Hyperbaric ethanol antagonism in mice: Studies on oxygen,nitrogen, strain and sex

Male and female C57BL/6J and male BALBc/J mice were injected with 3.6 g/kg ethanol or saline and exposed to 1–10 atmospheres absolute (ATA) air, to 1 ATA 80% helium-20% oxygen, or to 12 ATA helium-oxygen having oxygen partial pressures between 0.5 and 18 times normal. Hyperbaric helium-oxygen significantly reduced sleep-time and increased wake-up brain ethanol concentrations in all mice tested. The degree of antagonism was not enhanced by increasing the oxygen partial pressure. Hyperbaric air increased sleep-time and decreased wake-up brain ethanol concentration in C57 mice. Hyperbaric air induced a pressure-related lethal effect beginning at 6 ATA in intoxicated BALBs. These findings demonstrate that hyperbaric ehanol antagonism extends across strains and sexes, that the degree of antagonism cannot be enhanced by increasing the oxygen partial pressure, and that air is not suitable as an antagonistic hyperbaric gas. The findings are consistent with membrane theories of anesthesia.     

The effect of hyperbaric oxygen on acute experimental sulfide poisoning in the rat

In order to evaluate the efficiency of hyperbaric oxygen in experimental acute sulfide poisoning, we studied the effect of 1 ATA (atmosphere absolute) oxygen and sodium nitrite therapy. We then studied the effect of oxygen at 3 ATA alone and in combination with intraperitoneal sodium nitrite injection on rats poisoned by intraperitoneal injection of LD75 sulfide. Electroencephalogram and heart rate were continuously monitored. We also studied the effect of sodium nitrite and hyperbaric oxygen administered before the poisoning (protective effect). In our experimental set, death of untreated poisoned animals occurred within 5 min. There is a parallel between modification of the EEG pattern and apnea. Respiratory arrest always preceded cardiac arrest. Pure oxygen (1 ATA O2) is effective in preventing death in experimental sulfide poisoning. 3 ATA oxygen was significantly more effective in preventing death than 1 ATA oxygen, or sodium nitrite alone. The best therapeutic regimen was a combination of 3 ATA oxygen and sodium nitrite administration.     

Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue

Methaemoglobin is formed by oxidation of ferrous (FeII) haem to the ferric (FeIII) state and the mechanisms by which this occurs are complex. Most cases are due to one of three processes. Firstly, direct oxidation of ferrohaemoglobin, which involves the transfer of electrons from ferrous haem to the oxidising compound. This mechanism proceeds most readily in the absence of oxygen. Secondly, indirect oxidation, a process of co-oxidation which requires haemoglobin-bound oxygen and is involved, for example, in nitrite-induced methaemoglobinaemia. Thirdly, biotransformation of a chemical to an active intermediate that initiates methaemoglobin formation by a variety of mechanisms. This is the means by which most aromatic compounds, such as amino- and nitro-derivatives of benzene, produce methaemoglobin. Methaemoglobinaemia is an uncommon occupational occurrence. Aromatic compounds are responsible for most cases, their lipophilic nature and volatility facilitating absorption during dermal and inhalational exposure, the principal routes implicated in the workplace. Methaemoglobinaemia presents clinically with symptoms and signs of tissue hypoxia. Concentrations around 80% are life-threatening. Features of toxicity may develop over hours or even days when exposure, whether by inhalation or repeated skin contact, is to relatively low concentrations of inducing chemical(s). Not all features observed in patients with methaemoglobinaemia are due to methaemoglobin formation. For example, the intravascular haemolysis caused by oxidising chemicals such as chlorates poses more risk to life than the methaemoglobinaemia that such chemicals induce. If an occupational history is taken, the diagnosis of methaemoglobinaemia should be relatively straightforward. In addition, two clinical observations may help: firstly, the victim is often less unwell than one would expect from the severity of 'cyanosis' and, secondly, the 'cyanosis' is unresponsive to oxygen therapy. Pulse oximetry is unreliable in the presence of methaemoglobinaemia. Arterial blood gas analysis is mandatory in severe poisoning and reveals normal partial pressures of oxygen (pO2) and carbon dioxide (pCO2,), a normal 'calculated' haemoglobin oxygen saturation, an increased methaemoglobin concentration and possibly a metabolic acidosis. Following decontamination, high-flow oxygen should be given to maximise oxygen carriage by remaining ferrous haem. No controlled trial of the efficacy of methylene blue has been performed but clinical experience suggests that methylene blue can increase the rate of methaemoglobin conversion to haemoglobin some 6-fold. Patients with features and/or methaemoglobin concentrations of 30-50%, should be administered methylene blue 1-2 mg/kg/bodyweight intravenously (the dose depending on the severity of the features), whereas those with methaemoglobin concentrations exceeding 50% should be given methylene blue 2 mg/kg intravenously. Symptomatic improvement usually occurs within 30 minutes and a second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methaemoglobin formation. Methylene blue is less effective or ineffective in the presence of glucose-6-phosphate dehydrogenase deficiency since its antidotal action is dependent on nicotinamide-adenine dinucleotide phosphate (NADP+). In addition, methylene blue is most effective in intact erythrocytes; efficacy is reduced in the presence of haemolysis. Moreover, in the presence of haemolysis, high dose methylene blue (20-30 mg/kg) can itself initiate methaemoglobin formation. Supplemental antioxidants such as ascorbic acid (vitamin C), N-acetylcysteine and tocopherol (vitamin E) have been used as adjuvants or alternatives to methylene blue with no confirmed benefit. Exchange transfusion may have a role in the management of severe haemolysis or in G-6-P-D deficiency associated with life-threatening methaemoglobinaemia where methylene blue is relatively contraindicated.     

Ethanol-induced depression of aggression in mice antagonized by hyperbaric exposure

The present study investigated the effect of hyperbaric exposure on ethanol-induced depression of aggressive behavior measured by resident-intruder confrontations. Adult male CFW mice (residents) were paired with females and housed together for 26 days. Then, resident mice were intubated with either ethanol (2 g/kg) or water (20 ml/kg) and were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium oxygen (heliox) or 12 ATA heliox using a within-subjects counterbalanced design. Thirty minutes after intubation an intruder was introduced. Ethanol significantly decreased aggressive behaviors (attack latency, attack bites, sideways threats, tail rattles and pursuit) in 1 ATA-treated animals. Pressure completely antagonized the depression of aggression induced by ethanol. Ethanol alone and pressure alone did not significantly affect nonaggressive behaviors. There were no statistically significant differences between groups in blood ethanol concentrations 50 minutes after intubation. These results suggest that ethanol's effects on aggressive behavior result from the same membrane actions leading to loss of righting reflex, depression of locomotor activity, tolerance and dependence.     

Influence of rat brain superoxide dismutase inhibition by diethyldithiocarbamate upon the rate of development of central nervous system oxygen toxicity

Exposure to oxygen at pressures greater than 2.8 ATA (OHP) results in central nervous system toxicity seen as grand mal seizures. The time to onset of seizures (ts) is related to the pO2 above the 2.8 ATA threshold. The components of the endogenous antioxidant defense mechanism, superoxide dismutase (SOD), glutathione measured here as nonprotein sulfhydryl content (NPSH), glucose-6-phosphate dehydrogenase (G-6-PD), glutathione reductase (GR), and glutathione peroxidase (GPx) occur in brain. Their role in OHP-induced CNS toxicity is not clear. This study examined the effect of inhibition of SOD by diethyldithiocarbamate (DDC) on ts at 4 ATA O2. Antioxidant components (SOD, NPSH, G-6-PD, GR, and GPx) were measured in male Sprague-Dawley rats pretreated with 250, 500, and 1000 mg/kg DDC ip, 2 hr prior to termination in room air. SOD activity was inhibited 11, 31, and 49%, respectively, when compared with control values. Among the other antioxidant components, only GPx showed a significant loss of activity of 24% at 1000 mg/kg DDC. Rats were also pretreated 2 hr prior to exposure to hyperbaric oxygen with either 250, 500, or 1000 mg/kg DDC. Ts for the treated animals was significantly shortened by 12, 55, and 75%, respectively, compared to the saline-treated, oxygen-exposed control animals. These studies demonstrated that the rate of onset of CNS oxygen toxicity was increased by inhibition of SOD by DDC. These data suggested that SOD plays a role as part of an endogenous antioxidant defense mechanism in the brain.     

Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog

Summary In humans and in dogs, respectively, about 30 and 60% of the haemoglobin was oxidized to ferrihaemoglobin by intravenous injection of 4-dimethylaminophenol hydrochloride. Toluidine blue was found to accelerate the subsequent reduction of ferrihaemoglobin in dogs 2–3 times more rapidly than methylene blue. In man toluidine blue 2 mg/kg was about twice as effective as the same dose of methylene blue. Such doses of methylene blue caused side effects, and according to the dose-effect relationship a further increase in the rate of ferrihaemoglobin reduction with a further increase in the dose of catalyst was unlikely. Toluidine blue 4 mg/kg did not produce the side effects observed with methylene blue and accelerated the reduction of ferrihaemoglobin by 60% more than doses of 2 mg/kg. Its greater maximal effect, and the fact that it is better tolerated than methylene blue, imply that toluidine blue should be preferred for accelerating ferrihaemoglobin reduction in man.     

Reduced lethality from ethanol or ethanol plus pentobarbital in mice exposed to 1 or 12 atmospheres absolute helium-oxygen

The present experiments investigated the effects of 1 and 12 atmospheres absolute (ATA) helium-oxygen on potentially lethal doses of ethanol given alone or in combination with pentobarbital. Drug-naive, male C57BL/6J mice were injected IP with 5.4–6.5 g/kg ethanol, 4.5–6.9 g/kg ethanol plus 20 mg/kg pentobarbital, or 50–110 mg/kg pentobarbital plus 2.5 g/kg ethanol. Following injection, the mice were placed into chambers and exposed to environments of 1 ATA air, 1 ATA helium-oxygen, or 12 ATA helium-oxygen. Exposure to 1 or 12 ATA helium-oxygen significantly reduced the lethal effect (percent mortality at given doses and LD₅₀) of ethanol given alone or with 20 mg/kg pentobarbital when compared to animals exposed to 1 ATA air. The pattern and degree of reduction in lethality for the 1 and 12 ATA helium-oxygen treatments were similar, suggesting that the antagonism resulted from increased helium or decreased nitrogen and not from increased atmospheric pressure. Exposure to these environments did not reduce lethality in mice given 2.5 g/kg ethanol in combination with relatively high doses (50–110 mg/kg) of pentobarbital. These findings suggest that helium-oxygen breathing mixtures may be useful in the treatment of some overdose patients.     

Occupational Methaemoglobinaemia

Methaemoglobin is formed by oxidation of ferrous (Fe^II) haem to the ferric (F^III) state and the mechanisms by which this occurs are complex. Most cases are due to one of three processes. Firstly, direct oxidation of ferrohaemoglobin, which involves the transfer of electrons from ferrous haem to the oxidising compound. This mechanism proceeds most readily in the absence of oxygen. Secondly, indirect oxidation, a process of co-oxidation which requires haemoglobin-bound oxygen and is involved, for example, in nitrite-induced methaemoglobinaemia. Thirdly, biotransformation of a chemical to an active intermediate that initiates methaemoglobin formation by a variety of mechanisms. This is the means by which most aromatic compounds, such as amino- and nitro-derivatives of benzene, produce methaemoglobin. Methaemoglobinaemia is an uncommon occupational occurrence. Aromatic compounds are responsible for most cases, their lipophilic nature and volatility facilitating absorption during dermal and inhalational exposure, the principal routes implicated in the workplace. Methaemoglobinaemia presents clinically with symptoms and signs of tissue hypoxia. Concentrations around 80% are life-threatening. Features of toxicity may develop over hours or even days when exposure, whether by inhalation or repeated skin contact, is to relatively low concentrations of inducing chemical(s). Not all features observed in patients with methaemoglobinaemia are due to methaemoglobin formation. For example, the intravascular haemolysis caused by oxidising chemicals such as chlorates poses more risk to life than the methaemoglobinaemia that such chemicals induce. If an occupational history is taken, the diagnosis of methaemoglobinaemia should be relatively straightforward. In addition, two clinical observations may help: firstly, the victim is often less unwell than one would expect from the severity of ‘cyanosis’ and, secondly, the ‘cyanosis’ is unresponsive to oxygen therapy. Pulse oximetry is unreliable in the presence of methaemoglobinaemia. Arterial blood gas analysis is mandatory in severe poisoning and reveals normal partial pressures of oxygen (pO₂) and carbon dioxide (pCO₂,), a normal ‘calculated’ haemoglobin oxygen saturation, an increased methaemoglobin concentration and possibly a metabolic acidosis. Following decontamination, high-flow oxygen should be given to maximise oxygen carriage by remaining ferrous haem. No controlled trial of the efficacy of methylene blue has been performed but clinical experience suggests that methylene blue can increase the rate of methaemoglobin conversion to haemoglobin some 6-fold. Patients with features and/or methaemoglobin concentrations of 30–50%, should be administered methylene blue 1–2 mg/kg/bodyweight intravenously (the dose depending on the severity of the features), whereas those with methaemoglobin concentrations exceeding 50% should be given methylene blue 2 mg/kg intravenously. Symptomatic improvement usually occurs within 30 minutes and a second dose of methylene blue will be required in only very severe cases or if there is evidence of ongoing methaemoglobin formation. Methylene blue is less effective or ineffective in the presence of glucose-6-phosphate dehydrogenase deficiency since its antidotal action is dependent on nicotinamide-adenine dinucleotide phosphate (NADP⁺). In addition, methylene blue is most effective in intact erythrocytes; efficacy is reduced in the presence of haemolysis. Moreover, in the presence of haemolysis, high dose methylene blue (20–30 mg/kg) can itself initiate methaemoglobin formation. Supplemental antioxidants such as ascorbic acid (vitamin C), N-acetylcysteine and tocopherol (vitamin E) have been used as adjuvants or alternatives to methylene blue with no confirmed benefit. Exchange transfusion may have a role in the management of severe haemolysis or in G-6-P-D deficiency associated with life-threatening methaemoglobinaemia where methylene blue is relatively contraindicated.     

Hyperbaric oxygen protects against lipopolysaccharide-stimulated oxidative stress and mortality in rats

Free radicals and proinflammatory mediators have been implicated in the pathogenesis of endotoxic shock, a disease with high mortality caused by Gram-negative bacterial endotoxin. Hyperbaric oxygen is used as an adjuvant therapy for various inflammatory diseases and shows beneficial effects in lipopolysaccharide-induced shock syndrome. However, the underlying mechanisms for these effects are still to be defined. In this study, we investigated the effect of hyperbaric oxygen on inflammatory mediators, free radicals, and mortality in endotoxic rats. Wistar-Kyoto rats were injected with lipopolysaccharide (10 mg/kg) and then exposed to aminoguanidine, an inhibitor of inducible nitric oxide (NO) synthase (bolus injection 2 h after lipopolysaccharide), or hyperbaric oxygen (2 ATA for 60 min 1, 4, 9, and 24 h after lipopolysaccharide). Plasma tumor necrosis factor alpha (TNF-alpha), NO, and superoxide anion were detected and the vasorelaxation response and survival rate were assessed. The results demonstrated that increases in plasma TNF-alpha and NO, and the vasohyporeactivity induced by lipopolysaccharide treatment were significantly inhibited by hyperbaric oxygen and aminoguanidine. Mortality and vascular superoxide anion production of lipopolysaccharide treatment were also markedly reduced by hyperbaric oxygen treatment, but were not restored by aminoguanidine. None of the parameters was changed by hyperbaric oxygen treatment alone. Thus, repeated hyperbaric oxygen exposure significantly attenuated the inflammatory mediators, free radicals, and mortality in endotoxic rats.     

The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model.

Neurophysiological interactions between the competitive N-methyl-D-aspartate (NMDA) preferring receptor antagonist, CPP (3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate) and the high pressure neurological syndrome (HPNS) have been investigated in the non-human primate Papio anubis. Eight animals were exposed on two occasions to environmental pressures of 81 atmospheres absolute (ATA) in a hyperbaric chamber, using helium and oxygen. One exposure followed pretreatment with CPP (either 5 or 10 mg/kg i.v. plus 5 mg/kg/hr infusion), the other a saline control. Pretreatment with CPP delayed moderate signs of face tremor and myoclonus and abolished severe signs of whole body tremor and seizure activity. By 81 ATA, scores representing severity of HPNS were significantly reduced by CPP to a mean score, reflecting a level of just mild to moderate limb tremoring (P less than 0.001). Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions of the left cortex. Amplitude and frequency spectra were calculated and changes with pressure in the 4 conventional wavebands were analysed. The most striking change was the complete prevention by CPP of the 100% increase in the amplitude of alpha waves at 81 ATA in the frontal region (P less than 0.001). It is concluded that NMDA transmission has a major role in the expression of HPNS.     

Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury.

Tissue oxidases, especially xanthine oxidase, have been proposed as primary sources of toxic oxygen radicals in many experimental models of disease states. Among these, ischemia-reperfusion injury may be of the greatest clinical interest. In this paper we propose the use of methylene blue as a means of suppressing the production of superoxide radicals O2- by acting as an alternative electron acceptor for xanthine oxidase. Previous work has indicated that methylene blue accepts electrons from xanthine oxidase at the iron-sulfur center. Initial experiments in our laboratory demonstrated that (1) pairs of electrons from each enzymatic oxidation are transferred to methylene blue, (2) the reduction of methylene blue can be achieved by model iron-sulfur centers, similar to the iron-sulfur center of xanthine oxidase, (3) reduced methylene blue auto-oxidizes to produce H2O2 directly, rather than O2-, and (4) methylene blue is effective at non-toxic levels (2-5 mg/kg) in preventing free radical damage to liver and kidney tissues in an in vitro model of ischemia and reoxygenation. Accordingly, we propose that methylene blue may represent a new class of antioxidant drugs that competitively inhibit reduction of molecular oxygen to superoxide by acting as alternative electron acceptors for tissue oxidases. We have termed these agents "parasitic" electron acceptors.     

Behavioral effects of morphine on free-operant avoidance under hyperbaric pressure

Morphine sulfate was tested under hyperbaric pressure to assess its effects on behavior. Four male hooded rats were trained to avoid brief electric shocks under a free-operant unsignalled avoidance procedure. Using an individual organism design, we injected each rat subcutaneously with morphine sulfate (2.0, 4.0, 6.0, 8.0 mg/kg body wt.) or saline (0.1 ml/100 g body wt.). Rats were tested at 1.0 and 7.1 atmospheres absolute (ATA) in a dry hyperbaric chamber while breathing a mixture of helium and oxygen. Each session lasted 60 min. Overall, the analgesic effects of morphine at 1.0 and 7.1 ATA were found to be similar. Shock avoidance by a rat was found to be a monotonic function of the drug dose; the fewest shocks were associated with the 2.0 mg/kg dose. Increases pressure did not significantly affect the number of shocks received by a rat across doses. Total responding remained stable throughout the study, but the temporal pattern of responding was differently influenced by drug dose.     

The effect of vigabatrin on central nervous system oxygen toxicity in rats.

The toxicity of hyperbaric oxygen in the central nervous system is expressed by clinical and electroencephalographic (EEG) manifestations resembling those of generalized tonic-clonic seizures. In the search for drugs effective against these seizures, we tested vigabatrin, an irreversible inhibitor of GABA (gamma-aminobutyric acid) transaminase. Five different doses of vigabatrin (ranging from 50 to 500 mg/kg) or vehicle were injected i.p. in rats implanted with cortical electrodes, 4 h prior to exposure to 5 ATA (0.5 MPa) oxygen. EEG and spectral analysis of the background EEG activity were monitored for the different dosages of the drug. The duration of the latent period before the appearance of electrical discharges in the EEG was used as an index of oxygen toxicity. The protective effect of vigabatrin was dose-related, and complete protection against hyperoxic-induced discharges was at 180 mg/kg. The protective effect lasted 24 h and decreased gradually disappearing completely on the third day. An increase in the low frequency bands of the EEG and a decrease in the faster activity were correlated with the vigabatrin dosage injected. Our results suggest that vigabatrin has the potential of being a useful drug in the treatment and prevention of oxygen-induced seizures during hyperbaric oxygen therapy.     

Memory facilitation by methylene blue: dose-dependent effect on behavior and brain oxygen consumption

Methylene blue administered post-training improves memory retention in avoidance and appetitive tasks, and restores spatial memory impaired by an inhibitor of cytochrome oxidase. Methylene blue may improve memory retention by increasing brain oxygen utilization. We investigated which doses improve memory without nonspecific behavioral effects, and whether methylene blue enhances brain oxygen consumption. Different doses were evaluated 24 h after administration in wheel running, feeding, open field habituation and object recognition tests. The 1-10 mg/kg methylene blue-treated rats were not different from saline-treated rats in locomotion or feeding behavior. The 50-100 mg/kg doses decreased running wheel behavior. The 4 mg/kg dose improved behavioral habituation and object memory recognition. Dose-dependent effects of methylene blue on brain oxygen consumption revealed that low concentrations increased brain oxygen consumption in vitro and 24 h after in vivo administration. Therefore, methylene blue doses that increase brain oxygen consumption also facilitate memory retention.     

Pressure reversal of the depressant effect of ethanol on spontaneous behavior in rats

This study deals with the interaction between high pressure and a sub-hypnotic dose of ethanol in rats. Male Sprague-Dawley rats were given either ethanol 1.5 g/kg or saline IP and subsequently exposed to 1 atmosphere absolute pressure (ATA) air or to 1, 12, 24 or 48 ATA of helium-oxygen (heliox). The gas temperature was adjusted to offset ethanol and helium-induced hypothermia. Ethanol induced a characteristic unsteady pattern of locomotion which was completely reversed at 48 ATA, partially reversed at 24 ATA, but not affected at 12 ATA. Other behavioral effects of ethanol such as depression of total motor activity and rearing were similarly affected. Blood and brain concentrations of ethanol in the pressure groups did not differ significantly from concentrations measured in the 1 ATA groups. A similar pattern of reversal was observed whether the compression was initiated 4, 10 or 16 min after injection. These results show that hyperbaric exposure antagonizes the depressant effect of ethanol on spontaneous behavior in rats. This antagonism does not appear to be due to changes in ethanol distribution or elimination.     

Fear-dependent variations in continuous avoidance behavior of pigs

Rats performing on a progressive-ratio schedule that required five additional responses for each successive food reinforcement were administered d-amphetamine. The number of responses required increased until the next ratio was not completed within 15 min. The number of reinforcements obtained during a session increased with increasing doses of d-amphetamine from 0.25 mg/kg to a maximum behavioral effect at 1.0 to 2.0 mg/kg followed by a decline with higher doses. To assess the effects of hyperbaric air on the established d-amphetamine performance, the same doses were administered to rats breathing compressed air at seven times normal atmospheric pressure (7.1 ATA). In the hyperbaric condition the dose-effect function was displaced toward smaller doses such that the maximum behavioral effect was obtained at lower doses than under normal atmospheric pressure; doses that produced maximum behavioral effects under normal pressure produced a decline in reinforcements obtained.Supported by Naval Medical Research and Development Command, Navy Department, Research Subtask MPN 10.03.3021. The opinions and statements contained herein are the privates ones of the writer and are not to be construed as official or reflecting the views of the Navy Department or the naval service at large.     

Antidepressant-like effect of hyperbaric oxygen treatment in forced-swimming test in rats

The present study was undertaken to assess the antidepressant-like activity of hyperbaric oxygen (HBO) treatment and also to investigate whether in the forced-swimming test HBO treatment interacts with the antidepressant effects of fluoxetine, a selective serotonin reuptake inhibitor, and imipramine, which is mainly a noradrenaline reuptake inhibitor. HBO treatment (at 2.4 atmospheres absolute [ATA] for 60 min) significantly reduced the immobility time in this test; in other words, it displayed antidepressant-like activity. The coadministration of HBO with fluoxetine (5 mg/kg) or imipramine (5 mg/kg) at their ineffective doses produced greater inhibition of immobility time compared with HBO alone. In conclusion, HBO treatment might be an alternative approach to antidepressant therapy, alone or in combination with antidepressant drugs.     

Investigation of the effect of hyperbaric oxygen on experimental cyclosporine nephrotoxicity

Hyperbaric oxygen interacts with drugs which patients use concurrently with hyperbaric oxygen treatment, which may cause in potentiation or inhibition of both therapeutic and toxic effects. We examined the effect of hyperbaric oxygen therapy on experimental cyclosporine A nephrotoxicity. The study comprised four groups of rats: a control group, a cyclosporine A group (25 mg/kg/day intraperitoneally for four days), a hyperbaric oxygen group (60 min. every day for four days at 2.5 atmospheric pressure), and a cyclosporine A+hyperbaric oxygen group (CsA 25 mg/kg/day intraperitoneally for four days+hyperbaric oxygen for 60 min. every day for four days at 2.5 atmospheric pressure). Hyperbaric oxygen did not alter biochemical parameters. Cyclosporine A increased serum urea and serum creatinine levels and decreased creatinine clearance. In the cyclosporine A+hyperbaric oxygen group serum urea level increased more than in the cyclosporine A group. Cyclosporine A increased tubular epithelial cell apoptosis and necrosis score values. The numbers of apoptotic cells in proximal tubule epithelial cells in the cyclosporine A+hyperbaric oxygen group were significantly higher than those of the cyclosporine A group. We recommend that renal functions of the patients receiving cyclosporine A should be monitored during hyperbaric oxygen therapy.     

Antagonism of carbon monoxide-mediated brain lipid peroxidation by hyperbaric oxygen

The effects of oxygen at 1, 2, and 3, atmospheres absolute (ATA) were assessed on brain lipid peroxidation caused by carbon monoxide (CO) poisoning in a rat model. Oxygen at 3 ATA, but not 1 ATA, was found to prevent brain lipid peroxidation when administered to rats for 45 min, beginning 45 min subsequent to CO poisoning. Oxygen at 2 ATA had an intermediate effect. The action of hyperbaric oxygen could not be attributed to a more rapid diminution of carboxyhemoglobin, and appears to occur at the level of the brain tissue.     

The effects of non-competitive NMDA receptor antagonists on rats exposed to hyperbaric pressure

The high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.