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British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 2015 Jan 12;172(8):2062–2073. doi: 10.1111/bph.12994

Noble gases as cardioprotectants – translatability and mechanism

Kirsten F Smit 1, Nina C Weber 1, Markus W Hollmann 1, Benedikt Preckel 1,✉
PMCID: PMC4386981  PMID: 25363501

Abstract

Several noble gases, although classified as inert substances, exert a tissue-protective effect in different experimental models when applied before organ ischaemia as an early or late preconditioning stimulus, after ischaemia as a post-conditioning stimulus or when given in combination before, during and/or after ischaemia. A wide range of organs can be protected by these inert substances, in particular cardiac and neuronal tissue. In this review we summarize the data on noble gas-induced cardioprotection, focusing on the underlying protective mechanisms. We will also look at translatability of experimental data to the clinical situation.

Tables of Links

TARGETS
Other protein targetsa Enzymesf
HSP70 Akt (PKB)
GRPCRsb Caspase-3
5-HT3 receptor COX-2
Opioid receptors Endothelial (e) NOS
Ligand-gated ion channelsc ERK
Nicotinic ACh receptors GSK3β
NMDA receptors Haem oxygenase 1
Ion channelsd Inducible (i) NOS
KATP channel JNK
KCa channel MAPKAPK-2
K2P2.1 (TREK-1) channel MEK1
Catalytic receptorse Neuronal (n) NOS
CD11b P38 MAPK
CD18 PDK1
PKCα
PKCδ
PKCε
Tissue plasminogen activator
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LIGANDS
ACh LPS
ADP Morphine
ATP Propofol
Cyclosporin A Sevoflurane
Desflurane Staurosporine
Glycine TNF-α
ICAM-1 Urate oxidase
L-NAME VCAM-1
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These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 (

a,b,c,d,,e,fAlexander et al., 2013a,b,c,d,e,f,,,,,).

Introduction

The noble gases helium, neon, argon, krypton, xenon and radon are odourless, colourless, monatomic gases that are characterized by a filled outer shell of valence electrons, making them ‘inert’ or at least less capable of interaction with other compounds. However, some of these gases are already frequently used in medicine, for example, helium is applied to patients with severe airway disease because of its very low density (Rodrigo et al., 2002; Vorwerk and Coats, 2010). Xenon has been shown to act at the NMDA receptor (Franks et al., 1998), thereby inducing anaesthesia under normobaric conditions (Rossaint et al., 2003).

In recent years, several investigators demonstrated a tissue-protective effect of noble gases in different animal species as well as in humans (Preckel et al., 2006; Oei et al., 2010; Pagel, 2010; Deng et al., 2014). This protection was shown for various periods of ischaemia reperfusion, for example, when the gas was applied before organ ischaemia as an early or late preconditioning (LPC) stimulus (Weber et al., 2005a; Heinen et al., 2008; Huhn et al., 2009a), after ischaemia as a post-conditioning stimulus (Weber et al., 2008a; Huhn et al., 2009b) or when given in combination before, during and/or after ischaemia (Oei et al., 2012b). A wide range of organs can be protected by these inert substances, in particular the heart and neuronal tissue (Preckel et al., 2006; Oei et al., 2010; Coburn et al., 2012). This article will summarize the current knowledge on noble gas-induced cardioprotection and will focus on the mechanisms of protection and a possible translatability to the clinical situation.

Xenon

Cardioprotection by xenon

Anaesthetic properties of xenon have been described as early as 1951 (Cullen and Gross, 1951), and during the last two decades numerous studies evaluated molecular properties (Preckel et al., 2006) and the clinical benefits (Harris and Barnes, 2008) of xenon as an anaesthetic agent. With regard to the ongoing discussion on anaesthesia-induced post-operative cognitive dysfunction in elderly surgical patients, xenon might be advantageous compared with commonly used inhalational anaesthetics (Bronco et al., 2010; Stuttmann et al., 2010), although this protective effect has been challenged by other investigators (Rasmussen et al., 2006; Höcker et al., 2009).

By far the most information on organ protection by noble gases comes from studies using xenon as an inhalational agent. Experimental studies have clearly shown that xenon protects the brain (Limatola et al., 2010), spinal cord (Yamamoto et al., 2010; Yang et al., 2013), kidney (Ma et al., 2009), heart (Weber et al., 2005a,b,) and vascular endothelium (Weber et al., 2008c) from ischaemia reperfusion injury.

Applying the noble gas at the end of ischaemia and during the first minutes of reperfusion might also have protective effects leading to a reduction in infarct size by post-conditioning. In rabbits subjected to 30 min of coronary artery occlusion followed by 120 min of reperfusion, inhalation of xenon (70%) at the very end of regional myocardial ischaemia and during the first 15 min of reperfusion (post-conditioning) reduced infarct size (Preckel et al., 2000). Post-conditioning by sub-anaesthetic concentrations of xenon (20%) combined with mild hypothermia during early reperfusion also reduced myocardial damage in rats in vivo (Schwiebert et al., 2010).

In comparison to its use for post-conditioning, much more information is available for myocardial preconditioning with xenon. Cardioprotection by xenon might be established if the gas is given as an early (within 2–3 h) or late (within 12–24 h) preconditioning stimulus before organ ischaemia occurs: in rats subjected to 25 min of regional myocardial ischaemia followed by 2 h of reperfusion, xenon inhalation for three times 5 min before myocardial ischaemia significantly reduced infarct size from 51% of the area at risk to 28% (Weber et al., 2005a).

Mechanisms of xenon-induced cardioprotection

There are numerous enzymes and cellular structures involved in mediating the organ-protective effects of conditioning. Namely the survivor activating factor enhancement (SAFE) pathway and the reperfusion injury salvage kinase (RISK) pathway have been suggested to play significant roles in mediating tissue protection (Hausenloy et al., 2011). The SAFE pathway is influenced by, for example, the JAK, STAT pathways and the mitochondrial permeability transition pore (mPTP). The RISK pathway involves numerous intracellular mediators, such as PI3K, PKC, MAPK, glycogen synthase kinase 3β (GSK3β) and ERK (Hausenloy et al., 2011). It is likely that these pathways, which have mainly been described for ischaemic conditioning (Przyklenk, 2013), also play a significant role in pharmacological conditioning by noble gases. Figure 1 summarizes the possible mechanisms of noble gas-induced cardioprotection.

Figure 1.

Figure 1

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Schematic diagram showing mechanisms underlying the protective effects of noble gases. This figure is a summary of the mechanisms that may contribute to organ protection by noble gases, mainly via the RISK pathway. Gas names are shown in circles (He, Ar, Xe). Green arrows indicate an activating or up-regulatory effect, whereas red dots indicate a suppressive or down-regulatory effect. Bcl-2, B-cell lymphoma-2; DAG, diacylglycerol; IP3, inositol triphosphate-3; Mdm2, murine double minute-2; mKCa, mitochondrial Ca2+-sensitive potassium channel; p38MAPK, p38 MAPK; PDK-1, phosphoinositide-dependent PK-1; Pi, inorganic phosphate; ROS, reactive oxygen species.

Mechanism of xenon early preconditioning

The infarct size reduction by xenon preconditioning (Weber et al., 2005a) was completely blocked by infusion of a PKC inhibitor or a p38 MAPK inhibitor, demonstrating that these enzymes play a significant role in xenon-induced preconditioning. Xenon significantly increased phosphorylation of the isoform PKCε, and this effect was blocked by the PKC inhibitor but not by the MAPK inhibitor. These data show that p38 MAPK is located downstream of PKC in the signalling cascade of xenon-induced preconditioning. Further experiments revealed that p38 MAPK is directly activated by xenon (an effect again blocked by a PKC inhibitor) and that the downstream target of p38 MAPK, the MAPK-activated PK2 (MAPKAPK-2), is also phosphorylated after xenon preconditioning (Weber et al., 2005b). Using immunofluorescence staining, it was shown that xenon induced a translocation of PKCε from the cytosol to the membrane fraction of myocardial tissue. To summarize, xenon reduced infarct size by a PKCε and MAPK-dependent mechanism whereby the PKCε-dependent mechanism is mediated by a translocation of PKCε from the cytosol to the membrane fraction of the cardiomyocytes.

In addition to MAPKAPK-2, the small heat shock protein (HSP) 27 also plays an important role in the reorganization of the actin cytoskeleton network of the cell. HSP27 was phosphorylated and translocated to the particulate fraction of cell homogenates after xenon inhalation. From looking at the actin cytoskeleton, xenon was found to increase the polymerization of F-actin fibres, and these fibres were co-localized with the phosphorylated (p) HSP27 (Weber et al., 2005b).

A central role for PKC in mediating the protective effects of different kinds of preconditioning has been confirmed in different animal species as well as in humans (Simkhovich et al., 2013). PKC can be activated by translocation, by phosphorylation of a threonine or serine residue, mediated by the 3′phosphatidylinositol-dependent kinase-1 (PDK-1), as well as by free radical release induced by activation of the mitochondrial ATP-dependent potassium channel (KATP channel). Inhibitors of both target pathways blocked xenon-induced infarct size reduction as well as the phosphorylation of PKC (Weber et al., 2006b). The absence of PKC activation in the presence of a mitochondrial KATP channel blocker within the signalling cascade of xenon preconditioning makes it likely that the opening of the KATP channel takes place upstream of PKC activation. PDK-1 was time-dependently activated by xenon before PKCε was activated.

There are also other isoforms of PKC, namely PKCδ and PKCα. However, these isoforms were not involved in xenon preconditioning, suggesting an isoform-specific activation of PKCε by xenon (Weber et al., 2006a,b,). Similarly, other MAPKs, such as ERK (p44/42 MAPK) and the stress-activated p54/46 MAPK, are critically involved in cell differentiation, cell survival as well as in cellular apoptosis. Although ERK is involved in xenon-induced tissue protection and an inhibitor of ERK blocked the cardioprotective actions of xenon, blocking of JNK1/2 and JNK3 had no effect on xenon-induced infarct size reduction (Weber et al., 2006a). These data suggest a specific regulation of different kinases by xenon preconditioning in the heart (Weber et al., 2006a).

Mechanism of xenon-induced late preconditioning LPC

A second window of protection (LPC) occurs 12–24 h after application of a preconditioning stimulus and lasts up to 72 h. Xenon-induced LPC reduced infarct size in rat hearts subjected to regional ischaemia and reperfusion from 64 to 31% of the area at risk (Weber et al., 2008a). Co-administration of an inhibitor of COX-2 completely blocked this infarct size reduction, although there was no direct increase in COX-2 mRNA or COX-2 protein expression observed after xenon preconditioning.

Endothelial protection by xenon

An endothelial layer covers all vessels in the body, including coronary artery vessels. Cardioprotective effects of noble gases might therefore be mediated via changes within the endothelium. The endothelial cell surface is relatively non-adhesive for macromolecular structures, but this physiological property might be significantly altered after ischaemia and reperfusion. Increased pro-inflammatory cytokines such as TNF-α will increase the expression of cell adhesion molecules on the endothelial layer, thereby recruiting circulating leukocytes to the site of inflammation. In cultured HUVEC, TNF-α was applied to induce cell damage, leading to increased expression of intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules (Weber et al., 2008c). Pretreatment of the cells with xenon as a preconditioning stimulus (three times 5 min) reduced the expression of the mRNA and protein of ICAM-1 and VCAM-1, but had no effect on a third adhesion molecule, E-selectin. In addition, xenon prevented the TNF-α-induced increase in NF-κB transcriptional activity. Xenon thus most likely confers preconditioning via an ICAM-1- and VCAM-1-mediated pathway that includes inhibition of NF-κB activity.

Xenon blocks the calcium-dependent calcium influx in endothelial cells (Petzelt et al., 1999), thereby affecting mechanisms regulating the calcium release-activated calcium channel of the plasma membrane. Taken together, these data show that xenon might significantly alter endothelial function and, therefore, some of the organ-protective properties of xenon in different organs might be mediated by changes within the endothelium.

The organ-protective effects of xenon might also be caused by modulation of inflammatory reactions, which have been demonstrated in neuronal tissue (Fahlenkamp et al., 2010) as well as in blood (de Rossi et al., 2004). However, xenon had no effect on the inflammatory response to cardiopulmonary bypass (CPB) as measured by cytokine, pro-inflammatory IL-6 and anti-inflammatory IL-10, levels in a rat model of CPB (Clark et al., 2005). These data confirmed previous findings from in vitro experiments using human blood showing that xenon had no effect on the inflammatory response to CBP (Bedi et al., 2002).

How might inert gases be able to induce cellular changes?

Although xenon – like other noble gases – is supposed to be inert, it is obvious from the aforementioned experimental data that xenon is able to produce biological changes within different cells. Using X-ray crystallography studies, it has been suggested that xenon may disrupt conformational changes of the proteins urate oxidase, an intracellular globular protein with large hydrophobic cavities, and annexin V, a protein with a hydrophilic pore inside supposed to bind to cell membranes by a calcium-dependent action (Colloc'h et al., 2007). Binding sites of xenon within the respective proteins are flexible gas cavities with no water inside.

A series of cell membrane receptors has been shown to be influenced by xenon, for example, the NMDA receptors (Franks et al., 1998), the two-pore domain potassium channel TREK-1 (Gruss et al., 2004), the plasmalemmal KATP channel (Bantel et al., 2009), the nicotinic ACh receptor (Yamakura and Harris, 2000) as well as the 5-HT3 receptor (Suzuki et al., 2002). Most of this knowledge comes from neuronal cells. Whether these cellular effects also play a role in myocardial protection by xenon remain unclear. However, the KATP channel, at least the mitochondrial KATP channel, has been demonstrated to be critically involved in preconditioning of the heart (O'Rourke, 2004), and xenon-induced cardioprotection might be mediated partly via this channel. Regarding the previously mentioned actions on cerebral NMDA receptors, it has been shown that xenon competes with the co-agonist glycine at the glycine site of the NMDA receptor (Dickinson et al., 2007).

Translatability of xenon-related organ protection

The protective effects of xenon have been investigated in human tissue in vitro. Xenon limited cell loss and decreased caspase-3 activity in cultured human osteosarcoma cells, indicating an anti-apoptotic effect (Spaggiari et al., 2013). In cultured renal tubular cells (HK-2 cells) subjected to oxygen and glucose deprivation, xenon was the only noble gas with cell-protective properties (Rizvi et al., 2010). In this cell type subjected to hypoxia–hypothermia, xenon limited cell loss and promoted cell expression of HSP70 and haemoxygenase-1 (Zhao et al., 2013). In an isolated CPB system filled with blood from healthy human volunteers, xenon had no effect on cellular markers of inflammation caused by the extracorporeal circulation (Saravanan et al., 2009). Fahlenkamp et al. (2014) compared the effects of xenon and sevoflurane anaesthesia on leukocyte function in surgical patients. Leukocyte subpopulations were not different, and phagocytosis and oxidative burst of granulocytes were reduced to the same extent in both groups (Fahlenkamp et al., 2014). After ex vivo LPS stimulation, pro-inflammatory cytokine release was not affected by xenon. These data show that xenon has a minimal influence on inflammatory activity in humans.

Xenon has virtually no direct influence on myocardial blood flow and global haemodynamics in healthy and diseased hearts (Preckel et al., 2002a,b,). Therefore, the use of xenon has been advocated in cardiac-compromised patients (Baumert et al., 2005; 2008,; Bein et al., 2005), and several studies have demonstrated intraoperative preservation of myocardial contractility and stable haemodynamics (Coburn et al., 2005; Wappler et al., 2007; Schaefer et al., 2011). Despite the huge amount of experimental studies on xenon conditioning of the heart (Preckel et al., 2006) and neuronal tissue (Deng et al., 2014), there are, as yet, no studies clearly translating the conditioning properties of xenon found in experimental studies to humans. One reason might be the limited availability of xenon, leading to very high costs of this noble gas. Another limitation for using xenon in the clinical ischaemia reperfusion situation might have been the lack of suitable anaesthesia machines to safely and cost-effectively deliver xenon. More recently, some new machines have become available for xenon ventilation, and advances in recovery and recycling of xenon might further help to make use of this substance economically more viable (Dingley and Mason, 2007; Rawat and Dingley, 2010). Because xenon has many fewer haemodynamic side effects than routinely used volatile anaesthetics, such as sevoflurane and desflurane, it might be advantageous to investigate the possible beneficial effects of this noble gas in clinical studies on pre- and post-conditioning.

Lockwood et al. (2006) performed a feasibility and safety study, applying xenon to patients undergoing coronary artery bypass grafting using extracorporeal CPB. Although the study was not randomized and does not allow firm conclusions on myocardial injury, there was a tendency towards reduced troponin release in patients receiving 20–50% xenon compared with patients ventilated without any xenon. In contrast, in a randomized trial in 30 patients undergoing cardiac surgery there was no difference in post-operative troponin release when using xenon compared with sevoflurane anaesthesia (Stoppe et al., 2013). Bein et al. (2005) determined troponin and creatine kinase-muscle/brain release in high-risk surgical patients subjected to aortic surgery under inhalational anaesthesia with xenon or total i.v. anaesthesia with propofol. The authors found very low levels of myocardial damage markers, with no significant differences between groups, although three patients in the propofol group had elevated troponin values in the post-operative period compared with zero patients in the xenon group. All clinical studies included only few patients and, therefore, do not allow any firm conclusion to be drawn about cardioprotection of xenon in humans. A summary of the clinical studies concerning cardioprotection by xenon is given in Table 1. Recently, a clinical trial (NCT01294163) finished, which included more than 500 patients and compared the effects of xenon, propofol or sevoflurane-based anaesthesia on post-operative myocardial damage after coronary artery bypass graft surgery (Hofland, 2014). The results of this study should provide us with a definitive answer to the question of whether the beneficial cardioprotective effects of xenon observed in numerous animal studies are translatable to the clinical situation in humans.

Table 1.

Table summarizing available data of noble gas induced protection in human tissue

Injury Noble gas Type Method Outcome Reference
Staurosporine, mitochondrial toxins He, Ne, Ar, Kr, Xe (75%) Osteosarcoma cells Continuous Xe and Ar limited cell loss and decreased caspase-3 activation Spaggiari et al., 2013
Oxygen glucose deficiency He, Ne, Ar, Kr, Xe (75%) Renal tubular cells (HK-2) Preconditioning Xe protects against cell death, He is cytotoxic, other gases had no effect Rizvi et al., 2010
None Ar (50%) Astroglial cells Continuous Ar enhanced ERK1/2 activity in microglia via the upstream kinase MEK Fahlenkamp et al., 2012
Microglial cells (BV-2)
Oxygen glucose deficiency Xe (80%) Neuronal glial cells Preconditioning Xe limited cell loss via K-ATP channel activation Bantel et al., 2009
Hypothermia–hypoxia Xe (70%) Renal tubular cells (HK-2) Preconditioning Xe limited cell loss and promoted cell expression of HSP70 and haemoxygenase-1 Zhao et al., 2013
Post-conditioning
LPS lipoteichoic acid anti-CD3/anti-CD28 He (79%) Blood from healthy volunteers Preconditioning 30 and 60 min of helium inhalation does not affect immune system function Oei et al., 2012a
LPS Xe (60%) Blood from patients undergoing elective abdominal surgery Continuous Xe provides modest anti-inflammatory and no pro-inflammatory effect. ERK1/2 phosphorylation in leukocytes was reduced after 1 h of Xe anaesthesia Fahlenkamp et al., 2014
Cardiopulmonary bypass Xe (50%) Blood from healthy volunteers Continuous Xe had no effect on CPB induced leukocyte and platelet activation after CPB Saravanan et al., 2009
Cardiopulmonary bypass Xe (70%) Blood from healthy volunteers Continuous Xe had no effect on cytokine (IL-8, IL-10, TNF) and adhesion molecule expression L-selectin, CD18, CD11b) after CPB Bedi et al., 2002
Forearm I/R 15 min He (50%) Human volunteers Continuous He had no effect on endothelium, but decreased expression of CD11b and ICAM on leukocytes ad CD42b and PSGL-1 on platelets Lucchinetti et al., 2009
Forearm I/R 20 min He (79%) Human volunteers Preconditioning He protects post-ischaemic endothelial function Smit et al., 2013
Blocking eNOS did not abolish this effect
None Xe (59%) Healthy volunteers Continuous Xenon had minimal effects on coronary flow dynamics Schaefer et al., 2011
None Xe (65%) CAD patients undergoing non-cardiac surgery Continuous Xe anaesthesia has higher mean arterial blood pressure and better left ventricle ejection fraction Baumert et al., 2008
Out-of-hospital cardiac arrest Xe (47%) Out-of-hospital cardiac arrest patients Post-conditioning Xe + mild hypothermia is feasible and favourable with decreased troponin T release Arola et al., 2013
CABG Xe (45–50%) CABG Continuous Balanced xenon anaesthesia is feasible and safe Stoppe et al., 2013
Aortic surgery Xe (60%) Aortic surgery Continuous Xe does not improve haemodynamic parameters or troponin release compared with total venous anaesthesia Bein et al., 2008
CABG Xe (20, 35, 50%) CABG Continuous Xe was safely and efficiently delivered to CABG patients while on CPB Lockwood et al., 2006
None Xe (60–65%) Intracardiac device implantation Continuous Xe preserves mean arterial blood pressure and left ventricle ejection fraction compared with propofol Baumert et al., 2005
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Injury, injury type against which protection was induced; noble gas, type and concentration of gas used; type, type of patients or cell type; method, type of stimulus used; outcome, short summary of results; reference, reference of original paper.

CABG, coronary artery bypass grafting; CAD, coronary artery disease.

In a feasibility and safety study in adults with out-of-hospital cardiac arrest, xenon (at least 40%) was given for 24 h during mild hypothermia (Arola et al., 2013), initiated at the moment of intensive care unit admission. Because these patients have both cardiac as well as cerebral damage, xenon may be particularly advantageous in this patient population. The post-arrival incremental change of troponin T from baseline to 24, 48 and 72 h post-resuscitation was significantly lower in patients treated with xenon + mild hypothermia compared with patients treated solely with mild hypothermia. There was no safety issue observed in these post-cardiac arrest patients ventilated with a xenon–oxygen mixture. Although these data indicate that xenon might be a suitable treatment addition in patients with cardiac arrest, we have to take into account that all clinical studies only determine indirect parameters (e.g. enzyme release) for organ protection and that up to now no clinical outcome studies are available allowing a strong conclusion on xenon-induced organ protection in a clinical ischaemia reperfusion situation. With regard to neuroprotection, several small studies were not able to demonstrate any positive effect of xenon on incidence of post-operative cognitive dysfunction in the elderly (Rasmussen et al., 2006; Coburn et al., 2007; Höcker et al., 2009; Cremer et al., 2011). A clinical challenge might be the experimental finding that any kind of pre- and post-conditioning can be negatively influenced by co-morbidities such as hypertension (Oei et al., 2012b), diabetes (Weber et al., 2008b) or simply senescence (Heinen et al., 2008). As yet, no clinical data are available demonstrating a conditioning effect of xenon in co-morbid or elderly patients, although this group of patients is likely to be the most pertinant population for organ protection.

Helium

In contrast to xenon, the noble gas helium has no anaesthetic properties, and might therefore be used in awake patients subjected to ischaemia reperfusion situations, for example, during percutaneous coronary interventions in patients with myocardial infarction.

Helium has not been found to have any side effects on global or regional haemodynamics. Because helium has a low density, it reduces the energy needed to breathe and is, therefore, used in patients with airway diseases. Ventilators allowing application of helium by invasive and non-invasive ventilation strategies are available and, therefore, helium might also be used during heart or vascular surgery or in patients undergoing organ transplantation. Because this noble gas is much less expensive than xenon, helium might be an excellent alternative for organ protection in clinical ischaemia reperfusion situations.

Mechanisms of cardioprotection induced by helium

Preconditioning by helium

Besides xenon, the non-anaesthetic noble gas helium also exerts profound organ-protective effects (Oei et al., 2010). Three times 5 min inhalation of 70% helium before 30 min of coronary artery occlusion followed by 3 h of reperfusion significantly reduced infarct size in rabbit hearts (Pagel et al., 2007). These data show that the noble gas helium induces preconditioning of the heart.

Administration of a PI3K antagonist, a mitogen/ERK 1 (MEK1) inhibitor or an inhibitor of the 70 kDa ribosomal protein s6 kinase (p70s6kinase) abolished this helium-induced preconditioning, indicating a role for the so-called RISK pathway in helium-induced cardioprotection. As these pro-survival kinases inhibit GSK3β and apoptotic protein p53 degradation, Pagel et al. (2008a) investigated whether inhibition of GSK3β and p53 lowers the threshold of helium-induced protection. The authors could indeed demonstrate that with these pharmacological interventions the protection of helium could be facilitated, an effect that was also observed after morphine application (Pagel et al., 2009). These data indicate an opioid receptor-mediated mechanism in helium-induced preconditioning, which might play a significant role in patients subjected to ischaemia reperfusion as morphine is a routinely used opioid analgesic applied in these clinical situations.

Opening of the mPTP leads to mitochondrial dysfunction, and preconditioning might be beneficial by preserving cardiac mitochondrial function. The mPTP is postulated to be a possible end-effector for myocardial necrosis and apoptosis after ischaemia/reperfusion (I/R) injury, and prosurvival kinases (PI3K, ERK1/2) and their downstream targets (endothelial NOS, p53, GSK3β) all prevent opening of the mPTP (Hausenloy et al., 2009). Application of a selective mPTP opener abolished helium-induced early preconditioning (Pagel et al., 2008a), indicating that helium eventually inhibits mPTP opening. Prolongation of post-ischaemic acidosis has been shown to reduce myocardial infarct size (Preckel et al., 1998), and correction of acidic pH after restoration of blood flow can cause mPTP opening (Cohen et al., 2007), thereby inducing tissue damage. Transient alkalosis during early reperfusion abolished helium-induced cardioprotection, but the protection was restored by the mPTP inhibitor cyclosporine A (Pagel and Krolikowski, 2009). These data suggest that helium prevents mPTP opening by maintaining intracellular acidosis during early reperfusion. The effect of radical oxygen species and the mitochondrial ATP-regulated potassium channel (KATP) in helium preconditioning was investigated using the reactive oxygen species scavengers N-acetylcysteine and N-2-mercaptopropionyl glycine or the KATP channel blocker 5-hydroxydeconate respectively (Pagel et al., 2008b). All blockers completely abolished helium-induced cardioprotection indicating radical oxygen scavengers, and that KATP channels mediate helium preconditioning. In addition, infusion of the non-selective NOS inhibitor N-nitro-L-arginine methyl ester during helium preconditioning abolished cardioprotection, whereas infusion of a selective inducible NOS inhibitor or a selective neuronal NOS inhibitor had no effect, indicating that protection by helium is mediated by NO generated by endothelial NOS (Pagel et al., 2008c).

Cardiac mitochondrial function can be further analysed by the rate of oxygen consumption of isolated mitochondria after administration of a complex 2 substrate (state 2), ADP (state 3) and after complete phosphorylation of ADP to ATP (state 4) respectively. Preconditioning by helium increased state 4 respiration, thereby reducing the respiratory control index and suggesting a mild mitochondrial uncoupling. This effect was blocked by a selective Ca2+-sensitive potassium channel blocker iberiotoxin (Heinen et al., 2008). More recent data show that the activation of Ca2+-sensitive potassium channels by helium preconditioning is mediated via PKA (Huhn et al., 2012).

Interestingly, in helium-induced organ protection the involvement of various enzymes and kinases has only been shown by use of specific or non-specific blockers. Until now, for helium – in contrast to xenon – no significant up- or down-regulation or phosphorylation of the different kinases or its products has been demonstrated (Huhn et al., 2009b).

Post-conditioning by helium

To gain more mechanistic insights into the protective effect of helium, the expression of genes involved in cell death and survival pathways was investigated after helium post-conditioning in male rats subjected to ischaemia, I/R or I/R and 15 min of 70% helium at the onset of reperfusion (Oei et al., 2013). Helium post-conditioning caused the up-regulation of genes involved in necrosis (17 of 23) and pro-apoptosis (18 of 25). Simultaneously, 4 of 23 (necrosis) and 7 of 25 genes (pro-apoptosis) were down-regulated. The majority of anti-apoptotic genes (9 of 11) and genes involved in autophagy (24 of 32) were up-regulated after helium post-conditioning. These data suggest that helium post-conditioning at least partly prevents the execution of cell death programmes, thereby reducing myocardial infarct size.

Most of the aforementioned influences of helium on the heart were investigated in healthy myocardium. However, pathophysiological changes, for example, hypertension, diabetes mellitus or ageing, may block any conditioning effect. Helium conditioning is more difficult to obtain in diseased animals: it is abolished in aged rats (Heinen et al., 2008; Huhn et al., 2012) as well as in diabetic, Zucker obese rats (Huhn et al., 2009b). The combination of both, helium pre- with post-conditioning, was protective against infarct size development in spontaneous hypertensive rats, whereas each stimulus alone was not able to induce cardioprotection in the hypertensive rat heart (Oei et al., 2012b).

Effect of helium on caveolae and caveolins

Caveolae are cholesterol and sphingolipid-enriched invaginations of the plasma membrane. Caveolins, the structural proteins essential for caveolae formation, are critically involved in anaesthetic-induced cardioprotection (Horikawa et al., 2008). Helium inhalation decreased caveolin-1 and 3 expressions after 24 h (Weber et al., 2012). Buoyant caveolin-enriched fractions, indicative of increased caveolin formation, supported the results showing lower caveolin-1 and 3 levels in cytosolic and mitochondrial fractions, whereas caveolin-1/3 were accumulated in serum of mice 24 h after exposure to helium. These data indicate that caveolin-1 and 3 are secreted into the blood after helium inhalation (Weber et al., 2013) and support the hypothesis that circulating factors in the blood stream may be involved in inducing organ protection. This is in accord with other means of conditioning (Rassaf et al., 2014).

Translatability of helium-related organ protection

Similar to xenon, the tremendous bulk of data on helium-induced organ protection in the heart (Oei et al., 2010) was not definitively translated to the clinical situation.

Helium pre- and post-conditioning of the heart was investigated in patients undergoing coronary artery bypass grafting surgery. Patients were ventilated with a gas mixture of helium (70%) for 3 × 5 min before the start of the CPB or at the moment of coronary reperfusion after declamping the aorta. In contrast to what would be expected from experimental data, neither helium pre- or post-conditioning nor a combination of pre- and post-conditioning had any protective effect on post-operative troponin release (Smit et al., 2012).

Helium conditioning was investigated in healthy human volunteers subjected to forearm ischaemia and reperfusion. Using venous occlusion plethysmography to measure forearm blood flow responses to ACh before and after 20 min of forearm I/R, we recently demonstrated that three times 5 min of 79% helium inhalation prevented post-ischaemic endothelial dysfunction (Smit et al., 2013). A similar protection was observed 24 h after helium inhalation, demonstrating an early as well as a late endothelial preconditioning effect of helium in humans in vivo. Even after blocking endothelial NOS during helium inhalation, the endothelial protection was maintained (Smit et al., 2013), meaning that the involvement of NOS found in previous animal studies (Pagel et al., 2008c) could not be reconfirmed in humans.

Lucchinetti et al. (2009) applied 50% helium before, during and after ischaemia to healthy human volunteers and used post-ischaemic reactive hyperaemia to assess endothelial function before and after 15 min of forearm ischaemia. An increase in the pro-inflammatory marker CD11b and ICAM-1 on leukocytes and an attenuated expression of the pro-coagulant markers CD42b and PSGL-1 on platelets was observed. However, no changes in the post-occlusive hyperaemic reaction were determined. Although Smit et al. (2013) used 70% helium, Lucchinetti and colleagues applied 50% helium. These differences in helium concentration might have influenced the results, although in animal experiments helium as low as 30% induced myocardial protection (while 10% helium was not protective) (Huhn et al., 2009a). The discrepancies of the results between the two studies might also be due to the different protocols of helium administration, as it was previously shown that continuous administration of a pharmacological agent, for example, a volatile anaesthetic, does not induce cardioprotection, whereas intermitted application with more than one cycle of inhalation of a volatile anaesthetic did protect the human heart (Bein et al., 2008; Frässdorf et al., 2009). In contrast to the study by Lucchinetti et al. (2009), another study in human volunteers did not show any effect of helium on the responsiveness of the innate and early adaptive immune system after 30 and 60 min of helium inhalation (Oei et al., 2012a).

Other noble gases

Argon, neon and krypton

The noble gas argon has anaesthetic properties under hyperbaric conditions and is mainly investigated for its neuroprotective effects. After occlusion of the middle cerebral artery in rats, administration of 50% argon reduced cerebral infarct size (Ryang et al., 2011). In a model using cardiac arrest in rats, post-conditioning with 70% argon administered after resuscitation reduced histopathological damage of the neocortex and hippocampus. The mechanism underlying this neuroprotective effect includes up-regulation of ERK1/2 via MEK (Fahlenkamp et al., 2012). Unlike neuroprotection by xenon, there seems no role for the NMDA receptor in argon-induced organ protection (Harris et al., 2013). A recent study implicated a direct and concentration-dependent modulating effect of argon on enzymatic and thrombolytic effect of tissue plasminogen activator (David et al., 2012): a low concentration of argon (25%) blocked and high concentrations (75%) increased enzymatic and thrombolytic efficiency of tissue plasminogen activator. This might be interesting not only in patients with ischaemic stroke but also in patients with myocardial infarction. With respect to cardioprotection, three cycles of 70% argon inhalation interspersed with washout periods reduced infarct size after regional myocardial ischaemia in rabbits (Pagel et al., 2007). As yet, no clinical studies investigating organ-protective effects of argon are available. In human cultured osteosarcoma cells, argon (similar to xenon) limited the cell loss induced by the broad spectrum tyrosine kinase inhibitor staurosporine and several other mitochondrial toxins. In addition, argon inhibited the apoptotic activation of caspase-3 (Spaggiari et al., 2013).

Neon reduced infarct size after regional myocardial ischaemia in rabbits to the same extent as helium and argon (Pagel et al., 2007). No data on the underlying mechanisms are available. Neon and krypton had no neuroprotective effect in cortical neuronal cell cultures subjected to oxygen and glucose deprivation (Jawad et al., 2009). Interestingly, in this model helium had detrimental effects on the cells and increased cell damage. In human cultured renal tubular cells (HK2) neon, argon and krypton showed no protection from cell injury provoked again by oxygen and glucose deprivation (Rizvi et al., 2010). No clinical studies are available investigating possible beneficial effects of neon or krypton in ischaemia reperfusion situations in humans.

Conclusion

In addition to neuro- and cardioprotection, helium and xenon exert beneficial effects in the lung, kidney and liver. However, after summarizing the promising experimental data on tissue protection, it remains to be proven whether this beneficial effect can be translated to the clinical situation. At this moment, there are not enough clinical data to allow any conclusion, although a lot of studies have been initiated with protocols published in trial registrations. The recently finished study on cardioprotection by xenon in coronary artery bypass graft surgery patients will answer the question whether xenon protects against ischaemic cardiac damage after cardiac surgery. However, in this study, the most relevant group of patients, namely those patients with severely reduced myocardial function and very high risk for ischaemic damage (e.g. combined coronary artery and valve surgery), was excluded. Thus, future studies will have to include high-risk patients in order to show any beneficial effect on organ protection, thereby translating the promising experimental results from various models of organ damage to the clinical situation. A recent feasibility study has already demonstrated that high-risk patients can be safely ventilated with up to 50% of helium after cardiac arrest and resuscitation (Brevoord et al., 2012).

Conflict of interest

None of the authors has competing interests to be disclosed.

Glossary

CPB

cardiopulmonary bypass

GSK

glycogen synthase kinase

HSP

heat shock protein

I/R

ischaemia/reperfusion

ICAM

intracellular cell adhesion molecules

KATP

ATP-dependent potassium

LPC

late preconditioning

MAPKAPK-2

MAPK-activated PK2

MEK

mitogen/ERK

mPTP

mitochondrial permeability transition pore

PDK-1

3′phosphatidylinositol-dependent kinase-1

RISK

reperfusion injury salvage kinase

SAFE

survivor activating factor enhancement

VCAM

vascular cell adhesion molecule

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