Hyperoxic Preconditioning Research Articles

Endothelial Function and Hypoxic–Hyperoxic Preconditioning in Coronary Surgery with a Cardiopulmonary Bypass: Randomized Clinical Trial

A hypoxic-hyperoxic preconditioning (HHP) may be associated with cardioprotection by reducing endothelial damage and a beneficial effect on postoperative outcome in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Patients (n = 120) were randomly assigned to an HHP and a control group. A safe, inhaled oxygen fraction for the hypoxic preconditioning phase (10-14% oxygen for 10 min) was determined by measuring the anaerobic threshold. At the hyperoxic phase, a 75-80% oxygen fraction was used for 30 min. The cumulative frequency of postoperative complications was 14 (23.3%) in the HHP vs. 23 (41.1%), p = 0.041. The nitrate decreased after surgery by up to 20% in the HHP group and up to 38% in the control group. Endothelin-1 and nitric oxide metabolites were stable in HHP but remained low for more than 24 h in the control group. The endothelial damage markers appeared to be predictors of postoperative complications. The HHP with individual parameters based on the anaerobic threshold is a safe procedure, and it can reduce the frequency of postoperative complications. The endothelial damage markers appeared to be predictors of postoperative complications.

Influence of Hypoxic and Hyperoxic Preconditioning on Endothelial Function in a Model of Myocardial Ischemia-Reperfusion Injury with Cardiopulmonary Bypass (Experimental Study)

The aim of the experiment was to evaluate the effect of preconditioning based on changes in inspiratory oxygen fraction on endothelial function in the model of ischemia-reperfusion injury of the myocardium in the condition of cardiopulmonary bypass. The prospective randomized study included 32 rabbits divided into four groups: hypoxic preconditioning, hyperoxic preconditioning, hypoxic-hyperoxic preconditioning, and control group. All animals were anesthetized and mechanically ventilated. We provided preconditioning, then started cardiopulmonary bypass, followed by induced acute myocardial infarction (ischemia 45 min, reperfusion 120 min). We investigated endothelin-1, nitric oxide metabolites, asymmetric dimethylarginine during cardiopulmonary bypass: before ischemia, after ischemia, and after reperfusion. We performed light microscopy of myocardium, kidney, lungs, and gut mucosa. The endothelin-1 level was much higher in the control group than in all preconditioning groups after ischemia. The endothelin-1 even further increased after reperfusion. The total concentration of nitric oxide metabolites was significantly higher after all types of preconditioning compared with the control group. The light microscopy of the myocardium and other organs revealed a diminished damage extent in the hypoxic-hyperoxic preconditioning group as compared to the control group. Hypoxic-hyperoxic preconditioning helps to maintain the balance of nitric oxide metabolites, reduces endothelin-1 hyperproduction, and enforces organ protection.

Can Hyperoxic Preconditioning in Normobaric Hypoxia (3500m) Improve All-Out Exercise Performance in Highly Skilled Skiers? A Randomized Crossover Study.

The altering effects of hypoxia on aerobic/anaerobic performance are well documented and form the basis of this study. Application of hyperoxic gases (inspiratory fraction of oxygen [FiO2] > 0.2095) prior to competition or training (hyperoxic preconditioning) can compensate for the negative influence of acute hypoxia. To investigate whether oxygen supplementation immediately prior to exercise (FiO2 = 1.0) improves all-out exercise performance in normobaric hypoxia (3500m) in highly skilled skiers. In this single-blind, randomized, crossover study, 17 subjects performed a 60-second constant-load, all-out test in a normobaric hypoxic chamber. After a short period of adaptation to hypoxia (60 min), they received either pure oxygen or chamber air for 5 minutes prior to the all-out test (hyperoxic preconditioning vs nonhyperoxic preconditioning). Capillary blood was collected 3 times, and muscle oxygenation was assessed with near-infrared spectroscopy. Absolute and relative peak power (P = .073 vs P = .103) as well as mean power (P = .330 vs P = .569) did not significantly differ after the hyperoxic preconditioning phase. PaO2 increased from 51.3 (3) to 451.9 (89.0)mm Hg, and SaO2 increased from 88.2% (1.7%) to 100% (0.2%) and dropped to 83.8% (4.2%) after the all-out test. Deoxygenation (P = .700) and reoxygenation rates (P = .185) did not significantly differ for both preconditioned settings. Therefore, the authors conclude that hyperoxic preconditioning did not enhance 60-second all-out exercise performance in acute hypoxia (3500m).

Impact of Hyperoxic Preconditioning in Normobaric Hypoxia (3500m) on Balance Ability in Highly Skilled Skiers: A Randomized, Crossover Study.

To investigate whether hyperoxic preconditioning (pure-oxygen supplementation prior to exercise) improves balance ability and postural stability during normobaric hypoxia (3500m) in highly skilled skiers. In this single-blind randomized, crossover study, 19 subjects performed a 60-s balance test (MFT S3-Check) in a normobaric hypoxic chamber. After a short period of adaptation to hypoxia (60min), they received either pure oxygen or chamber air for 5min prior to a balance test (hyperoxic preconditioning vs nonhyperoxic preconditioning). Capillary blood was collected 3 times. Balance performance, indexed by sensory (P = .097), stability (P = .937), and symmetry (P = .202) scores, was not significantly different after the hyperoxic preconditioning phase. Balance performance decreased over time (no group difference). After hyperoxic preconditioning, arterial partial pressure of oxygen increased from 52.7 (4.5)mm Hg to 212.5 (75.8)mm Hg, and oxygen saturation of hemoglobin increased from 85.8% (3.5%) to 98.9% (0.7%) and remained significantly elevated to 90.1% (2.0%) after the balance test. A hyperoxic preconditioning phase does not affect balance performance under hypoxic environmental conditions. A performance-enhancing effect, at least in terms of coordinative functions, was not supported by this study.

Myocardial Protection against Ischemic and Reperfusion Injuries (Experimental Study).

The effects of hypoxic, hyperoxic, and hypoxic-hyperoxic preconditioning were examined in the prospective study on narcotized and artificially ventilated rabbits. Under artificial circulation, acute myocardial ischemia was modeled by ligation of anterior descending coronary artery, which was followed by reperfusion. The degree of ventricular arrhythmias was assessed, and the ischemic area was evaluated in percent of the area at risk. Microscopic characterization of the myocardium was employed to assess the cardioprotective effect of hypoxic and/or hyperoxic preconditioning. According to Kruskal-Wallis test, the greatest resistance of the myocardium to ischemic and reperfusion injury was observed after hypoxic-hyperoxic preconditioning (H=42.459; p=0.009). The rabbits subjected to this type of preconditioning demonstrated the least damaged myocardium in comparison with nonconditioned controls.

Hypoxic and hyperoxic preconditioning in organ protection against ischemia-reperfusion injury: experimental study

Hypoxic and hyperoxic preconditioning in organ protection against ischemia-reperfusion injury: experimental study

Hyperbaric oxygen and hyperbaric air preconditioning induces ischemic tolerance to transient forebrain ischemia in the gerbil

Ischemic preconditioning with sublethal stress triggers defensive mechanisms against ischemic brain damage; however, such manipulations are potentially dangerous and, therefore, safe stimuli have been sought. Hyperoxia preconditioning by administration of hyperbaric (HBO) or normobaric oxygen (NBO) may have neuroprotective potential. The aim of this study was to determine whether preconditioning with HBO and air (HBA) applied at 2.5 absolute pressure (ATA) or NBO preconditioning induces ischemic tolerance in the brain of gerbils subjected to 3min transient cerebral ischemia. Neuronal cell survival, changes in brain temperature, the generation of factors involved in neurodegeneration and basic behavior in nest building were all tested. Hyperoxic preconditioning prevented ischemia-induced neuronal cell loss, reduced the number of TUNEL positive cells in the CA1 region of the hippocampus and improved the nest building process compared to untreated ischemic animals. Preconditioning also suppressed the production of reactive oxygen species and increased Bax expression normally observed after an ischemic episode. Only HBO preconditioning inhibited ischemia-evoked increases in brain temperature. Our results show that hyperoxic preconditioning results in induction of ischemic tolerance and prevents ischemia-induced neuronal damage in the gerbil brain. Pressurized air preconditioning was as effective as HBO or NBO preconditioning in providing neuroprotection. The observed neuroprotection probably results from mild oxidative stress evoked by increased brain tissue oxidation and activation of antioxidant and antiapoptotic defenses.

Hypoxic and hyperoxic preconditioning in myocardial protection against ischemia-reperfusion injury: experimental study

Hypoxic and hyperoxic preconditioning in myocardial protection against ischemia-reperfusion injury: experimental study

Cisplatin toxicity reduced in human cultured renal tubular cells by oxygen pretreatment

Cisplatin is an effective and widely used chemotherapy agent and its side effects, particularly nephrotoxicity, limit its usage and related platinum-based drugs. Cisplatin nephrotoxicity is mainly due to extremely increase in reactive oxygen species (ROS) generation leading to kidney tubular cell death. Preconditioning with oxidative stress has been demonstrated to stimulate the cellular adaptation to subsequent severe oxidative stress. Short term oxygen pre-exposure as a mild oxidative stress may enhance some endogenous defense mechanisms, so its effect on Cisplatin induced cell death was investigated in present research. We studied the effects of hyperoxic environment pre-exposure on Cisplatin toxicity in an in-vitro model of cultured human embryonic tubular epithelial cells (AD293). Viability of AD293 cells, as evaluated by MTT-assay, was affected by Cisplatin in a time (1–4 h) dependent model. Biochemical markers of cell apoptosis were evaluated using immunoblotting. Pretreatment with nearly pure oxygen (≥90%) for 2 h significantly reduced the level of cell damage. Activated caspase 3 and Bax/Bcl-2 ratio were significantly increased in Cisplatin-treated cells. Oxygen pretreatment inhibited caspase 3 activation and decreased Bax/Bcl-2 ratio. Oxygen pre-treatment itself not showed any cytotoxicity in exposure times up to 3 h. Our data indicate that hyperoxic preconditioning reduces Cisplatin toxicity in cultured human tubular epithelial cells. The exact mechanism of protection is unclear, though enhancement of some endogenous defense mechanisms and subsequently scavenging of free oxygen radicals may play an important role.

Flying before diving: induction of neuroprotection against CNS‐oxygen toxicity (CNS‐OT) seizures while breathing 100% oxygen at 5 atmospheres absolute (ATA)

In clinical and military procedures, excesses of hyperbaric oxygen (HBO) can cause CNS‐OT. We tested the hypothesis that oxidative preconditioning (PC), using a sub‐lethal dose of HBO, induces neuroprotection against seizures.99 male rats were implanted with radio‐telemetry transmitters to record diaphragmatic electromyogram, ECG, EEG, body temperature and activity. After 1 week, rats underwent PC for 1hr, every other day for 3 times over 5 days using: a‐b) air at 1ATA (control) or 2ATA; c‐d) 100%O2 at 1 or 2ATA; e) hyperbaric normoxia, f) 2ATA using 90% helium (Heliox) and g) nitrogen (Nitrox); h) normobaric hypoxia (10%O2); and i) hypobaric (0.5ATA) normoxia and j) hypobaric hypoxia (10%O2 at 0.5ATA). 24h after last PC treatment, rats were placed in a hyperbaric chamber and exposed to 5ATA O2, until CNS‐OT. Data were collected and latency to seizure (LS) determined.Results showed:1) hyperoxic PC did not provide neuroprotection against seizure; 2) inert gases PC (2ATA Nitrox/Heliox) decreased LS by 57/78%; 3) hypobaric PC significantly extended LS by 56% and 38%; and 4) hippocampi western blot suggested that hyperbaric pressure per se accelerates the CNS‐OT via downregulation of Early Growth Response‐1, involved in neuroprotection against oxidative stress.Exposing rats to intermittent flights at~16.000 feet before diving at 5ATA O2 decreases CNS‐OT risks, whereas air dives exacerbate the risk of CNS‐OT. (ONR)

Hyperoxic preconditioning fails to confer additional protection against ischemia-reperfusion injury in acute diabetic rat heart.

Experimental studies show that detrimental effects of ischemia-reperfusion (I/R) injury can be attenuated by hyperoxic preconditioning in normal hearts, however, there are few studies about hyperoxia effects in diseased myocardium. The present study was designed to assess the cardioprotective effects of hyperoxia pretreatment (≥ 95 % O2) in acute diabetic rat hearts. Normal and one week acute diabetic rats were either exposed to 60 (H60) and 180 (H180) min of hyperoxia or exposed to normal atmospheric air (21 % O2). Then hearts were isolated immediately and subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size, cardiomyocyte apoptosis, enzymes release and ischemia induced arrhythmias were determined. Heart of diabetic control rats had less infarct size and decreased LDH and CK-MB release compared to normal hearts. 60 and 180 min of hyperoxia reduced myocardial infarct size and enzymes release in normal hearts. 180 min of hyperoxia also decreased cardiomyocytes apoptosis in normal state. On the other hand, protective values of hyperoxia were not significantly different in diabetic hearts. Moreover, hyperoxia reduced severity of ventricular arrhythmias in normal rat hearts whereas; it did not confer any additional antiarrhythmic protection in diabetic hearts. These findings suggest that diabetic hearts are less susceptible to ischemia-induced arrhythmias and infarction. Hyperoxia greatly protects rat hearts against I/R injury in normal hearts, however, it could not provide added cardioprotective effects in acute phase of diabetes.

Neuroplasticity of CNS oxygen toxicity (CNS‐OT): increased risk of seizure due to hyperbaric preconditioning (PC) and kindling effect

CNS‐OT limits the use of hyperbaric O2 (HBO2) clinically and in military diving. We studied the effects of preconditioning (PCs) gas mixtures and dive/seizure history on the latency to seizure (LS) in 118 adult rats implanted with a radio‐transmitter to record EEGs. After ≥1 wk recovery, rats underwent: a) hyperoxic PC at 1‐ 2ATA in pure O2; b) hyperbaric normoxic PC at 2ATA using Heliox/Nitrox; and c) air PC at 1ATA (control) or 2ATA. All PC protocols were conducted 3x, followed 24hr after the last treatment by one dive to 5ATA to seizure. Hyperoxic PC did not provide neuroprotection against seizure, decreasing LS by 51% (2ATA O2) and 42% (1ATA O2). Hyperbaric normoxic PC (2ATA Nitrox/Heliox) decreased LS by 78/89%. Western blot analyses of rat hippocampi suggest that hyperbaric pressure per se (normoxia+inert gases) accelerate onset of CNS‐OT by downregulation of Early Growth Response‐1, an early response gene involved in neuroprotection from oxidative stress. Also, in the absence of PC, rats experiencing 1 seizure/wk over 3–5wk developed a kindling response to HBO2 compared to rats that experienced 1 seizure/wk over 2wk, causing a LS decrease of 74% (4 ATA) and 55% (5 ATA) due to kindling (ONR).

In vivo hyperoxic preconditioning protects against rat-heart ischemia/reperfusion injury by inhibiting mitochondrial permeability transition pore opening and cytochrome c release

In vivo hyperoxic preconditioning (PC) has been shown to protect against ischemia/reperfusion (I/R) myocardial damage. Mitochondrial permeability transition pore (MPTP) opening is an important event in cardiomyocyte cell death occurring during I/R and therefore a possible target for cardioprotection. We tested the hypothesis that in vivo hyperoxic PC, obtained by mechanical ventilation of animals, could protect heart against I/R injury by inhibiting MPTP opening and cytochrome c release from mitochondria. Mechanically ventilated rats were first exposed to a short period of hyperoxia and isolated hearts were subsequently subjected to I/R in a Langendorff apparatus. Hyperoxic PC significantly improved the functional recovery of hearts on reperfusion, reduced the infarct size, and decreased necrotic damage as shown by the reduced release of lactate dehydrogenase. Mitochondria from hyperoxic PC hearts were less sensitive than mitochondria from reperfused heart to MPTP opening. In addition, hyperoxic PC prevented mitochondrial NAD+ depletion, an indicator of MPTP opening, and cytochrome c release as well as cardiolipin oxidation/depletion associated with I/R. Together, these results demonstrate that hyperoxic PC protects against heart I/R injury by inhibiting MPTP opening and cytochrome c release. Thus, in vivo hyperoxic PC may represent a useful strategy for the treatment of cardiac I/R injury and could have potential applications in clinical practice.

Environmental Damage to the Retina and Preconditioning: Contrasting Effects of Light and Hyperoxic Stress

Environmental stress (bright light, hypoxia) can "condition" retinal photoreceptors, increasing their resistance to subsequent stress. The present study tests whether another photoreceptor-lethal stress, hyperoxia, can induce similar resistance. Vulnerability to hyperoxia was tested in young adult C57BL/6J mice exposed to 1000 lux cyclic light for 1 week or to 50% O2 for 1 week and then to 75% O2 for 2 weeks. Vulnerability to light was tested in Balb/cJ mice exposed to 300 lux cyclic light for 2 days or to 75% O2 for 2 weeks and then to 1000 lux cyclic light for 1 week. Retinas were analyzed for photoreceptor death, levels of stress-related proteins (GFAP, FGF-2, MnSOD, acrolein), and the regulation of candidate neuroprotective genes (HSP70.1, Ledgf, FGF-13, Timp2). Light preconditioning did not cause measurable death of photoreceptors but reduced photoreceptor death induced by subsequent hyperoxic or light stress, reduced levels of stress-related proteins, and maintained the length and organization of photoreceptor outer segments. Hyperoxic preconditioning caused measurable cell death but provided no protection against subsequent hyperoxic or light stress. Of the four candidate neuroprotective proteins examined, the regulation of only one (Timp2) seemed associated with the neuroprotection observed. Light preconditioning, causing only minimal damage to photoreceptors, induced protection against subsequent stress from both hyperoxia and light. By contrast, hyperoxic preconditioning caused measurable photoreceptor damage but induced no protection against light or hyperoxia. These data suggest a separation between stress-induced damage to photoreceptors and the upregulation of protective mechanisms, encouraging the search for ways to protect the retina without damaging it.

Ischemia and reperfusion-induced arrhythmias: role of hyperoxic preconditioning

Hyperoxic preconditioning is known to protect the heart against necrosis and contractile dysfunction, but protection against arrhythmias has not been well characterized. The authors hypothesized that pre-exposure to normobaric hyperoxia (H) reduces ischemia and reperfusion-induced arrhythmias in isolated rat hearts. Following 60 and 180 min of hyperoxia treatment, rat hearts were isolated immediately (H60 and H180) or 24 h afterward (H60/24 and H180/24), and subjected to 30 min of regional ischemia followed by 120 min of reperfusion. Occurrence, number, and duration of arrhythmias were analyzed during ischemia and reperfusion. In addition, cardiac infarct size was also assessed. Sixty and 180 min of breathing hyperoxic gas induced significant protection against severe ischemia and reperfusion-induced arrhythmias. Total number of premature ventricular beats was markedly attenuated by hyperoxia pre-exposure, especially in H60 and H180 groups. Duration of ventricular tachycardia and ventricular fibrillation was also affected by hyperoxia. Hyperoxia reduced the number of ventricular tachycardia episodes in ischemia and reperfusion phase. Accordingly, severity of arrhythmias (arrhythmia score) and infarct size were lower in hyperoxia-treated groups. The effects were more pronounced using hyperoxia immediately before harvesting the heart. These results indicate that hyperoxic preconditioning attenuates ventricular ischemia and reperfusion-induced arrhythmias in isolated rat hearts, decreases cardiac infarct size, and improves postischemic heart function. The effects seem to depend on the time course after hyperoxia treatment.

Hyperoxia-Induced Protection against Rat's Renal Ischemic Damage: Relation to Oxygen Exposure Time

Background. Pre-exposure to hyperoxic gas (≥ 95%) has been shown to protect the heart and central nervous system from ischemia-reperfusion injury. In the present study, we investigated whether oxygen pretreatment induces delayed renal protection in rats. The possible role of some renal antioxidant agents was also investigated. Materials and methods. Adult male Wistar rats were kept in a hyperoxic (HO) (≥ 95% O2) environment for 0.5 h, 1 h, 2 h, 3 h, 6 h, and 2 h/day for three consecutive days and 4 h/day for six consecutive days, and control group (IR) animals were kept in the cage with no HO, one day before subjecting their kidney to 40 minutes of ischemia and 24h of reperfusion. Renal function was assessed by comparing plasma creatinine (Cr), blood urea nitrogen (BUN), creatinine clearance (CLCr), and fractional excretion of sodium (FENa%). Histopathological injury score was also determined according to the Jablonski method. To examine the antioxidant system induction by hyperoxia, we measured renal catalase and superoxide dismutase activity, and renal glutathione and malondialdehyde content. Results. Our data demonstrated that only in 4 h/day HO for six consecutive days, the renal function tests (Cr, CLCr, BUN, and FENa%) and Jablonski histological injury were better than control group (p < 0.05). The beneficial effect of oxygen pretreatment in this group was associated with increased renal catalase activity compared with those obtained from control group (p < 0.05). Conclusion. The present study demonstrates that repeated exposure to hyperoxic (≥ 95% O2) environment can reduce subsequent rat's renal ischemia-reperfusion damage. Induction of endogenous antioxidant system may partially explain this beneficial effect of hyperoxic preconditioning.

In Vivo Hyperoxic Preconditioning Prevents Myocardial Infarction by Expressing Bcl-2

Preconditioning with oxidative stress has been demonstrated in vitro to stimulate the cellular adaptation to subsequent severe oxidative stress. However, it is uncertain whether this preconditioning works in vivo. In the present study, we examined in vivo the beneficial effect of oxidative preconditioning. After rats were pretreated with whole-body hyperoxygenation (100% O(2) at 3 atmosphere for 20 mins, four cycles with 20-min intermission), isolated hearts were subjected to 45-min ischemia followed by 90-min reperfusion. This hyperoxic preconditioning significantly reduced infarct size, cytochrome-c release, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTD nick-end labeling-positive cell frequency in the left ventricle, biphasically with an early (30-min) and a delayed (48-hr) effect after the hyperoxygenation. Mechanistically, the NF-kappaB activity and Bcl-2 expression were enhanced in the hearts, and a NF-kappaB inhibitor, pyrrolidine dithiocarbamate, abolished the Bcl-2 induction as well as the infarct-limiting effect. An antioxidant, N-acetylcysteine, and protein kinase C (PKC) inhibitors chelerythrine and Gö 6983 also blocked the preconditioning effects. These results indicate that hyperoxia induces myocardial tolerance against ischemia-reperfusion injury in association with Bcl-2 induction by NF-kappaB activation through reactive oxygen species and PKC-dependent signaling pathway.