duration (Huneke et al., 2004). In cardiac Na+ nels is supported by the observation that exocytosis, evoked by channels (Nav1.5), volatile anesthetics at clinically relevant con- + depolarization with elevated extracellular K (which is insensitive centrations inhibit peak I Na and affect steady-state fast- as well to TTX), was relatively insensitive to isoflurane (Hemmings et al., as slow-inactivation (Stadnicka et al., 1999; Ouyang and Hem- 2005a). Isoflurane has also shown to inhibit excitatory postsynap- mings, 2007). This can, in combination with other cardiodepres- tic currents (EPSCs) in the rat calyx of Held due to inhibition sant drugs, slow conduction and lead to tachyarrhythmias. Na+ of neurotransmitter release caused by a reduction of presynap- channels have also been implicated as potential targets for neuro- tic action potential amplitude (Wu et al., 2004). These effects of protection by volatile anesthetics (Hemmings, 2004). The possible volatile anesthetics on synaptic transmission result primarily from role of voltage-gated Na+ channels and other beneficial and detri- inhibition of action potential-evoked synaptic vesicle exocytosis, mental side effects of volatile anesthetics in brain and other organs most likely as a result of Na+ channel blockade upstream of Ca2+ cannot be excluded. entry and exocytosis. In vivo studies on rodents have implicated spinal Na+ chan- CONCLUSION nels in immobilization, a major component of general anesthesia. Both electrophysiological and functional studies indicate that Intravenous infusion of lidocaine, a classical local anesthetic, or presynaptic voltage-gated Na+ channels are inhibited by clin- + intrathecal administration of riluzole,another potent Na channel ically used concentrations of volatile anesthetics. This leads to inhibitor, significantly increases the potency of volatile anesthetics reductions in evoked neurotransmitter release that is both brain

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region and neurotransmitter selective. The selective inhibition release and its inhibition by volatile anesthetics and other Na+ of glutamate release underlies a reduction in excitatory synaptic channel inhibitors. transmission with resultant nervous system depression. Detailed information regarding the presynaptic localization, function, and ACKNOWLEDGMENTS regulation of speciﬁc Na+ channel subtypes is currently lack- Supported by NIH grant GM58055 (Hugh C. Hemmings Jr.) and ing. Further studies are necessary to identify the roles of speciﬁc DFG (German Research Foundation) grant HE4551/5-1 (Karl F. presynaptic Na+ channel subtypes in mediating neurotransmitter Herold).

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Frontiers in Pharmacology | Pharmacology of Ion Channels and Channelopathies March 2012 | Volume 3 | Article 50 | 6 Herold and Hemmings Jr Sodium channels and volatile anesthetics

Schlame,M.,and Hemmings,H. (1995). Ulbricht, W. (1998). Effects of veratri- nerve terminal Na+ channel sub- minimum alveolar concentration in Inhibition by volatile anesthetics dine on sodium currents and fluxes. type expression and Na+ channel- rats. Anesth. Analg. 107, 875–878. of endogenous glutamate release Rev. Physiol. Biochem. Pharmacol. dependent glutamate and GABA Zimmerman, S. A., Jones, M. V., and from synaptosomes by a presynap- 133, 1–54. release in rat CNS. J. Neurochem. Harrison, N. L. (1994). Potentia- tic mechanism. Anesthesiology 82, Wakasugi, M., Hirota, K., Roth, S. 113, 1611–1620. tion of gamma-aminobutyric acid 1406–1416. H., and Ito, Y. (1999). The effects Wu, X., Sun, J., Evers, A., Crow- AreceptorCl− current correlates Seeman, P. (1974). The actions of general anesthetics on excitatory der, M., and Wu, L. (2004). with in vivo anesthetic potency. J. of nervous system drugs on and inhibitory synaptic transmis- Isoflurane inhibits transmitter Pharmacol. Exp. Ther. 270, 987–991. cell membranes. Hosp. Pract. 9, sion in area CA1 of the rat hip- release and the presynaptic action 93–101. pocampus in vitro. Anesth. Analg. 88, potential. Anesthesiology 100, Conflict of Interest Statement: The Shiraishi, M., and Harris, R. (2004). 676–680. 663–670. authors declare that the research was Effects of alcohols and anesthetics Weakly, J. N. (1969). Effect of barbi- Xing, Y., Zhang, Y., Stabernack, C. conducted in the absence of any com- on recombinant voltage-gated Na+ turates on “quantal” synaptic trans- R., Eger, E. I. II, and Gray, A. T. mercial or financial relationships that channels. J. Pharmacol. Exp. Ther. mission in spinal motoneurons. J. (2003). The use of the potassium could be construed as a potential con- 309, 987–994. Physiol. (Lond.) 204, 63–77. channel activator riluzole to test flict of interest. Sirois, J. E., Lynch, C. III, and Bayliss, D. Westphalen, R., and Hemmings, H. whether potassium channels medi- A. (2002). Convergent and recipro- (2003). Selective depression by gen- ate the capacity of isoflurane to pro- Received: 21 December 2011; paper pend- cal modulation of a leak K+ current eral anesthetics of glutamate versus duce immobility. Anesth. Analg. 97, ing published: 08 January 2012; accepted: and I(h) by an inhalational anaes- GABA release from isolated cortical 1020–1024. 07 March 2012; published online: 30 thetic and neurotransmitters in rat nerve terminals. J. Pharmacol. Exp. Zhang, Y., Guzinski, M., Eger, E. I., March 2012. brainstem motoneurones. J. Physiol. Ther. 304, 1188–1196. Laster, M. J., Sharma, M., Har- Citation: Herold KF and Hemmings HC (Lond.) 541, 717–729. Westphalen, R., and Hemmings, H. ris, R. A., and Hemmings, H. C. Jr (2012) Sodium channels as targets Stadnicka, A., Kwok, W. M., Hartmann, (2006). Volatile anesthetic effects on (2010). Bidirectional modulation for volatile anesthetics. Front. Pharmacol. H. A., and Bosnjak, Z. J. (1999). glutamate versus GABA release from of isoflurane potency by intrathe- 3:50. doi: 10.3389/fphar.2012.00050 Effects of halothane and isoflurane isolated rat cortical nerve terminals: cal tetrodotoxin and veratridine This article was submitted to Frontiers on fast and slow inactivation of 4-aminopyridine-evoked release. J. in rats. Br. J. Pharmacol. 159, in Pharmacology of Ion Channels and human heart hH1a sodium chan- Pharmacol. Exp. Ther. 316, 216–223. 872–878. Channelopathies, a specialty of Frontiers nels. Anesthesiology 90, 1671–1683. Westphalen, R. I., Kwak, N. B., Daniels, Zhang, Y., Laster, M. J., Eger, E. in Pharmacology. Tibbs, G. R., Barrie, A. P.,Van Mieghem, K., and Hemmings, H. C. Jr. (2011). I., Sharma, M., and Sonner, J. Copyright © 2012 Herold and Hem- F. J., Mcmahon, H. T., and Nicholls, Regional differences in the effects M. (2007). Lidocaine, MK-801, mings Jr. This is an open-access article D. G. (1989). Repetitive action of isoflurane on neurotransmit- and MAC. Anesth. Analg. 104, distributed under the terms of the Cre- potentials in isolated nerve terminals ter release. Neuropharmacology 61, 1098–1102. ative Commons Attribution Non Com- in the presence of 4-aminopyridine: 699–706. Zhang, Y., Sharma, M., Eger, E. I., mercial License, which permits non- effects on cytosolic free Ca2+ and Westphalen, R. I., Yu, J., Krivitski, M., Laster, M. J., Hemmings, H. C., commercial use, distribution, and repro- glutamate release. J. Neurochem. 53, Jih, T. Y., and Hemmings, H. C. and Harris, R. A. (2008). Intrathecal duction in other forums, provided the 1693–1699. Jr. (2010). Regional differences in veratridine administration increases original authors and source are credited.