Skip Navigation LinksHome > July 2006 - Volume 105 - Issue 1 > Molecular Mechanisms Transducing the Anesthetic, Analgesic,...
Anesthesiology:
Review Article

Molecular Mechanisms Transducing the Anesthetic, Analgesic, and Organ-protective Actions of Xenon

Preckel, Benedikt M.D., D.E.A.A.*; Weber, Nina C. Ph.D.†; Sanders, Robert D. B.Sc., M.B., B.S.‡; Maze, Mervyn M.B., Ch.B., F.R.C.P., F.R.C.A., F.Med.Sci.§; Schlack, Wolfgang M.D., D.E.A.A.∥
Section Editor(s): Warltier, David C. M.D., Ph.D., Editor

Free Access
Article Outline
Collapse Box

Author Information

Collapse Box

Abstract

The anesthetic properties of xenon have been known for more than 50 yr, and the safety and efficacy of xenon inhalational anesthesia has been demonstrated in several recent clinical studies. In addition, xenon demonstrates many favorable pharmacodynamic and pharmacokinetic properties, which could be used in certain niche clinical settings such as cardiopulmonary bypass. This inert gas is capable of interacting with a variety of molecular targets, and some of them are also modulated in anesthesia-relevant brain regions. Besides these anesthetic and analgesic effects, xenon has been shown to exert substantial organoprotective properties, especially in the brain and the heart. Several experimental studies have demonstrated a reduction in cerebral and myocardial infarction after xenon application. Whether this translates to a clinical benefit must be determined because preservation of myocardial and cerebral function may outweigh the significant cost of xenon administration. Clinical trials to assess the impact of xenon in settings with a high probability of injury such as cardiopulmonary bypass and neonatal asphyxia should be designed and underpinned with investigation of the molecular targets that transduce these effects.
THE noble gas xenon has been known for more than 50 yr to have anesthetic properties1; however, its clinical utility has been limited by relatively high manufacturing costs owing to its rarity in the atmosphere.2 Recently, the safety and efficacy of xenon inhalational anesthesia has been demonstrated in a variety of clinical settings3,4; in particular, xenon possesses favorable pharmacokinetic,4,5 analgesic,6–8 cardiovascular,3,9,10 and safety properties.5,11 Despite these desirable attributes, which make it an attractive anesthetic agent,5 its high cost outweighs its routine use for general anesthesia.
Xenon is often referred to as inert because it is not transformed under biologic conditions; however, xenon is capable of interacting with a variety of molecular targets that may translate into desirable benefit for patients at risk of acute injury to the cardiovascular or nervous system or both.5,12 In this review, we summarize the current data that have led us to believe that xenon could be used in the future to protect the heart and brain both in surgical and nonsurgical settings.
Back to Top | Article Outline

Physical and Chemical Properties

Xenon is the 54th element in the Periodic Table of the Elements and exists as a monoatomic gas. In common with the other inert gases, its outer shell is completely filled with electrons. Therefore, xenon has a low propensity to receive or release electrons, making it unlikely to form covalent bonds. Only under extreme nonbiologic conditions can halides of xenon (e.g., XeF2, XeF4) be created. Xenon has a low ionization potential, allowing its electron shell to be polarized by surrounding molecules, thereby inducing a dipole that enables biologic interactions, including binding to proteins.13 Xenon can associate with amino acid side chains of the active site of enzymes like serine proteinases (including elastases and collagenases)14,15; these enzymes can form a specific binding cavity for one single xenon atom without inducing major changes in protein structure.14 It has been demonstrated that xenon binds within the heme cavity of cytochrome P-450 monooxygenases and is capable of inhibiting the catalytic activity of some enzymes in vitro.16
Back to Top | Article Outline

Putative Sites of Anesthetic Action

While several molecular targets in anesthesia-relevant brain regions are modulated by xenon, there is still no direct evidence to support one mechanism, although the role of glutamate receptors seems to be a pivotal one from recent studies involving Caenorhabditis elegans.17,18
Back to Top | Article Outline
Receptor Effects
Most general anesthetics act on one or more superfamilies of ligand-gated ion channels; e.g., the γ-aminobutyric acid type A (GABAA), glycine, 5-hydroxytryptamine type 3A, and neuronal nicotinic acetylcholine (nACh) receptors are targets for several general anesthetics, including barbiturates, propofol, benzodiazepines, and halogenated inhalational agents.19 Recent data has indicated that xenon induces anesthesia in a unique way by inhibiting excitatory glutamatergic signaling,18 although it remains unclear which subtype of glutamate-gated receptors is responsible for xenon's effects. This is certainly a feasible mechanism of anesthesia20,21 and also has potential to explain the difference in potency between halogenated agents and xenon. Which of the three subtypes of postsynaptic glutamate-gated ion channels (referred to by its most selective ligand, namely N-methyl-d-aspartate [NMDA], kainic acid, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] receptors) is the prime target is currently under debate. Recent data from an elegant series of experiments in C. elegans has shown that inhibition of non-NMDA receptors mediate the “anesthetic” effects of xenon. Using sophisticated pharmacogenomic techniques, Crowder et al. 18 demonstrated that mutation of the glr-1 glutamate receptor subunit (homolog of the AMPA subunit Glur1) reduced xenon's ability to induce “anesthesia.” Mutation of nmr-1 (which encodes the pore-forming subunit of the NMDA receptor in C. elegans) did not affect the behavioral effects induced by xenon. As pointed out by the authors, multiple caveats must be introduced when interpreting these effects; e.g., “anesthesia” in C. elegans is a change in behavioral phenotype that is not necessarily analogous to anesthesia in humans. Furthermore, there is a huge difference in genotype between humans and C. elegans. Nonetheless, the work supports the notion that xenon induces anesthesia by inhibiting glutamatergic signaling.
Xenon has been shown to noncompetitively block the NMDA subtype of the glutamate receptor in cultures of rat hippocampal neurons22; contrastingly, the fast component of the glutamate postsynaptic current that is mediated by the AMPA receptor was not affected.22,23 Xenon did inhibit the current generated when the artificial agonist kainate is directly applied to recombinant AMPA receptors24; however, when the receptor was activated by its natural agonist glutamate using an ultrarapid application system to outside-out membrane patches to mimic synaptic conditions, the sensitivity of this subtype to xenon was negligible. Weigt et al.25 recently demonstrated that xenon inhibits AMPA- and kainate-induced membrane currents in cultured cortical neurons when glutamate was applied to whole cells using a slower application time. However, it seems likely that, under conditions that mimic natural synapses in mammalian systems,23,24 non-NMDA receptors are insensitive to xenon. When NMDA receptors were expressed in Xenopus oocytes, xenon again inhibited NMDA receptor currents. The controversy will continue as to whether non-NMDA receptors are important targets for xenon; however, the current evidence firmly indicates that xenon inhibits NMDA receptor signaling, and this is regarded as the prime mechanism by which xenon induces anesthesia.
Xenon has little or no effect on the inhibitory GABAA receptors in cultured rat hippocampal neurons,22 which are quite sensitive to several other gaseous anesthetics.19 There was no effect of xenon on GABAergic inhibitory postsynaptic currents or on currents evoked by exogenous application of GABA in cultured neurons containing excitatory and inhibitory synapses.23 However, in recombinant GABA receptor complexes expressed in human embryonic kidney cells and Xenopus oocytes, xenon enhanced the inhibitory GABAergic transmission.26,27 In human homomeric glycine receptors, xenon potentiated the current response to applied glycine, suggesting a contribution to the prolongation of the inhibitory postsynaptic potential.28 However, because xenon exerts little effect on inhibitory neurotransmission in neuronal systems, there is currently little evidence to suggest that effects at GABA and glycine receptors contribute to the xenon anesthetic state.
The nACh receptors are found in presynaptic and postsynaptic locations within the central nervous system, acting by modulating transmitter release.29 Various combinations of subunits of the nACh receptor are known, and it has been shown that isoflurane and propofol inhibited the most prevalent neuronal subtype (α4)22)3 of the nACh receptor but had no effect on the (α7)5 nACh receptor subtype, even at high concentrations.30 In contrast, halothane inhibited both receptor subunits.29 Xenon inhibited (α4)22)3 nACh receptors expressed in Xenopus oocytes, whereas the α4β4 nACh receptor was only slightly affected.27 These data were extended by findings of Suzuki et al.,31 who demonstrated that xenon reversibly inhibited the ACh-induced currents in human homomeric (α7)5 nACh receptors in a concentration-dependent manner. This effect was noncompetitive and voltage independent.31 Despite the high sensitivity of nACh receptors to anesthetic agents, effects at this receptor are not thought to be critical for anesthesia.32 Xenon at clinical relevant concentrations competitively inhibited the 5-hydroxytryptamine type 3A receptor independently of the membrane potential.33 The clinical consequence of this effect is unknown.
The two-pore-domain potassium channel (so named because of two pore-forming consensus regions identified in their primary sequence) has been recently proposed as a target for general anesthesia.34–36 Some members of this superfamily, the TREK-1 and the TASK-3, are activated by halogenated anesthetics like halothane.37 Gruss et al. 34 demonstrated that xenon is as effective as halothane in activating TREK channels. However, in contrast to the potent halogenated anesthetic halothane, the gaseous anesthetic had no effect on TASK channels. Similar to halogenated anesthetics,38 xenon interacts with the cytoplasmic C-terminus of TREK channels, but this region is unlikely to contain primary binding sides for the atom.34 The amino acid Glu306 has been found to play a major role in modulation of TREK-1 by arachidonic acid and membrane stretch and may be important for the activating effects of xenon on these channels.34
Back to Top | Article Outline
Second Messenger Signaling
General anesthesia may result from interference at the synaptic level of Ca2+-dependent transmitter release; in addition, modulation of second messenger systems may alter postsynaptic neuronal responses to released neurotransmitter. Changes in neuronal Ca2+ homeostasis may alter neurotransmission in the brain and contribute to the production of the anesthetic state. In human endothelial cells, adenosine triphosphate induced a typical Ca2+ change comprising of internal Ca2+ release and an additional Ca2+-induced Ca2+ influx from the outside.39 In endothelial cells incubated with xenon, only the first part of the adenosine triphosphate–induced Ca2+ response was observed, and the Ca2+-dependent Ca2+ influx was absent. If xenon was removed, the cells again showed both parts of the Ca2+ response.39 These data indicate that xenon affects mechanisms regulating the Ca2+ release–activated Ca2+ channel of plasma membranes. The plasma membrane Ca2+–adenosine triphosphatase (PMCA) is one Ca2+ transport system found in neurons responsible for maintaining low cytosolic calcium concentrations.40 The PMCA activity is selectively inhibited by halogenated anesthetics at clinical concentrations.41 In rat brain synaptic plasma membranes, xenon inhibits PMCA pump activity, resulting in an increase in neuronal Ca2+ concentration and altered excitability in these cells.42 In C6 rat glioma cells, PMCA activity was inhibited by xenon in clinical relevant concentrations, and this effect was potentiated in the presence of halothane.43 The rate of phospholipid methylation in rat brain synaptosomal membranes is linked to the coupling of neuronal excitation to neurotransmitter release. Xenon increased phospholipid methylation and simultaneously depressed PMCA activity.44
The neurotransmitter nitric oxide may play a role in anesthetic action45; nitric oxide–dependent decrease in cyclic guanosine monophosphate occurs in halothane- and isoflurane-anesthetized rats in several brain areas. Contrastingly, xenon, like ketamine, increased cyclic guanosine monophosphate in the spinal cord, brainstem, and hippocampus,46 although neuronal nitric oxide synthase activity was not altered by xenon.46 Xenon exerts some effects on second messenger signaling; however, currently it is unclear how this causally relates to the production of anesthesia.
Back to Top | Article Outline
Neurotransmitter Release
The hypothalamus is a crucial homeostatic center in the brain, and the noradrenergic neuronal activity therein modulates physiologic states including consciousness and the cardiovascular system. The posterior hypothalamus is involved in the regulation of the autonomic nervous system, and an increase in norepinephrine concentration in the posterior hypothalamus increases sympathetic tone. In rats, xenon stimulates noradrenergic neurons in the hypothalamus more potently than does nitrous oxide, as measured by microdialysis in rats.47 This may be one mechanism contributing to the hypnotic and the sympathotonic effects of xenon.
In the rat cerebral cortex, xenon induced an initial increase in ACh release, followed by a gradual decrease, as measured by brain microdialysis in vivo.48 In addition, xenon had no effect on acetylcholinesterases measured in vitro.49 Currently, the relevance of xenon's effects on the cholinergic system to the mechanisms of anesthesia, amnesia, analgesia, and organoprotection are unknown and requires further study.
Back to Top | Article Outline

Putative Sites for Antinociception

The precise mechanism for the antinociceptive effect of xenon remains to be elucidated. In spinal cord–intact cats, xenon suppressed spinal cord dorsal horn neurons.50 Xenon directly inhibited the nociceptive responsiveness of spinal dorsal horn neurons in spinally transected cats51; therefore, unlike nitrous oxide, xenon's antinociceptive action does not require the involvement of the descending inhibitory system.52 In support of this, Ohara et al.53 reported that xenon exerted potent antinociceptive action in rats independently of opioidergic or adrenergic receptors. Rather, there seems to be a direct suppression of polysynaptic transmission within the dorsal horn as reflected by a diminution in the slow ventral root response to stimulation of the primary afferents by xenon.54 As a generic class, the NMDA receptor antagonists induce profound analgesia, and this may be the mechanism for xenon's analgesic properties. Consistent with this premise, xenon has been shown to reduce formalin-induced nociception and hyperalgesia at various ages, indicating an age-independent antinociceptive profile, unlike nitrous oxide, which is ineffective in the young.6,8 Xenon exerts potent antinociceptive action at the level of the spinal cord, but the above studies do not exclude contribution from supraspinal sites (in the intact animal); e.g., activation of the midbrain reticular network with xenon may indicate activation of the supraspinal antinociceptive system.55
Back to Top | Article Outline

Neuroprotection

N-methyl-d-aspartate receptors play a pivotal role in the propagation of acute neuronal injury56; hence, many have advocated the use of NMDA antagonists to interrupt the pathogenesis of acute neuronal injury. Xenon has been shown to be surprisingly potent as a neuroprotectant in a variety of in vitro and in vivo models. Crucially, xenon provides marked protection against injury well below anesthetic concentrations, with IC50 concentrations in some models as low as 10–20% of an atmosphere. Xenon decreases acute neuronal injury in response to both the exogenous administration of excitotoxins or through deprivation of oxygen and glucose in a neuronal–glial mouse coculture system.57 In vivo, xenon prevents the morphologic and functional consequences of acute neuronal injury provoked by ischemia (middle cerebral artery occlusion) in adult mice,58 cardiopulmonary bypass in adult rats,59 and excitotoxins in adult rats.57
Many NMDA receptor antagonists may reduce the neuronal damage after cerebral ischemia but concomitantly produce psychotomimetic side effects.60,61 These effects were observed after ketamine and nitrous oxide administration, but not after xenon.62 A reliable marker of neuronal toxicity is the c-Fos expression in distinct cerebral regions.63 Xenon, in contrast to nitrous oxide or ketamine, does not induce c-Fos expression in the retrosplenial and posterior cingulate nuclei in rats in vivo.62 It is also possible that the combined use of NMDA receptor antagonists may exacerbate neurotoxicity. Nagata et al.64 demonstrated that nitrous oxide alone produced a small amount of c-Fos expression but significantly enhanced ketamine-induced neurotoxicity. In contrast, xenon alone exhibited no neurotoxicity and concentration-dependently reduced the ketamine-induced c-Fos expression in rat posterior cingulate and retrosplenial cortices.64
Fig. 1
Fig. 1
Image Tools
Hypothermia is the only therapeutic intervention that has, so far, been shown to provide even a modicum of neuroprotection in the clinical setting65,66; therefore, we sought to determine the possible convergence of hypothermia and xenon on similar signaling pathways. When applied individually, both xenon and hypothermia reduced acute neuronal injury after oxygen–glucose deprivation. When applied together, the neuronal protection provided by the combination was significantly greater than could be expected from a simply additive interaction (fig. 1). Such a synergistic interaction with hypothermia may be a unique feature of xenon because it is not present with another NMDA receptor antagonist, gavestinel. A Van't Hoff analysis revealed that a surprisingly large increase in the enthalpy is associated with hypothermia-induced reduction in injury-induced lactate dehydrogenase release when xenon is present, which is considerably larger than could plausibly be attributed to the enthalpy of binding of xenon to its putative site(s) on the NMDA receptor, and that more complex mechanisms must be operating. Using an in vivo neonatal rat model of hypoxic–ischemic injury, the synergistic interaction of the two neuroprotectant interventions was confirmed using both morphologic and functional measures of outcome.67
Back to Top | Article Outline
Putative Mechanisms for Xenon's Neuroprotective Properties
Fig. 2
Fig. 2
Image Tools
Fig. 3
Fig. 3
Image Tools
Xenon exerts its neuroprotective effect through an antiapoptotic mechanism67 and did not produce apoptotic neurodegeneration in neonatal rats.68 Using flow cytometry of sorted cultured mouse neurons, xenon's neuroprotective action seems also to be mediated via antiapoptotic pathways (fig. 2). Brief (10-min) exposure of cortical neuronal cells in primary culture to glutamate resulted in a significant decrease in cell viability (23 ± 8%) when assessed 24 h later by fluorescent-activated cell sorting after staining with propidium iodide (for cell death) and annexin V (for apoptosis). Exposure to xenon doubled the number of viable cells, and this improvement exclusively resulted from a reduction in the amount of apoptosis (fig. 3). Necrotic cell death, on the other hand, was not reduced with xenon exposure when compared with the control group. A similar antiapoptotic effect of xenon was noted when injury was acute neuronal injury provoked by NMDA exposure or by oxygen–glucose deprivation.
Fig. 4
Fig. 4
Image Tools
Xenon's antiapoptotic effect was also confirmed in in vivo studies (fig. 3). In rat pups injured by hypoxia–ischemia, xenon alone, as well as a neuroprotective combination of subtherapeutic interventions with xenon (20%) and hypothermia (35°C), significantly increased cell viability by decreasing apoptosis as assessed by morphologic criteria. These data were corroborated by immunoblotting that established a decrease in the proapoptotic factor Bax and an increase in the antiapoptotic factor BclXL (fig. 4).
Xenon also interacts synergistically with isoflurane, another anesthetic capable of providing neuroprotection. Neuroprotection of isoflurane is at least in part a result of GABAA receptor stimulation,69 and the potentiated neuroprotective effect of a combination with xenon may be due to their differing mechanisms of action. Consistent with this concept, NMDA-induced Ca2+ influx, which is thought to be a critical event involved in excitotoxic neuronal death,70 was reduced after administration of xenon in cortical cell cultures.71
The striatum is a subcortical structure mostly resistant to neuroprotective interventions. Xenon at 50%, but not nitrous oxide, reduced ischemic brain damage in the striatum. However, David et al.71 also showed an intriguing effect at higher concentrations of xenon (75%); xenon at this concentration was not neuroprotective. Despite the reported “potentially neurotoxic” effect of xenon, no evidence was presented to support this statement; no difference in infarct volume was observed between 75% xenon and controls.
In addition to the effects mediated via the NMDA receptor, xenon protects cortical neurons against hypoxia-related cell damage via Ca2+-dependent mechanisms.72 Petzelt et al.73 demonstrated in dopaminergic neurons a xenon-induced neuroprotection. Nerve growth factor–differentiated pheochromocytoma cells (PC-12 cells) include D1- and D2-dopamine receptors and release dopamine as a result of increased release and reduced uptake rate of dopamine after hypoxia. This dopamine release is linked to cellular damage as evidenced by lactate dehydrogenase release from the cells. Xenon prevented the dopamine release in PC-12 cells induced by 2 h of hypoxia, and this neuroprotective effect was reduced after buffering intracellular Ca2+ using a Ca2+ chelator.73 This is of special interest because NMDA antagonist neurotoxicity has been linked to excess dopaminergic activation,62 and xenon, which itself lacks toxicity62 and protects against ketamine induced neurotoxicity,64 seems to prevent dopamine induced toxicity. The role of dopamine in the mechanism of NMDA antagonist toxicity and xenon's neuroprotective effects requires further investigation.
Table 1
Table 1
Image Tools
In a neuronal–glial cell coculture, preexposure to xenon for 2 h caused a concentration-dependent reduction of lactate dehydrogenase release from cells deprived of oxygen and glucose 24 h later; xenon's preconditioning effect was abolished by cycloheximide, a protein synthesis inhibitor.74 Preconditioning with xenon decreased propidium iodide staining in a hippocampal slice culture model subjected to oxygen–glucose deprivation. In an in vivo model of neonatal asphyxia involving hypoxic–ischemic injury to 7-day-old rats, preconditioning with xenon reduced infarction size when assessed 7 days after injury, and sustained improvement in neurologic function was still evident after 30 days. Contrastingly, we observed no preconditioning with nitrous oxide.74 From our in vivo experiments, quantitative immunoblotting revealed that the phosphorylated Ca2+/cAMP-responsive element binding protein and brain-derived neurotrophic factor74 are significantly up-regulated after xenon exposure, with a time course similar to that of the preconditioning response; this provides an important clue as to which signaling pathways are involved. Neither brain-derived neurotrophic factor nor the phosphorylated Ca2+/cAMP-responsive element binding protein levels changed after nitrous oxide exposure.74 The molecular effects of xenon on the central nervous system are summarized in table 1.
Back to Top | Article Outline

Putative Sites for Xenon on the Cardiovascular System

In isolated guinea pig hearts, 40–80% xenon did not significantly alter heart rate, atrioventricular conduction time, left ventricular pressure, coronary flow, oxygen extraction or consumption, cardiac efficiency, or flow responses to bradykinin.75 In isolated cardiomyocytes, the amplitudes of the Na+, the L-type Ca2+, and the inward-rectifier K+ channel were not altered by 80% xenon, suggesting that it does not affect the cardiac action potential.75 These results indicate that xenon has no physiologically important effects on the guinea pig heart.
Electrophysiologic studies on cardiomyocytes revealed that halogenated anesthetics depress Ca2+ currents through L-type Ca2+ channels, thereby producing negative inotropic effects and shorten the duration of the action potential.76 In human atrial myocytes, xenon at a concentration of 70% did not depress L-type Ca2+ currents, as measured by patch clamp techniques.77 Voltage-gated potassium currents are responsible for the repolarization of cardiomyocytes and influence the timing of the refractory period. Transient potassium outward currents were only slightly inhibited, and sustained potassium currents were not affected by xenon.77
In vivo, xenon had minor direct negative inotropic effects when administered selectively into the coronary artery system using a coronary bypass system.10 In vitro, xenon neither depressed myocardial contractility nor influenced the positive inotropic stimulation of isoproterenol or the force-frequency relation in cardiac muscle bundles78; these effects are consistent with xenon's stable cardiovascularly profile.5
Back to Top | Article Outline

Cardioprotection

Fig. 5
Fig. 5
Image Tools
Xenon also has cardioprotective effects: Given during reperfusion, it reduced infarct size after regional myocardial ischemia in rabbits in vivo.79 Application of a substance after ischemia during initial reperfusion was recently termed “postconditioning.” Xenon can also induce cardioprotection via the “preconditioning” mechanism (whereby a previous stimulus or stressor provides protection against a later injury). Ischemic preconditioning describes the protection of myocardial tissue against infarction by short, nonlethal periods of ischemia. In the past years, the halogenated (volatile) anesthetics, e.g., isoflurane80,81 or sevoflurane,82 have been recognized to mimic the strong cardioprotection exerted by ischemic preconditioning (pharmacologic or anesthetic-induced preconditioning). Pharmacologic activation of different receptors mimics ischemic preconditioning and activates inhibitory G proteins83 and protein kinase C (PKC) (for details, see fig. 5).84 This activation of PKC affects other signaling pathways, such as Raf-MEK1-MAP kinases and the PI3-kinase-Akt cascade.85 Moreover, the release of free radicals activates different kinases, including PKC (mainly its ϵ-isoform),86 tyrosine kinases,87 and mitogen-activated protein kinases (MAPKs),88 which act as triggers and/or mediators of the resulting cardioprotection (for review, see Das et al. 89). Recent data indicate that also xenon is able to induce preconditioning of the heart in vivo. In anesthetized rats subjected to 25 min of coronary artery occlusion followed by 120 min of reperfusion, either xenon or isoflurane was administered during three 5-min periods before ischemia.9 Xenon inhalation resulted in a significant reduction of the infarct size compared with controls. Calphostin C, an inhibitor of PKC, and the p38 MAPK inhibitor SB203580 abolished the preconditioning effects of xenon and isoflurane. These data suggest that PKC and p38 MAPK are key mediators of xenon-induced preconditioning. PKC-ϵ is one of the isoforms present in cardiac myocytes and is mainly implicated in preconditioning mechanisms. PKC isoforms have been shown to be mainly regulated via translocation to different cell compartments and subsequent phosphorylation, resulting in their activation. By use of a phosphospecific antibody against PKC-ϵ, it was demonstrated that xenon leads to a marked phosphorylation of PKC-ϵ compared with controls.9 Calphostin C abolished the effect of xenon on PKC-ϵ phosphorylation. PKC-ϵ translocates from cytosolic to membrane regions upon different stimuli. Both xenon and isoflurane increased the amount of PKC-ϵ in the membrane fraction compared with controls. The translocation to membrane fraction could be blocked by calphostin C. By using immunohistochemical techniques, Uecker et al.90 observed that isoflurane-induced preconditioning leads to translocation of PKC-δ and PKC-ϵ to nuclei (PKC-δ and PKC-ϵ), to mitochondria (PKC-δ), and to the sarcolemma and intercalated disks (PKC-ϵ). Only phosphorylation of PKC-δ on serine643 was increased after isoflurane administration but not phosphorylation of PKC-ϵ. The PKC blockers chelerythrine and rottlerin blocked PKC activation and anesthetic-induced cardioprotection. We examined whether other than the ϵ isoforms of PKC are involved in xenon induced preconditioning.91 In rat hearts in vivo, application of rottlerin, an inhibitor of PKC-δ, had no effect on infarct size. Activation of PKC isoforms during the preconditioning stimulus may be time dependent.92 However, Western blot analysis showed no influence of xenon preconditioning on phosphorylation of PKC-α at four different time points during the preconditioning protocol, suggesting an isoform specific activation of PKC-ϵ by xenon.
Activation of PKC affects other downstream signaling pathways like the MAPK cascade, and in this context, it has been shown that PKC-ϵ interacts with MAPK during cardioprotection. Xenon induced a significant increase of p38 MAPK phosphorylation and calphostin C abrogated this effect, demonstrating that p38 MAPK is located downstream of PKC in the signaling cascade of xenon-induced preconditioning.9 p38 MAPK is suggested to interact with the actin cytoskeleton via the MAPK-activated protein kinase-2 (MAPKAPK-2) and heat shock protein (HSP) 27. Xenon preconditioning induced phosphorylation of MAPKAPK-2 and HSP27, and both effects could be blocked by calphostin C and SB203580. Xenon enhanced the translocation of HSP27 to the particulate fraction and increased F-actin polymerization. F-actin and HSP27 were colocalized after xenon preconditioning.93 These data show that xenon induces cardioprotection by preconditioning and that activation of PKC-ϵ and its downstream target p38 MAPK are central molecular mechanisms involved. Xenon activates MAPKAPK-2 and HSP-27 downstream of PKC and p38 MAPK, and these data link preconditioning by xenon in the myocardium to the actin cytoskeleton.
We also investigated the role of the p44/42 MAPK (extracellular signal–regulated kinase, ERK) and the stress-activated p54/46 MAPK (SAPK/JNK) in xenon induced preconditioning.94 Both kinases play a key role in differentiation and cell survival as well as in apoptosis regulation. The ERK inhibitor PD 98059 completely abolished the observed cardioprotection offered by xenon, demonstrating an involvement of ERK 1/2 in the signal transduction. Interestingly, SP 600125, a JNK inhibitor, had no effect on infarct size reduction by xenon. In addition, the phosphorylation state of SAPK/JNK was not influenced by xenon as demonstrated by Western blot analysis. These data suggest that besides the p38 MAPK, also ERK is involved in xenon preconditioning. However, the third member of the MAPK family, the SAPK/JNK, is not a mediator of xenon preconditioning, suggesting a highly specific regulation of different kinases by xenon in the myocardium.
Table 2
Table 2
Image Tools
Several investigators have demonstrated the existence of a second episode of myocardial protection (late preconditioning), which begins 12–24 h after the preconditioning stimulus and lasts for 48–72 h. In contrast to early preconditioning, the phenomenon of late preconditioning was long thought not to be induced by halogenated anesthetics.95 Interestingly, there exists increasing evidence from different in vivo models that isoflurane, sevoflurane, and desflurane produce a second window of cardioprotection.96–98 Preliminary results from our laboratory show that xenon also induces late cardioprotection similar to ischemic late preconditioning. However, the molecular mechanisms behind this xenon-induced late cardioprotection remain unknown and need further investigations. Molecular effects of xenon on the heart are summarized in table 2.
It would be interesting to define the most effective strategy for organoprotection. Ischemic preconditioning can reduce infarct size to less than 20% of the area at risk,99 and anesthetic induced preconditioning reduced infarct size to approximately 30% of the area at risk.81 Preconditioning by sevoflurane further reduced infarct size after ischemic late preconditioning.82 Because of differences in species, tissue preparations, and preconditioning protocols, it is difficult to directly compare the different experimental studies with the regard to the extent of cardioprotection. In studies from our laboratory, the cardioprotection by xenon was to the same extent as the cardioprotection by isoflurane.9,93
Back to Top | Article Outline

Other Molecular Effects Exerted by Xenon

In embryonic rat brain astroglial cells, xenon produced a block of the cell cycle at metaphase, and this effect was completely reversible by slightly increasing intracellular Ca2+ concentration.100 In human endothelial cells, the block in the cell cycle was at the G2–M transition and at metaphase, again reversible by increasing intracellular Ca2+ concentration.101 Therefore, xenon interferes with Ca2+-dependent regulatory systems, but so far, no specific event or defined regulatory complex of the Ca2+ signaling system has been identified.
In human whole blood in vitro, xenon did not affect the unstimulated or agonist-induced platelet glycoprotein expression, the activation of the glycoprotein IIb/IIIa receptor, or the platelet-related hemostasis, suggesting no altered platelet function.102 An investigation on neutrophil and monocyte function demonstrated no effect on the respiratory burst activity of these cells but an increased phagocytosis activity of neutrophils.103 Therefore, xenon preserves neutrophil and monocyte antibacterial capacity in vitro. Selectins are involved in the initial contact between neutrophils and endothelial cells. Xenon increased the removal of selectins from neutrophil surface, thereby probably inhibiting the adhesion of neutrophils to the endothelium.104 This might have implications in the recruitment of neutrophils to an inflammatory site. In addition, adhesion molecule receptors are involved in the pathophysiology of ischemia–reperfusion injury. Xenon administration only during reperfusion reduced myocardial infarct size after regional ischemia in rabbits,79 and modulation of neutrophil function may be one underlying mechanism. Adhesion molecules facilitate leukocyte migration into injured tissue. However, expression of adhesion molecules on mice brain endothelial cells was not affected by 75% xenon, suggesting no antiinflammatory actions at the vascular endothelium.105 In an isolated cardiopulmonary bypass system, xenon had no immunomodulatory effects and did not change interleukin-8 or interleukin-10 levels.106 In human monocytes in vitro, xenon increased the lipopolysaccharide-induced production of tumor necrosis factor α and interleukin-6 and activated nuclear transcription factor κB.107 In contrast, isoflurane inhibited activation of nuclear transcription factor κB.
Back to Top | Article Outline

Conclusion

Xenon exerts several interesting properties including pronounced organoprotective effects in various experimental settings against ischemia–reperfusion injury of the heart and the brain. Whether this translates to a clinical benefit must be rapidly determined because preservation of myocardial and cerebral function may outweigh the significant cost of xenon administration. Clinical trials to assess the impact of xenon in settings with predictable injury such as cardiopulmonary bypass and neonatal asphyxia should be designed and underpinned with investigation of the molecular targets involved in the mechanism of action of xenon-induced neuroprotection and cardioprotection.
Back to Top | Article Outline

References

1. Cullen SC, Gross EG: The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 113:580–3

2. Goto T, Nakata Y, Morita S: Will xenon be a stranger or a friend? The cost, benefit, and future of xenon anesthesia. Anesthesiology 2003; 98:1–2

3. Coburn M, Kunitz O, Baumert J-H, Hecker K, Haaf S, Zühlsdorff A, Beeker T, Rossaint R: Randomized controlled trial of the haemodynamic and recovery effects of xenon or propofol anaesthesia. Br J Anaesth 2005; 94:198–202

4. Rossaint R, Reyle-Hahn M, Schulte am Esch J, Scholz J, Scherpereel P, Vallet B, Giunta F, Del Turco M, Erdmann W, Tenbrinck R, Hammerle AF, Nagele P: Multicenter randomized comparison of the efficacy and safety of xenon and isoflurane in patients undergoing elective surgery. Anesthesiology 2003; 98:6–13

5. Sanders RD, Franks NP, Maze M: Xenon: No stranger to anaesthesia. Br J Anaesth 2003; 91:709–17

6. Fukuda T, Nishimoto C, Hisano S, Miyabe M, Toyooka H: The analgesic effect of xenon on the formalin test in rats: A comparison with nitrous oxide. Anesth Analg 2002; 95:1300–4

7. Petersen-Felix S, Luginbühl M, Schnider TW, Curatolo M, Arendt-Nielsen L, Zbinden AM: Comparison of the analgesic potency of xenon and nitrous oxide in humans evaluated by experimental pain. Br J Anaesth 1998; 81:742–7

8. Ma D, Sanders RD, Halder S, Rajakumaraswamy N, Franks NP, Maze M: Xenon exerts age-independent antinociception in Fischer rats. Anesthesiology 2004; 100:1313–8

9. Weber NC, Toma O, Wolter JI, Obal D, Müllenheim J, Preckel B, Schlack W: The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-e and p38 MAPK. Br J Pharmacol 2005; 144:123–32

10. Preckel B, Ebel D, Müllenheim J, Fräβdorf J, Thämer V, Schlack W: The direct myocardial effects of xenon in the dog heart in vivo. Anesth Analg 2002; 94:545–51

11. Baur CP, Klingler W, Jurkat-Rott K, Froeba G, Schoch E, Marx T, Georgieff M, Lehmann-Horn F: Xenon does not induce contracture in human malignant hyperthermia muscle. Br J Anaesth 2000; 85:712–6

12. Preckel B, Schlack W: Xenon: Cardiovascularly inert? Br J Anaesth 2004; 92:786–9

13. Trudell JR, Koblin DD, Eger EI: A molecular description of how noble gases and nitrogen bind to a model site of anesthetic action. Anesth Analg 1998; 87:411–8

14. Schiltz M, Fourme R, Broutin I, Prange T: The catalytic site of serine proteinases as a specific binding cavity for xenon. Structure 1995; 3:309–16

15. Prange T, Schiltz M, Pernot L, Colloc'h N, Longhi S, Bourguet W, Fourme R: Exploring hydrophobic sites in proteins with xenon or krypton. Proteins 1998; 30:61–73

16. LaBella FS, Stein D, Queen G: The site of general anesthesia and cytochrome P450 monooxygenases: Occupation of the enzyme heme pocket by xenon and nitrous oxide. Eur J Pharmacol 1999; 381:R1–3

17. Nagele P, Metz LB, Crowder CM: Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2004; 101:8791–6

18. Nagele P, Metz LB, Crowder CM: Xenon acts by inhibition of non–N-methyl-d-aspartate receptor mediated glutamatergic neurotransmission in Caenorhabditis elegans. Anesthesiology 2005; 103:508–13

19. Franks NP, Lieb WR: Molecular and cellular mechanisms of general anesthesia. Nature 1994; 367:607–14

20. Dildy-Mayfield JE, Eger EI II, Harris RA: Anesthetics produce subunit-selective actions on glutamate receptors. J Pharmacol Exp Ther 1996; 276:1058–65

21. Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci 1999; 55:1278–303

22. Franks NP, Dickinson R, De Sousa SL, Hall AC, Lieb WR: How does xenon produce anaesthesia? Nature 1998; 396:324

23. De Sousa SLM, Dickinson R, Lieb WR, Franks NP: Contrasting synaptic actions of the inhalational general anesthetics isoflurane and xenon. Anesthesiology 2000; 92:1055–66

24. Plested AJR, Wildman SS, Lieb WR, Franks NP: Determinants of the sensitivity of AMPA receptors to xenon. Anesthesiology 2004; 100:347–58

25. Dinse A, Föhr KJ, Georgieff M, Beyer C, Bulling A, Weigt HU: Xenon reduces glutamate-, AMPA-, and kainate-induced membrane currents in cortical neurones. Br J Anaesth 2005; 94:479–85

26. Hapfelmeier G, Zieglgansberger W, Haseneder R, Schneck H, Kochs E: Nitrous oxide and xenon increase the efficacy of GABA at recombinant mammalian GABAA receptors. Anesth Analg 2000; 91:1542–9

27. Yamakura T, Harris RA: Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels: Comparison with isoflurane and ethanol. Anesthesiology 2000; 93:1095–101

28. Daniels S, Roberts RJ: Post-synaptic inhibitory mechanisms of anaesthesia: Glycine receptors. Toxicol Lett 1998; 101:71–6

29. Mori T, Zhao X, Zuo Y, Aistrup GL, Nishikawa K, Marszalec W, Yeh JZ, Narahashi T: Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons. Mol Pharmacol 2001; 59:732–43

30. Flood P, Ramirez-Latorre J, Role L: a4b2 neuronal nicotinic acetylcholine receptors in the central nervous system are inhibited by isoflurane and propofol, but a7-type nicotinic acetylcholine receptors are unaffected. Anesthesiology 1997; 86:859–65

31. Suzuki T, Ueta K, Sugimoto M, Uchida I, Mashimo T: Nitrous oxide and xenon inhibit the human (a7)5 nicotinic acetylcholine receptor expressed in xenopus oocyte. Anesth Analg 2003; 96:443–8

32. Violet JM, Downie DL, Nakisa RC, Lieb WR, Franks NP: Differential sensitivities of mammalian neuronal and muscle nicotinic acetylcholine receptors to general anesthetics. Anesthesiology 1997; 86:866–74

33. Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T: The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydoxytryptamine 3 receptors expressed in Xenopus oocytes. Anesthesiology 2002; 96:699–704

34. Gruss M, Bushell TJ, Bright DP, Lieb WR, Mathie A, Franks NP: Two-pore-domain K+ channels are a novel target for the anesthetic gases xenon, nitrous oxide, and cyclopropane. Mol Pharmacol 2004; 65:443–52

35. Nicoll RA, Madison DV: General anesthetics hyperpolarize neurons in the vertebrate central nervous system. Science 1982; 217:1055–7

36. Patel AJ, Honore E: Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci 2001; 24:339–46

37. Patel AJ, Honore E: Anesthetic-sensitive 2P domain K+ channels. Anesthesiology 2001; 95:1013–21

38. Patel A, Honore E, Lesage F, Fink M, Romey G, Lazdunski M: Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 1999; 2:422–6

39. Petzelt C, Osés-Prieto J, Klett FF, Schmehl W, Kox WJ: Effects of xenon on intracellular Ca2+ release in human endothelial cells. Exp Biol Online 1997; 2:3–9

40. Penniston JT, Enyedi A: Plasma membrane Ca2+ pump: Recent developments. Cell Physiol Biochem 1994; 4:148–59

41. Fomitcheva I, Kosk-Kosicka D: Volatile anesthetics selectively inhibit the Ca2+-transporting ATPase in neuronal and erythrocyte plasma membranes. Anesthesiology 1996; 84:1189–95

42. Franks JJ, Horn J-L, Janicki PK, Singh G: Halothane, isoflurane, xenon, and nitrous oxide inhibit calcium ATPase pump activity in rat brain synaptic plasma membranes. Anesthesiology 1995; 82:108–17

43. Singh G, Janicki PK, Horn J-L, Janson VE, Franks JJ: Inhibition of plasma membrane Ca2+-ATPase pump activity in cultured C6 glioma cells by halothane and xenon. Life Sci 1995; 56:PL219–24

44. Horn J-L, Janicki PK, Franks JJ: Nitrous oxide and xenon enhance phospholipid-N-methylation in rat brain synaptic plasma membranes. Life Sci 1995; 56:PL455–60

45. Johns RA: Nitric oxide, cyclic guanosine monophosphate, and the anesthetic state. Anesthesiology 1996; 58:457–9

46. Galley HF, Le Cras AE, Logan SD, Webster NR: Differential nitric oxide synthase activity, cofactor availability and cGMP accumulation in the central nervous system during anaesthesia. Br J Anaesth 2001; 86:388–94

47. Yoshida H, Kushikata T, Kubota T, Hirota K, Ishihara H, Matsuki A: Xenon inhalation increases norepinephrine release from the anterior and posterior hypothalamus in rats. Can J Anesth 2001; 48:651–5

48. Shichino T, Murakawa M, Adachi T, Miyazaki Y, Segawa H, Fukuda K, Mori K: Effects of xenon on acetylcholine release in the rat cerebral cortex in vivo. Br J Anaesth 2002; 88:866–8

49. Ishiguro Y, Kikuchi T, Etsuki H, Niimi Y, Goto T, Morita S, Irie T: Does xenon anesthesia inhibit cholinesterase? An in vitro radiometric assessment. Anesthesiology 2003; 98:791–2

50. Utsumi J, Adachi T, Miyazaki Y, Kurata J, Shibata M, Murakawa M, Arai T, Mori K: The effect of xenon on spinal dorsal horn neurons: A comparison with nitrous oxide. Anesth Analg 1997; 84:1372–6

51. Miyazaki Y, Adachi T, Utsumi J, Shichino T, Segawa H: Xenon has greater inhibitory effects on spinal dorsal horn neurons than nitrous oxide in spinal cord transected cats. Anesth Analg 1999; 88:893–7

52. Fujinaga M, Maze M: Neurobiology of nitrous oxide induced antinociceptive effects. Mol Neurobiol 2002; 25:167–89

53. Ohara A, Mashimo T, Zhang P, Inagaki Y, Shibuta S, Yoshiya I: A comparative study of the antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg 1997; 85:931–6

54. Watanabe I, Takenoshita M, Sawada T, Uchida I, Mashimo T: Xenon suppresses nociceptive reflex in newborn rat spinal cord in vitro; comparison with nitrous oxide. Eur J Pharmacol 2004; 496:71–6

55. Utsumi J, Adachi T, Kurata J, Miyazaki Y, Shibata M, Murakawa M, Arai T, Mori K: Effect of xenon on central nervous system electrical activity during sevoflurane anaesthesia in cats: Comparison with nitrous oxide. Br J Anaesth 1998; 80:628–33

56. Hardingham GE, Bading H: The Yin and Yang of NMDA receptor signalling. Trends Neurosci 2003; 26:81–9

57. Wilhelm S, Ma D, Maze M, Franks NP: Effects of xenon on in vitro and in vivo models of neuronal injury. Anesthesiology 2002; 96:1485–91

58. Homi HM, Yokoo N, Ma D, Warner DS, Franks NP, Maze M, Grocott HP: The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice. Anesthesiology 2003; 99:876–81

59. Ma D, Yang H, Lynch J, Franks NP, Maze M, Grocott HP: Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat. Anesthesiology 2003; 98:690–8

60. Allen HL, Iversen LL: Phencyclidine, dizocilpine, and cerebrocortical neurons (letter). Science 1990; 247:221

61. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW: Nitrous oxide (laughing gas) is a NMDA antagonist, neuroprotectant and neurotoxin. Nature Med 1998; 4:460–3

62. Ma D, Wilhelm S, Maze M, Franks NP: Neuroprotective and neurotoxic properties of the inert gas xenon. Br J Anaesth 2002; 89:739–46

63. Gass P, Herdegen T, Bravo R, Kiessling M: Induction and suppression of immediate early genes in specific rat brain regions by the non-competitive N-methyl-D-aspartate receptor antagonist MK-801. Neuroscience 1993; 53:749–58

64. Nagata A, Nakao S, Nishizawa N, Masuzawa M, Inada T, Murao K, Miyamoto E, Shingu K: Xenon inhibits but N2O enhances ketamine-induced c-Fos expression in the rat posterior cingulate and retrosplenial cortices. Anesth Analg 2001; 92:362–8

65. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557–63

66. The Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549–56

67. Ma D, Hossain M, Chow A, Arshad M, Battson RM, Sanders RD, Mehmet H, Edwards DD, Franks NP, Maze M: Xenon and hypothermia combine synergistically to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005; 58:182–93

68. Williamson PB, Ma D, Hossain M, Franks NP, Maze M: Xenon does not cause apoptotic neurodegeneration in the neonatal rat, and protects against isoflurane-induced apoptosis (abstract). Anesthesiology 2004; 101 (suppl):A-864

69. Ma D, Hossain M, Rajakumaraswamy N, Franks NP, Maze M: Combination of xenon and isoflurane produces a synergistic protective effect against oxygen-glucose deprivation injury in a neuronal-glial co-culture model. Anesthesiology 2003; 99:748–51

70. Goldberg MP, Choi DW: Combined oxygen and glucose deprivation in cortical cell culture: Calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci 1993; 13:3510–24

71. David HN, Leveille F, Chazalviel L, MacKenzie ET, Buisson A, Lemaire M, Abraini JH: Reduction of ischemic brain damage by nitrous oxide and xenon. J Cereb Blood Flow Metab 2003; 23:1168–73

72. Petzelt C, Blom P, Schmehl W, Müller J, Kox WJ: Prevention of neurotoxicity in hypoxic cortical neurons by the noble gas xenon. Life Sci 2003; 72:1909–18

73. Petzelt C, Blom P, Schmehl W, Mueller J, Kox WJ: Xenon prevents cellular damage in differentiated PC-12 cells exposed to hypoxia. BMC Neurosci 2004; 5:55

74. Ma D, Hossain M, Pettet GKJ, Luo Y, Lim T, Akimov S, Sanders RD, Franks NP, Maze M: Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab 2006; 26:199–208

75. Stowe DF, Rehmert GC, Kwok WM, Weigt HU, Georgieff M, Bosnjak ZJ: Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes. Anesthesiology 2000; 92:516–22

76. Bosnjak ZJ, Supan FD, Rusch NJ: The effects of halothane, enflurane, and isoflurane on calcium current in isolated canine ventricular cells. Anesthesiology 1991; 74:340–5

77. Hüneke R, Jüngling E, Skasa M, Rossaint R, Lückhoff A: Effects of the anesthetic gases xenon, halothane, and isoflurane on calcium and potassium currents in human atrial cardiomyocytes. Anesthesiology 2001; 95:999–1006

78. Schroth S, Schotten U, Alkanoglu O, Reyle-Hahn M, Hanrath P, Rossaint R: Xenon does not impair the responsiveness of cardiac muscle bundles to positive inotropic and chronotropic stimulation. Anesthesiology 2002; 96:422–7

79. Preckel B, Müllenheim J, Moloschavij A, Thämer V, Schlack W: Xenon administration during early reperfusion reduces infarct size after regional ischemia in the rabbit heart in vivo. Anesth Analg 2000; 91:1327–32

80. Cason BA, Gamperl AK, Slocum RE, Hickey RF: Anesthetic-induced preconditioning: Previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology 1997; 87:1182–90

81. Müllenheim J, Ebel D, Fräβdorf J, Preckel B, Thämer V, Schlack W: Isoflurane preconditions myocardium against infarction via release of free radicals. Anesthesiology 2002; 96:934–40

82. Müllenheim J, Ebel D, Bauer M, Otto F, Heinen A, Fräβdorf J, Preckel B, Schlack W: Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits. Anesthesiology 2003; 99:624–31

83. Kirsch GE, Codina J, Birnbaumer L, Brown AM: Coupling of ATP-sensitive K+ channels to A1 receptors by G proteins in rat ventricular myocytes. Am J Physiol 1990; 259:H820–26

84. Speechly-Dick ME, Grover GJ, Yellon DM: Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. Circ Res 1995; 77:1030–5

85. Takahashi T, Ueno H, Shibuya M: VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 1999; 18:2221–30

86. Yang XM, Sato H, Downey JM, Cohen MV: Protection of ischemic preconditioning is dependent upon a critical timing sequence of protein kinase C activation. J Mol Cell Cardiol 1997; 29:991–9

87. Baines CP, Wang L, Cohen MV, Downey JM: Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning's anti-infarct effect in the rabbit heart. J Mol Cell Cardiol 1998; 30:383–92

88. Weinbrenner C, Liu GS, Cohen MV, Downey JM: Phosphorylation of Tyrosine 182 of p38 mitogen activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Mol Cell Cardiol 1997; 29:2383–91

89. Das DK, Engelman RM, Maulik N: Oxygen free radical signaling in ischemic preconditioning. Ann N Y Acad Sci 1999; 874:49–65

90. Uecker M, Da Silva R, Grampp T, Pasch T, Schaub MC, Zaugg M: Translocation of protein kinase C isoforms to subcellular targets in ischemic and anesthetic preconditioning. Anesthesiology 2003; 99:138–47

91. Wirthle NM, Weber NC, Wolter JI, Toma O, Schlack W, Preckel B: Xenon preconditioning induces isoform-specific activation of protein kinase C in the rat heart. Anästhesiologie und Intensivmedizin 2005; 12-2:196–7

92. Toma O, Weber NC, Wolter JI, Obal D, Preckel B, Schlack W: Desflurane preconditioning induces time-dependent activation of protein kinase C epsilon and extracellular signal regulated kinase 1 and 2 in the rat heart in vivo. Anesthesiology 2004; 101:1372–80

93. Weber NC, Toma O, Wolter JI, Wirthle NM, Schlack W, Preckel B: Mechanisms of xenon and isoflurane induced preconditioning: A potential link to the cytoskeleton via the MAPKAPK-2/HSP27 pathway. Br J Pharmacol 2005; 146:445–55

94. Weber NC, Toma O, Stursberg J, Schlack W, Preckel B: Mechanisms of xenon induced preconditioning: Xenon differently regulates p44/42 MAPK (ERK1/2) and p54/46 MAPK (JNK1/2) (abstract). Anesthesiology 2005; 103 (suppl):A-491

95. Kehl F, Pagel PS, Krolikowski JG, Gu W, Toller WG, Warltier DC, Kersten JR: Isoflurane does not produce a second window of preconditioning against myocardial infarction in vivo. Anesth Analg 2002; 95:1162–8

96. Lutz MR, Liu H: Sevoflurane produces a delayed window of protection in young rat myocardium and fails to in aged rat myocardium (abstract). Anesthesiology 2004; 101 (suppl):A-732

97. Wakeno-Takahashi M, Otani H, Nakao S, Imamura H, Shingu K: Isoflurane induces second window of preconditioning through upregulation of inducible nitric oxide synthase in the rat heart. Am J Physiol Heart Circ Physiol 2005; 289:H2585–91

98. Smul T, Stumpner J, Lange M, Roewer N, Kehl F: Desflurane induces a 1st and 2nd window of preconditioning against myocardial infarction. FASEB J 2005; 19:A691–386.12

99. Müllenheim J, Schlack W, Fräβdorf J, Heinen A, Preckel B, Thämer V: Additive protective effects of late and early ischaemic preconditioning are mediated by the opening of KATP channels in vivo. Pflugers Arch 2001; 442:178–87

100. Petzelt C, Taschenberger G, Schmehl W, Hafner M, Kox WJ: Xenon induces metaphase arrest in rat astrocytes. Life Sci 1999; 65:901–13

101. Petzelt C, Taschenberger G, Schmehl W, Kox WJ: Xenon-induced inhibition of Ca2+-regulated transitions in the cell cycle of human endothelial cells. Pflugers Arch 1999; 437:737–44

102. De Rossi LW, Horn NA, Baumert HJ, Gutensohn K, Hutschenreuter G, Rossaint R: Xenon does not affect human platelet function in vitro. Anesth Analg 2001; 93:635–40

103. De Rossi LW, Gott K, Horn NA, Hecker K, Hutschenreuter G, Rossaint R: Xenon preserves neutrophil and monocyte function in human whole blood. Can J Anesth 2002; 49:942–5

104. De Rossi LW, Horn NA, Stevanovic A, Buhre W, Hutschenreuter G, Rossaint R: Xenon modulates neutrophil adhesion molecule expression in vitro. Eur J Anaesthesiol 2004; 21:139–43

105. Yamamoto H, Takata M, Merczin N, Franks NP, Maze M: Xenon's effect on adhesion molecule expression in inflammation model of mouse brain endothelial cell (abstract). Anesthesiology 2003; 99 (suppl):A-477

106. Bedi A, McBride WT, Armstrong MA, Murray JM, Fee JPH: Xenon has no effect on cytokine balance and adhesion molecule expression within an isolated cardiopulmonary bypass system. Br J Anaesth 2002; 89:546–50

107. De Rossi LW, Brueckmann M, Rex S, Barderschneider M, Buhre W, Rossaint R: Xenon and isoflurane differentially modulate lipopolysaccharide-induced activation of the nuclear transcription factor KB and production of tumor necrosis factor-a and interleukin-6 in monocytes. Anesth Analg 2004; 98:1007–12

Cited By:

This article has been cited 38 time(s).

Physiological Research
Biological effects of noble gases
Ruzicka, J; Benes, J; Bolek, L; Markvartova, V
Physiological Research, 56(): S39-S44.

Anaesthesia
The uses of helium and xenon in current clinical practice
Harris, PD; Barnes, R
Anaesthesia, 63(3): 284-293.
10.1111/j.1365-2044.2007.05253.x
CrossRef
British Journal of Anaesthesia
Advances in pharmacology and therapeutics
Hopkins, PM; Hardman, JG
British Journal of Anaesthesia, 103(1): 1-2.
10.1093/bja/aep168
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Cardioprotection by Volatile Anesthetics: Established Scientific Principle or Lingering Clinical Uncertainty?
Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 23(5): 589-593.
10.1053/j.jvca.2009.07.001
CrossRef
Neuroimage
Xenon-induced changes in CNS sensitization to pain
Adolph, O; Koster, S; Georgieff, M; Bader, S; Fohr, KJ; Kammer, T; Herrnberger, B; Gron, G
Neuroimage, 49(1): 720-730.
10.1016/j.neuroimage.2009.08.034
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Cardioprotection by Noble Gases
Pagel, PS
Journal of Cardiothoracic and Vascular Anesthesia, 24(1): 143-163.
10.1053/j.jvca.2009.03.016
CrossRef
Journal of Physical Chemistry B
Evidences of Xenon-Induced Structural Changes in the Active Site of Cyano-MetMyoglobins: A H-1 NMR Study
Anedda, R; Era, B; Casu, M; Fais, A; Ceccarelli, M; Corda, M; Ruggerone, P
Journal of Physical Chemistry B, 112(): 15856-15866.
10.1021/jp807959u
CrossRef
European Journal of Pharmacology
The xenon-mediated antagonism against the NMDA receptor is non-selective for receptors containing either NR2A or NR2B subunits in the mouse amygdala
Haseneder, R; Kratzer, S; Kochs, E; Hofelmann, D; Auberson, Y; Eder, M; Rammes, G
European Journal of Pharmacology, 619(): 33-37.
10.1016/j.ejphar.2009.08.011
CrossRef
Neuroscience Letters
Neuroprotective interaction produced by xenon and dexmedetomidine on in vitro and in vivo neuronal injury models
Rajakumaraswamy, N; Ma, DQ; Hossain, M; Sanders, RD; Franks, NP; Maze, M
Neuroscience Letters, 409(2): 128-133.
10.1016/j.neulet.2006.09.020
CrossRef
Anesthesia and Analgesia
Inhibition of glycogen synthase kinase or the apoptotic protein p53 lowers the threshold of helium cardioprotection in vivo: The role of mitochondrial permeability transition
Pagel, PS; Krolikowski, JG; Pratt, PF; Shim, YH; Amour, J; Warltier, DC; Weihrauch, D
Anesthesia and Analgesia, 107(3): 769-775.
10.1213/ane.0b013e3181815b84
CrossRef
Journal of Cardiothoracic and Vascular Anesthesia
Morphine Reduces the Threshold of Helium Preconditioning Against Myocardial Infarction: The Role of Opioid Receptors in Rabbits
Pagel, PS; Krolikowski, JG; Amour, J; Warltier, DC; Weihrauch, D
Journal of Cardiothoracic and Vascular Anesthesia, 23(5): 619-624.
10.1053/j.jvca.2008.12.020
CrossRef
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie
The ideal gas Xenon - An ideal anesthetic?
Bein, B; Hoecker, J; Scholz, J
Anasthesiologie Intensivmedizin Notfallmedizin Schmerztherapie, 42(): 784-790.

Molecular Pain
Xenon inhibits excitatory but not inhibitory transmission in rat spinal cord dorsal horn neurons
Georgiev, SK; Furue, H; Baba, H; Kohno, T
Molecular Pain, 6(): -.
ARTN 25
CrossRef
CNS Drug Reviews
Neuroprotective effects of propofol in acute cerebral injury
Adembri, C; Venturi, L; Pellegrini-Giampietro, DE
CNS Drug Reviews, 13(3): 333-351.

Neuroscience Letters
Neuroprotection (and lack of neuroprotection) afforded by a series of noble gases in an in vitro model of neuronal injury
Jawad, N; Rizvi, M; Gua, JT; Adeyi, O; Tao, GC; Maze, M; Ma, DQ
Neuroscience Letters, 460(3): 232-236.
10.1016/j.neulet.2009.05.069
CrossRef
Biophysical Journal
Bubbles, gating, and anesthetics in ion channels
Roth, R; Gillespie, D; Nonner, W; Eisenberg, RE
Biophysical Journal, 94(): 4282-4298.
10.1529/biophysj.107.120493
CrossRef
Neuroscience
Xenon Preconditioning Confers Neuroprotection Regardless of Gender in A Mouse Model of Transient Middle Cerebral Artery Occlusion
Limatola, V; Ward, P; Cattano, D; Gu, J; Giunta, F; Maze, M; Ma, D
Neuroscience, 165(3): 874-881.
10.1016/j.neuroscience.2009.10.063
CrossRef
Anesthesia and Analgesia
The mechanism of helium-induced preconditioning: A direct role for nitric oxide in rabbits
Pagel, PS; Krolikowski, JG; Pratt, PF; Shim, YH; Amour, J; Warltier, DC; Weihrauch, D
Anesthesia and Analgesia, 107(3): 762-768.
10.1213/ane.0b013e3181815995
CrossRef
Anesthesia and Analgesia
Xenon does not affect gamma-aminobutyric acid type a receptor binding in humans
Salmi, E; Laitio, RM; Aalto, S; Maksimow, AT; Langsjo, JW; Kaisti, KK; Aantaa, R; Oikonen, V; Metsahonkala, L; Nagren, K; Korpi, ER; Scheinin, H
Anesthesia and Analgesia, 106(1): 129-134.
10.1213/01.ane.0000287658.14763.13
CrossRef
Neuroscience Letters
Xenon induces transcription of ADNP in neonatal rat brain
Cattano, D; Valleggi, S; Ma, DQ; Kastsiuchenka, O; Abramo, A; Sun, P; Cavazzana, AO; Natale, G; Maze, M; Giunta, F
Neuroscience Letters, 440(3): 217-221.
10.1016/j.neulet.2008.05.086
CrossRef
Anesthesia and Analgesia
Transient Metabolic Alkalosis During Early Reperfusion Abolishes Helium Preconditioning Against Myocardial Infarction: Restoration of Cardioprotection by Cyclosporin A in Rabbits
Pagel, PS; Krolikowski, JG
Anesthesia and Analgesia, 108(4): 1076-1082.
10.1213/ane.0b013e318193e934
CrossRef
Anesthesia and Analgesia
Closed-Circuit Xenon Delivery Using a Standard Anesthesia Workstation
Rawat, S; Dingley, J
Anesthesia and Analgesia, 110(1): 101-109.
10.1213/ANE.0b013e3181be0e17
CrossRef
Laboratory Animals
The haemodynamic and catecholamine response to xenon/remifentanil anaesthesia in Beagle dogs
Francis, RCE; Reyle-Hahn, MS; Hohne, C; Klein, A; Theruvath, I; Donaubauer, B; Busch, T; Boemke, W
Laboratory Animals, 42(3): 338-349.
10.1258/la.2007.007048
CrossRef
British Journal of Anaesthesia
Intranasal application of xenon: describing the pharmacokinetics in experimental animals and the increased pain tolerance within a placebo-controlled experimental human study
Froeba, G; Georgieff, M; Linder, EM; Fohr, KJ; Weigt, HU; Holstrater, TF; Kolle, MA; Adolph, O
British Journal of Anaesthesia, 104(3): 351-358.
10.1093/bja/aep395
CrossRef
Anesthesia and Analgesia
Noble gases without anesthetic properties protect myocardium against infarction by activating prosurvival signaling kinases and inhibiting mitochondrial permeability transition in vivo
Pagel, PS; Krolikowski, JG; Shim, YH; Venkatapuram, S; Kersten, JR; Weihrauch, D; Warltier, DC; Pratt, PF
Anesthesia and Analgesia, 105(3): 562-569.
10.1213/01.ane.0000278083.31991.36
CrossRef
Anesthesia and Analgesia
Remote Exposure to Xenon Produces Delayed Preconditioning Against Myocardial Infarction In Vivo: Additional Evidence That Noble Gases Are Not Biologically Inert
Pagel, PS
Anesthesia and Analgesia, 107(6): 1768-1771.
10.1213/ane.0b013e3181887506
CrossRef
Radiology
Xenon ventilation CT with a dual-energy technique of dual-source CT: Initial experience
Chae, EJ; Seo, JB; Goo, HW; Kim, N; Song, KS; Lee, SD; Hong, SJ; Krauss, B
Radiology, 248(2): 615-624.
10.1148/radiol.2482071482
CrossRef
Anesthesia and Analgesia
The effective concentration 50 (EC50) for propofol with 70% xenon versus 70% nitrous oxide
Barakat, AR; Schreiber, MN; Flaschar, J; Georgieff, M; Schraag, S
Anesthesia and Analgesia, 106(3): 823-829.
10.1213/ane.0b013e318161534b
CrossRef
Anesthesia and Analgesia
Xenon Preconditioning: The Role of Prosurvival Signaling, Mitochondrial Permeability Transition and Bioenergetics in Rats
Mio, Y; Shim, YH; Richards, E; Bosnjak, ZJ; Pagel, PS; Bienengraeber, M
Anesthesia and Analgesia, 108(3): 858-866.
10.1213/ane.0b013e318192a520
CrossRef
Hepatitis Monthly
Xenon: A Solution for Anesthesia in Liver Disease?
Dabbagh, A; Rajaei, S
Hepatitis Monthly, 12(): -.
ARTN e8437
CrossRef
Anesthesiology
Xenon and the Pharmacology of Fear
Hemmings, HC; Mantz, J
Anesthesiology, 109(6): 954-955.
10.1097/ALN.0b013e31818d4964
PDF (84) | CrossRef
Anesthesiology
Xenon Reduces N-Methyl-d-aspartate and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor–mediated Synaptic Transmission in the Amygdala
Haseneder, R; Kratzer, S; Kochs, E; Eckle, V; Zieglgänsberger, W; Rammes, G
Anesthesiology, 109(6): 998-1006.
10.1097/ALN.0b013e31818d6aee
PDF (1399) | CrossRef
Anesthesiology
Sympathetic Nervous System: Evaluation and Importance for Clinical General Anesthesia
Neukirchen, M; Kienbaum, P
Anesthesiology, 109(6): 1113-1131.
10.1097/ALN.0b013e31818e435c
PDF (1675) | CrossRef
Anesthesiology
Xenon Attenuates Excitatory Synaptic Transmission in the Rodent Prefrontal Cortex and Spinal Cord Dorsal Horn
Haseneder, R; Kratzer, S; Kochs, E; Mattusch, C; Eder, M; Rammes, G
Anesthesiology, 111(6): 1297-1307.
10.1097/ALN.0b013e3181c14c05
PDF (1278) | CrossRef
Critical Care Medicine
Neuroprotective properties of xenon and helium in an in vitro model of traumatic brain injury: One small step or one big jump?*
Fodale, V; Santamaria, LB; Grasso, G
Critical Care Medicine, 36(2): 647-648.
10.1097/CCM.0B013E318162EDA3
PDF (1135) | CrossRef
Current Opinion in Anesthesiology
Update on inhalational anaesthetics
De Hert, SG; Preckel, B; Schlack, WS
Current Opinion in Anesthesiology, 22(4): 491-495.
10.1097/ACO.0b013e32832bca38
PDF (112) | CrossRef
Journal of Neurosurgical Anesthesiology
Clinical Use of Xenon in 2 Elderly Patients
Cattano, D; Forfori, F; Giunta, F
Journal of Neurosurgical Anesthesiology, 20(2): 156-158.
10.1097/ANA.0b013e318163b38a
PDF (180) | CrossRef
Journal of Neurosurgical Anesthesiology
Xenon Up-regulates Several Genes That are not Up-regulated by Nitrous Oxide
Valleggi, S; Cavazzana, AO; Bernardi, R; Ma, D; Natale, G; Maze, M; Davide, C; Giunta, F
Journal of Neurosurgical Anesthesiology, 20(4): 226-232.
10.1097/ANA.0b013e31817da878
PDF (263) | CrossRef
Back to Top | Article Outline

© 2006 American Society of Anesthesiologists, Inc.

Publication of an advertisement in Anesthesiology Online does not constitute endorsement by the American Society of Anesthesiologists, Inc. or Lippincott Williams & Wilkins, Inc. of the product or service being advertised.
Login

Article Tools

Images

Share