Modulation by the Noble Gas Helium of Tissue Plasminogen Activator: Effects in a Rat Model of Thromboembolic Stroke.

INTERVENTIONS: Helium has been shown to provide neuroprotection in mechanical model of acute ischemic stroke by inducing hypothermia, a condition shown by itself to reduce the thrombolytic and proteolytic properties of tissue plasminogen activator. However, whether or not helium interacts with the thrombolytic drug tissue plasminogen activator, the only approved therapy of acute ischemic stroke still remains unknown. This point is not trivial since previous data have shown the critical importance of the time at which the neuroprotective noble gases xenon and argon should be administered, during or after ischemia, in order not to block tissue plasminogen activator-induced thrombolysis and to obtain neuroprotection and inhibition of tissue plasminogen activator-induced brain hemorrhages. MEASUREMENTS AND MAIN RESULTS: We show that helium of 25-75 vol% inhibits in a concentration-dependent fashion the catalytic and thrombolytic activity of tissue plasminogen activator in vitro and ex vivo. In vivo, in rats subjected to thromboembolic brain ischemia, we found that intraischemic helium at 75 vol% inhibits tissue plasminogen activator-induced thrombolysis and subsequent reduction of ischemic brain damage and that postischemic helium at 75 vol% reduces ischemic brain damage and brain hemorrhages. CONCLUSIONS: In a clinical perspective for the treatment of acute ischemic stroke, these data suggest that helium 1) should not be administered before or together with tissue plasminogen activator therapy due to the risk of inhibiting the benefit of tissue plasminogen activator-induced thrombolysis; and 2) could be an efficient neuroprotective agent if given after tissue plasminogen activator-induced reperfusion.

Crystallographic studies with xenon and nitrous oxide provide evidence for protein-dependent processes in the mechanisms of general anesthesia.

BACKGROUND: The mechanisms by which general anesthetics, including xenon and nitrous oxide, act are only beginning to be discovered. However, structural approaches revealed weak but specific protein-gas interactions. METHODS: To improve knowledge, we performed x-ray crystallography studies under xenon and nitrous oxide pressure in a series of 10 binding sites within four proteins. RESULTS: Whatever the pressure, we show (1) hydrophobicity of the gas binding sites has a screening effect on xenon and nitrous oxide binding, with a threshold value of 83% beyond which and below which xenon and nitrous oxide, respectively, binds to their sites preferentially compared to each other; (2) xenon and nitrous oxide occupancies are significantly correlated respectively to the product and the ratio of hydrophobicity by volume, indicating that hydrophobicity and volume are binding parameters that complement and oppose each other's effects; and (3) the ratio of occupancy of xenon to nitrous oxide is significantly correlated to hydrophobicity of their binding sites. CONCLUSIONS: These data demonstrate that xenon and nitrous oxide obey different binding mechanisms, a finding that argues against all unitary hypotheses of narcosis and anesthesia, and indicate that the Meyer-Overton rule of a high correlation between anesthetic potency and solubility in lipids of general anesthetics is often overinterpreted. This study provides evidence that the mechanisms of gas binding to proteins and therefore of general anesthesia should be considered as the result of a fully reversible interaction between a drug ligand and a receptor as this occurs in classical pharmacology.

Short-term development of behavioral sensitization to amphetamine requires N-methyl-D-aspartate- and nicotinic-dependent mechanisms in the nucleus accumbens.

Repeated administration of psychostimulant drugs, such as amphetamine, induces an enhanced behavioral response to subsequent drug challenge. This behavioral sensitization is proposed to model the increased drug craving observed in human psychostimulant abusers. Current thinking is that the ventral tegmental area, but not the nucleus accumbens, plays a critical role in the development of behavioral sensitization. Here, we report that the concomitant blockade of glutamatergic and nicotinic ionotropic receptors in the core of the nucleus accumbens blocks the development of behavioral sensitization to amphetamine and further abolishes the increase in extracellular dopamine release induced by amphetamine in the nucleus accumbens. These findings demonstrate that the development of behavioral sensitization to amphetamine depends, in addition to the well-known role of the ventral tegmental area, on glutamatergic and nicotinic-dependent mechanisms in the core of the nucleus accumbens and further indicate that the dopaminergic mesolimbic pathway must be viewed as a single coordinated system of critical importance in the development of behavioral sensitization to psychostimulant drugs.

Hemodynamic profiles of intubated and mechanically ventilated carbon monoxide-poisoned patients during systemic hyperbaric oxygen therapy.

BACKGROUND: Carbon monoxide (CO) poisoning can be a life threatening condition. Systemic hyperbaric oxygen (HBO) therapy is used to induce CO detoxification. However, little is known about the hemodynamic response to HBO in severely intoxicated patients. METHODS: We retrospectively analyzed the medical records of 6 CO-poisoned patients treated with propofol, rocuronium bromide, and HBO. The HBO protocol comprised 3 HBO treatments (HBOT1 to HBOT3) within 24 hours. During all HBO sessions heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse blood pressure (ΔBP) were measured every five minutes. Non-parametric tests were used to compare data between HBO sessions. RESULTS: HR increased significantly as the number of HBOT increased, from 68 beats per minute (bpm) during HBOT1 to 77 and 86 bpm during HBOT2 and HBOT3, respectively (p < 0.05). In addition, while no significant change was found for DBP, both SBP and ΔBP showed a transient and significant increase during HBOT2, compared to HBOT1, that did not return to basal values during HBOT3. CONCLUSION: Based on previous studies that have established the respective effects of rocuronium bromide, propofol, HBO, and CO alone on HR, SBP, and ΔBP, it is concluded that the hemodynamic responses observed in the present study are likely to be due to CO. If such, given that neither HR nor SBP and ΔBP returned to basal values by the end of HBOT3, it is suggested that more than 3 HBOT sessions could be necessary to provide full hemodynamic recovery in CO-poisoned patients.

Pressure-response analysis of anesthetic gases xenon and nitrous oxide on urate oxidase: a crystallographic study.

The remarkably safe anesthetics xenon (Xe) and, to lesser extent, nitrous oxide (N(2)O) possess neuroprotective properties in preclinical studies. To investigate the mechanisms of pharmacological action of these gases, which are still poorly known, we performed both crystallography under a large range of gas pressure and biochemical studies on urate oxidase, a prototype of globular gas-binding proteins whose activity is modulated by inert gases. We show that Xe and N(2)O bind to, compete for, and expand the volume of a hydrophobic cavity located just behind the active site of urate oxidase and further inhibit urate oxidase enzymatic activity. By demonstrating a significant relationship between the binding and biochemical effects of Xe and N(2)O, given alone or in combination, these data from structure to function highlight the mechanisms by which chemically and metabolically inert gases can alter protein function and produce their pharmacological effects. Interestingly, the effects of a Xe:N(2)O equimolar mixture were found to be equivalent to those of Xe alone, thereby suggesting that gas mixtures containing Xe and N(2)O could be an alternative and efficient neuroprotective strategy to Xe alone, whose widespread clinical use is limited due to the cost of production and availability of this gas.

Interactions between nitrous oxide and tissue plasminogen activator in a rat model of thromboembolic stroke.

BACKGROUND: Preclinical evidence in rodents has suggested that inert gases, such as xenon or nitrous oxide, may be promising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has shown that xenon interacts with tissue-type plasminogen activator (tPA), a well-recognized approved therapy of acute ischemic stroke. Although intraischemic xenon inhibits tPA-induced thrombolysis and subsequent reduction of brain damage, postischemic xenon virtually suppresses both ischemic brain damage and tPA-induced brain hemorrhages and disruption of the blood-brain barrier. The authors investigated whether nitrous oxide could also interact with tPA. METHODS: The authors performed molecular modeling of nitrous oxide binding on tPA, characterized the concentration-dependent effects of nitrous oxide on tPA enzymatic and thrombolytic activity in vitro, and investigated the effects of intraischemic and postischemic nitrous oxide in a rat model of thromboembolic acute ischemic stroke. RESULTS: The authors demonstrate nitrous oxide is a tPA inhibitor, intraischemic nitrous oxide dose-dependently inhibits tPA-induced thrombolysis and subsequent reduction of ischemic brain damage, and postischemic nitrous oxide reduces ischemic brain damage, but in contrast with xenon, it increases brain hemorrhages and disruption of the blood-brain barrier. CONCLUSIONS: In contrast with previous studies using mechanical acute stroke models, these data obtained in a clinically relevant rat model of thromboembolic stroke indicate that nitrous oxide should not be considered a good candidate agent for treating acute ischemic stroke compared with xenon.

Structure-function perturbation and dissociation of tetrameric urate oxidase by high hydrostatic pressure.

Structure-function relationships in the tetrameric enzyme urate oxidase were investigated using pressure perturbation. As the active sites are located at the interfaces between monomers, enzyme activity is directly related to the integrity of the tetramer. The effect of hydrostatic pressure on the enzyme was investigated by x-ray crystallography, small-angle x-ray scattering, and fluorescence spectroscopy. Enzymatic activity was also measured under pressure and after decompression. A global model, consistent with all measurements, discloses structural and functional details of the pressure-induced dissociation of the tetramer. Before dissociating, the pressurized protein adopts a conformational substate characterized by an expansion of its substrate binding pocket at the expense of a large neighboring hydrophobic cavity. This substate should be adopted by the enzyme during its catalytic mechanism, where the active site has to accommodate larger intermediates and product. The approach, combining several high-pressure techniques, offers a new (to our knowledge) means of exploring structural and functional properties of transient states relevant to protein mechanisms.

Repeated administration of amphetamine induces a shift of the prefrontal cortex and basolateral amygdala motor function.

The role of the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in the expression of behavioural locomotor sensitization to amphetamine (Amph) has been poorly studied. In the present study, we investigated how lidocaine infused in the mPFC or BLA modulated motor responses to acute and repeated (sensitization) Amph administration. We showed that reversible blockade of mPFC or BLA by lidocaine increased both locomotor and rearing responses to acute Amph, but blocked the expression of behavioural sensitization to Amph. These findings indicate that under free-lidocaine conditions repeated administration of Amph would produce a shift of mPFC and BLA motor function from an inhibitory to a facilitatory role in response to Amph. We propose that this phenomenon may be of major critical importance in the development of drug dependence.

Neuroprotective effects of xenon: a therapeutic window of opportunity in rats subjected to transient cerebral ischemia.

Brain insults are a major cause of acute mortality and chronic morbidity. Given the largely ineffective current therapeutic strategies, the development of new and efficient therapeutic interventions is clearly needed. A series of previous investigations has shown that the noble and anesthetic gas xenon, which has low-affinity antagonistic properties at the N-methyl-D-aspartate (NMDA) receptor, also exhibits potentially neuroprotective properties with no proven adverse side effects. Surprisingly and in contrast with most drugs that are being developed as therapeutic agents, the dose-response neuroprotective effect of xenon has been poorly studied, although this effect could be of major critical importance for its clinical development as a neuroprotectant. Here we show, using ex vivo and in vivo models of excitotoxic insults and transient brain ischemia, that xenon, administered at subanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia, a critical event known to be involved in excitotoxicity, to reduction of subsequent cell injury and neuronal death. Maximal neuroprotection was obtained with xenon at 50 vol%, a concentration at which xenon further exhibited significant neuroprotective effects in vivo even when administered up to 4 h after intrastriatal NMDA injection and up to at least 2 h after induction of transient brain ischemia.

Oxygen pressurized X-ray crystallography: probing the dioxygen binding site in cofactorless urate oxidase and implications for its catalytic mechanism.

The localization of dioxygen sites in oxygen-binding proteins is a nontrivial experimental task and is often suggested through indirect methods such as using xenon or halide anions as oxygen probes. In this study, a straightforward method based on x-ray crystallography under high pressure of pure oxygen has been developed. An application is given on urate oxidase (UOX), a cofactorless enzyme that catalyzes the oxidation of uric acid to 5-hydroxyisourate in the presence of dioxygen. UOX crystals in complex with a competitive inhibitor of its natural substrate are submitted to an increasing pressure of 1.0, 2.5, or 4.0 MPa of gaseous oxygen. The results clearly show that dioxygen binds within the active site at a location where a water molecule is usually observed but does not bind in the already characterized specific hydrophobic pocket of xenon. Moreover, crystallizing UOX in the presence of a large excess of chloride (NaCl) shows that one chloride ion goes at the same location as the oxygen. The dioxygen hydrophilic environment (an asparagine, a histidine, and a threonine residues), its absence within the xenon binding site, and its location identical to a water molecule or a chloride ion suggest that the dioxygen site is mainly polar. The implication of the dioxygen location on the mechanism is discussed with respect to the experimentally suggested transient intermediates during the reaction cascade.

Neuroprotection by nitrous oxide: facts and evidence.

BACKGROUND AND OBJECTIVE: Preliminary studies have shown that nitrous oxide, like xenon, may possess potentially neuroprotective properties. However, because of its possible neurotoxic and proneurotoxic effects (obtained under particular conditions) and its bad reputation at anesthetic concentrations, no thorough investigations have been performed on the potentially neuroprotective properties of nitrous oxide. The aim of this study was to investigate the possible neuroprotective effects of nitrous oxide at nonanesthetic concentrations on different models of excitotoxic insult and brain ischemia. MEASUREMENTS AND MAIN RESULTS: Here, we show using multiple models of ex vivo and in vivo excitotoxic insults and brain ischemia that nitrous oxide, administered alone at nonanesthetic doses, offers global neuroprotection from reduction of neurotransmitter release induced by ischemia to reduction of subsequent cell injury. In vivo, in rats subjected to transient cerebral ischemia, nitrous oxide at 50 vol% offers full neuroprotection at both the histologic and neurologic outcome levels when administered up to 2 hrs, but not 3 hrs, after ischemia onset. CONCLUSIONS: These data provide experimental evidence that nitrous oxide, which is a cost-efficient and easily available gas, has potentially neuroprotective properties in rodents when given alone at nonanesthetic concentrations. Therefore, because there is a lot at stake for the affected patients and society--in terms of easy access to treatment, profound impact of brain damage, cost of treatment, and subsequent financial cost on society--we believe that further studies should investigate thoroughly the possible potential clinical interest of nitrous oxide for the treatment of ischemic stroke in terms of optimal indications, type of ischemic injury, duration and time points for treatment, and the optimal concentration of gas to be used in clinical circumstances.

NMDA-induced striatal brain damage and time-dependence reliability of thionin staining in rats.

Excitotoxic neuronal death induced by intracerebral injection of NMDA is a widely used model for investigating the potentially neuroprotective action of pharmacological agents against brain insults involving excitotoxic processes. Surprisingly, the time-course of NMDA-induced brain damage yet has not been investigated in the rat. Answering this question clearly needs to be assessed, given that the validity of preclinical neuroprotection studies requires to be insured that brain damage has reached a plateau that corresponds to the maximal extension of neuronal death at the time the brain is removed for histological analysis. Here, we investigated the time-course of neuronal death and the time-dependence validity of thionin coloration in rats that were given an intrastriatal injection of NMDA of 50 nmol or 70 nmol. Our results show that, whatever the dose used, NMDA-induced brain damage reaches its maximal value 24-48 h after the insult. They further indicate that the volume values of brain damage as estimated by thionin coloration constitute reliable data when the brain is removed up to 48 h after injection of NMDA. However, if the brain is removed more than 48 h after the excitotoxic insult onset, there is no alternative of using other techniques, such as immunochemical or neuroimaging techniques.

Modulation by group I mGLU receptor activation and group III mGLU receptor blockade of locomotor responses induced by D1-like and D2-like receptor agonists in the nucleus accumbens.

Evidence for functional motor interactions between group I and group III metabotropic glutamatergic (mGlu) receptors and dopamine neurotransmission is now clearly established [David, H.N., Abraini, J.H., 2001a. The group I metabotropic glutamate receptor antagonist S-4-CPG modulates the locomotor response produced by the activation of D1-like, but not D2-like, dopamine receptors in the rat nucleus accumbens. Eur. J. Neurosci. 15, 2157-2164, David, H.N., Abraini, J.H., 2002. Group III metabotropic glutamate receptors and D1-like and D2-like dopamine receptors interact in the rat nucleus accumbens to influence locomotor activity. Eur. J. Neurosci. 15, 869-875]. Nevertheless, whether or not and how, activation of group I and blockade of group III mGlu receptors modulate the motor responses induced by the activation of dopaminergic receptors in the NAcc still remains unknown. Answering this question needs to be assessed since functional interactions between neurotransmitters in the NAcc are well known to depend upon the level of activation of glutamatergic and/or dopaminergic receptors and because the effects of glutamatergic receptor agonists and antagonists on dopaminergic receptor-mediated locomotor responses are not always reciprocal as shown in previous studies. Our results show that activation of group I mGlu receptors by DHPG in the NAcc potentiated the locomotor response induced by intra-NAcc activation of D1-like receptors and blocked those induced by D2-like presynaptic or postsynaptic receptors. Alternatively, blockade of group III mGlu receptors by MPPG in the NAcc potentiated the locomotor responses mediated by D1-like receptors and by D2-like postsynaptic receptors and inhibited that induced by D2-like presynaptic receptors. These results compiled with previous data demonstrate that group I mGlu receptors and group III mGlu receptors can modulate the locomotor responses produced by D1-like and/or D2-like receptor agonists in a complex phasic and tonic fashion.

Tirofiban, a Glycoprotein IIb/IIIa Antagonist, Has a Protective Effect on Decompression Sickness in Rats: Is the Crosstalk Between Platelet and Leukocytes Essential?

In its severest forms, decompression sickness (DCS) may extend systemically and/or induce severe neurological deficits, including paralysis or even death. It seems that the sterile and ischemic inflammatory phenomena are consecutive to the reaction of the bubbles with the organism and that the blood platelet activation plays a determinant role in the development of DCS. According to the hypotheses commonly put forward, the bubbles could either activate the platelets by direct contact or be the cause of abrasion of the vascular epithelium, which would expose the basal plate glycogen and then prompt the platelets to activate. The purpose of this study is to confirm anti-platelet drugs specific to GPIIb/IIIa integrin could prevent DCS, using a rat model. There is a significant difference concerning the incidence of the drug on the clinical status of the rats (p = 0.016), with a better clinical outcome for rats treated with tirofiban (TIR) compared with the control rats (p = 0.027), even if the three anti-GPIIb/IIIa agents used have limited respiratory distress. TIR limited the decrease in platelet counts following the hyperbaric exposure. TIR help to prevent from DCS. TIR is specific to GPIIb/IIIa whereas eptifibatide and abciximab could inhibit αVß3 and αMß2 involved in communication with the immune system. While inhibiting GPIIb/IIIa could highlight a platelet-dependent inflammatory pathway that improves DCS outcomes, we wonder whether inhibiting the αVß3 and αMß2 communications is not a wrong approach for limiting mortality in DCS.

Reduction in the Level of Plasma Mitochondrial DNA in Human Diving, Followed by an Increase in the Event of an Accident.

Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity or trauma. In the context of decompression sickness (DCS), the course of which is sometimes erratic, we hypothesize that mtDNA plays a not insignificant role particularly in neurological type accidents. This study is based on the comparison of circulating mtDNA levels in humans presenting with various types of diving accidents, and punctured upon their admission at the hyperbaric facility. One hundred and fourteen volunteers took part in the study. According to the clinical criteria there were 12 Cerebro DCS, 57 Medullary DCS, 15 Vestibular DCS, 8 Ctrl+ (accident-free divers), and 22 Ctrl- (non-divers). This work demonstrates that accident-free divers have less mtDNA than non-divers, which leads to the assumption that hyperbaric exposure degrades the mtDNA. mtDNA levels are on average greater in divers with DCS compared with accident-free divers. On another hand, the amount of double strand DNA (dsDNA) is neither significantly different between controls, nor between the different DCS types. Initially the increase in circulating oligonucleotides was attributed to the destruction of cells by bubble abrasion following necrotic phenomena. If there really is a significant difference between the Medullary DCS and the Ctrl-, this difference is not significant between these same DCS and the Ctrl+. This refutes the idea of massive degassing and suggests the need for new research in order to verify that oxidative stress could be a key element without necessarily being sufficient for the occurrence of a neurological type of accident.

Thirty-five Day Fluoxetine Treatment Limits Sensory-Motor Deficit and Biochemical Disorders in a Rat Model of Decompression Sickness.

According to the OECD statistical base for 2014, anti-depressants will, on average, be distributed at a rate of 62 daily doses per 1,000 inhabitants for the 25 countries surveyed (Health at a glance: Europe 2014; OECD Health Statistics; World Health Organization and OECD Health Statistics, 2014). Divers must be concerned. On another hand, divers are potentially exposed to decompression sickness including coagulation inflammation and ischemia, which can result in neurological lesions or even death. The purpose of this study is to assess whether chronic treatment with anti-depressants may represent a contraindication to the practice of an at-risk activity, such as, scuba diving, or even presents a benefit by attenuating the severity of the symptoms. We study for the first time the effect of a 35-day fluoxetine treatment (20 mg/kg) on the occurrence of decompression sickness in laboratory rats (n = 79). Following exposure to the hazardous protocol, there is a significant correlation between the type of treatment and the clinical status of the rats in favor of a better clinical prognosis for the rats treated with fluoxetine with a significantly higher number of No DCS status and a lower number of Severe DCS status in the Flux, compared to Controls. The treatment modifies the rat performances both significantly and favorably during the physical and behavioral tests, just like their biological and biochemical constants. After decompression, rats under treatment display lower sensory-motor deficit and lowers biochemical disorders. From a biological point of view, we conclude fluoxetine should not be seen as a contraindication for diving on the basis of anticipated increased physiological risk.

A method for calculating the gas volume proportions and inhalation temperature of inert gas mixtures allowing reaching normothermic or hypothermic target body temperature in the awake rat.

The noble gases xenon (Xe) and helium (He) are known to possess neuroprotective properties. Xe is considered the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen (O2) in air, conditions that could impair or at least reduce the intrinsic neuroprotective properties of Xe by increasing the critical care patient's respiratory workload and body temperature. In contrast, He has a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is unfortunately far less potent than Xe at providing neuroprotection. Therefore, combining Xe with He could allow obtaining, depending on the gas inhalation temperature and composition, gas mixtures with neutral or hypothermic properties, the latter being advantageous in term of neuroprotection. However, calculating the thermal properties of a mixture, whatever the substances - gases, metals, rubbers, etc. - is not trivial. To answer this question, we provide a graphical method to assess the volume proportions of Xe, He and O2 that a gas mixture should contain, and the inhalation temperature to which it should be administered to allow a clinician to maintain the patient at a target body temperature.

Xenon-helium gas mixture at equimolar concentration of 37.5% protects against oxygen and glucose deprivation-induced injury and inhibits tissue plasminogen activator.

Xenon (Xe) is considered to be the golden standard neuroprotective gas. However, Xe has a higher molecular weight and lower thermal conductivity and specific heat than those of nitrogen, the main diluent of oxygen in air. These physical characteristics could impair or at least reduce the intrinsic neuroprotective action of Xe by increasing the patient's respiratory workload and body temperature. In contrast, helium (He) is a cost-efficient gas with a lower molecular weight and higher thermal conductivity and specific heat than those of nitrogen, but is far less potent than Xe. In this study, we hypothesized that mixing Xe and He could allow obtaining a neuroprotective gas mixture with advantageously reduced molecular weight and increased thermal conductivity. We found that Xe and He at the equimolar concentration of 37.5% reduced oxygen-glucose deprivation-induced increase in lactate dehydrogenase in brain slices, an ex vivo model of acute ischemic stroke. These results together with the effects of Xe-He on the thrombolytic efficiency of tissue plasminogen activator are discussed.

Argon Exposure Induces Postconditioning in Myocardial Ischemia-Reperfusion.

BACKGROUND AND PURPOSE: Cardioprotection against ischemia-reperfusion (I/R) damages remains a major concern during prehospital management of acute myocardial infarction. Noble gases have shown beneficial effects in preconditioning studies. Because emergency proceedings in the context of myocardial infarction require postconditioning strategies, we evaluated the effects of argon in such protocols on mammalian cardiac tissue. EXPERIMENTAL APPROACHES: In rat, cardiac I/R was induced in vivo by transient coronary artery ligature and cardiac functions were evaluated by magnetic resonance imaging. Hypoxia-reoxygenation (H/R)-induced arrhythmias were evaluated in vitro using intracellular microelectrodes on both rat-isolated ventricle and a model of border zone in guinea pig ventricle. Hypoxia-reoxygenation loss of contractile force was assessed in human atrial appendages. In those models, postconditioning was induced by 5 minutes application of argon at the time of reperfusion. KEY RESULTS: In the in vivo model, I/R produced left ventricular ejection fraction decrease (24%) and wall motion score increase (36%) which was prevented when argon was applied in postconditioning. In vitro, argon postconditioning abolished H/R-induced arrhythmias such as early after depolarizations, conduction blocks, and reentries. Recovery of contractile force in human atrial appendages after H/R was enhanced in the argon group, increasing from 51% ± 2% in the nonconditioned group to 83% ± 7% in the argon-treated group ( P < .001). This effect of argon was abolished in the presence of wortmannin and PD98059 which inhibit prosurvival phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and MEK/extracellular receptor kinase 1/2 (ERK 1/2), respectively, or in the presence of the mitochondrial permeability transition pore opener atractyloside, suggesting the involvement of the reperfusion injury salvage kinase pathway. CONCLUSION AND IMPLICATIONS: Argon has strong cardioprotective properties when applied in conditions of postconditioning and thus appears as a potential therapeutic tool in I/R situations.