Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity

In hyperbaric oxygen (HBO(2)) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO(2) exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO(2) from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with central NOS inhibition. In inhibitor-treated animals, autonomic discharges, cardiovascular pressures, catecholamine release, and cerebral blood flow all remained below baseline throughout exposure to HBO(2). In control animals, however, initial declines in these parameters were followed by significant increases above their baselines. In awake animals, central NOS inhibition significantly decreased the incidence of clonic-tonic convulsions or delayed their onset, compared with controls. The novel findings of this study are that NO produced by nNOS in the periventricular regions of the brain plays a critical role in the events leading to both CNS toxicity in HBO(2) and to the associated sympathetic hyperactivation involved in pulmonary injury.     

Free radical generation in the brain precedes hyperbaric oxygen-induced convulsions.

We tested the hypothesis that hyperbaric oxygenation (HBO) generates free radicals in the brain before the onset of neurological manifestations of central nervous system (CNS) oxygen poisoning. Chronically cannulated, conscious rats were individually placed in a transparent pressure chamber and exposed to (1) 5 atmospheres absolute (ATA) oxygen for 15 min (n = 4); (2) 5 ATA oxygen for 30 min (n = 5), during which no visible convulsions occurred; (3) 5 ATA oxygen for 30 min with recurrent convulsions (n = 6); (4) 5 ATA oxygen until the appearance of the first visible convulsions (n = 5); (5) 4 ATA oxygen for 60 min during which no convulsions occurred (n = 5); and (6) 5 ATA air for 30 min (n = 5, controls). Immediately before compression, 1 mL of 0.1 M of alpha-phenyl-N-tert-butyl nitrone (PBN) was administered intravenously (iv) for spin trapping. At the termination of each experiment, rats were euthanized by pentobarbital iv and decompressed within 1 min. Brains were rapidly removed for preparation of lipid extracts (Folch). The presence of PBN spin adducts in the lipid extracts was examined by electron spin resonance (ESR) spectroscopy. ESR spectra from unconvulsed rats exposed to 5 ATA oxygen for 30 min revealed both oxygen-centered and carbon-centered PBN spin adducts in three of the five brains. One of the five rats in this group showed an ascorbyl signal in the ESR spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)     

PCO(2) threshold for CNS oxygen toxicity in rats in the low range of hyperbaric PO(2).

Central nervous system (CNS) oxygen toxicity, as manifested by the first electrical discharge (FED) in the electroencephalogram, can occur as convulsions and loss of consciousness. CO(2) potentiates this risk by vasodilation and pH reduction. We suggest that CO(2) can produce CNS oxygen toxicity at a PO(2) that does not on its own ultimately cause FED. We searched for the CO(2) threshold that will result in the appearance of FED at a PO(2) between 507 and 253 kPa. Rats were exposed to a PO(2) and an inspired PCO(2) in 1-kPa steps to define the threshold for FED. The results confirmed our assumption that each rat has its own PCO(2) threshold, any PCO(2) above which will cause FED but below which no FED will occur. As PO(2) decreased from 507 to 456, 405, and 355 kPa, the percentage of rats that exhibited FED without the addition of CO(2) (F(0)) dropped from 91 to 62, to 8 and 0%, respectively. The percentage of rats (F) having FED as a function of PCO(2) was sigmoid in shape and displaced toward high PCO(2) with the reduction in PO(2). The following formula is suggested to express risk as a function of PCO(2) and PO(2) [abstract: see text] where P(50) is the PCO(2)for the half response and N is power. A small increase in PCO(2) at a PO(2) that does not cause CNS oxygen toxicity may shift an entire population into the risk zone. Closed-circuit divers who are CO(2)retainers or divers who have elevated inspired CO(2)are at increased risk of CNS oxygen toxicity.     

一氧化氮合成酶在不同压力氧气导致的肺型氧中毒中的表达变化

目的：临床上过量使用氧气可导致肺型氧中毒的发生,目前有文献认为常压氧和高压氧导致的肺型氧中毒具有不同的发病机制。本实验拟探讨一氧化氮合成酶在不同压力氧气导致的肺型氧中毒中的表达变化。方法：60只雄性SD大鼠,随机分为6组（n=10）,分别暴露于1绝对压（atmosphere absolute,ATA）、1．5ATA、2ATA、2．5ATA、3ATA,100％氧气中56、20、10、8、6h,暴露于空气组作为对照。出舱后测定各组大鼠肺组织湿干比、支气管肺泡灌洗液蛋白含量。收集肺组织,裂解提取蛋白。行Western blot检测内皮一氧化氮合酶（eNOS）、神经型一氧化氮合酶（eNOS）的表达变化。结果：相对于正常对照组,1．0ATA组肺湿干比、支气管肺泡灌洗液蛋白量表达明显增高。随着氧分压的增高,这种改变减弱。和1．0ATA组相比,高压氧组的肺湿干比、肺泡灌洗液蛋白含量显著降低。各个氧气压力暴露组大鼠肺组织中nNOS的含量没有明显改变。而eNOS含量则在氧气压力为2ATA时明显降低（P〈0．05）,氧气压力为2．5ATA及3ATA时明显增高（P〈0．05）。结论：eNOS在肺中的表达量随着氧气压力的变化而改变。     

Latency of oxygen toxicity of the central nervous system in rats as a function of carbon dioxide production and partial pressure of oxygen

Oxygen toxicity of the central nervous system (CNS) can occur as convulsions and loss of consciousness, with no warning symptoms. A quantitative study of the effect of metabolic rate on sensitivity to oxygen toxicity was made in the rat. A group of 19 rats were exposed (126 exposures) to 12 combinations of four pressures (456, 507, 608 and 709 kPa) and three ambient temperatures (15, 23 and 29°C) until the appearance of the first electrical discharge (FED) preceding clinical convulsions. Carbon dioxide production (V˙CO₂) was also measured. A thermoneutral zone (mean V˙CO₂ 0.87 ml · g⁻¹ · h⁻¹) existed between the temperatures of 24 and 29°C; at temperatures lower than this, the metabolic rate increased by 1.2 to 4 times the resting level. Latency of FED decreased linearly with the increase in V˙CO₂ at all four oxygen pressures. The slopes (absolute value) and intercepts decreased with the increase in oxygen pressure. This linear relationship made possible the derivation of an equation which described latency of the FED as a function of both oxygen pressure and metabolic rate. Various environmental and other physiological factors that have been said to influence sensitivity to CNS oxygen toxicity, enhancing the effect of the partial pressure of oxygen, can be explained by their effect on metabolic rate. It is suggested that in situations where there is a risk of oxygen toxicity of the CNS, that risk would be reduced by a lower metabolic rate. Accepted: 4 May 1998     

Latency to CNS oxygen toxicity in rats as a function of PCO2 and PO2

Central nervous system (CNS) oxygen toxicity can occur as convulsions and loss of consciousness, without any premonitory symptoms. We have made a quantitative study of the effect of inspired carbon dioxide on sensitivity to oxygen toxicity in the rat. Rats were exposed to four oxygen pressures (PO(2); 456, 507, 608 and 709 kPa) and an inspired partial pressure of carbon dioxide (PCO(2)) in the range 0-12 kPa until the appearance of the electroencephalograph first electrical discharge (FED) that precedes the clinical convulsions. Exposures were conducted at a thermoneutral temperature of 27 degrees C. Latency to the FED decreased linearly with the increase in PCO(2) at all four PO(2) values studied. This decrease, which is probably related to the cerebral vasodilatory effect of carbon dioxide, reached a minimal value that remained constant on further elevation of PCO(2). The slopes (absolute value) and intercepts of latency to the FED as a function of carbon dioxide decreased with the increase in PO(2). This log-linear relationship made possible the derivation of equations that describe latency to the FED as a function of both PO(2) and PCO(2) in the PCO(2) - dependent range: Latency (min) = e((5.19-0.0040)(P)(O(2)))-e((2.77-0.0034)(P)(O(2))) x PCO(2) (kPa), and in the PCO(2)-independent range: Latency(min) = e((2.44-0. 0009)(P)(O(2))). A PCO(2) as low as 1 kPa significantly reduced the latency to the FED. It is suggested that in closed-circuit oxygen diving, any accumulation of carbon dioxide should be avoided in order to minimize the risk of CNS oxygen toxicity.     

Renal functions following hyperbaric oxygen toxicity in conscious rats

The after-effects of renal function were studied in rats exposed to hyperbaric oxygen (HBO) at either 4.8 ATA for 60 min or 6.8 ATA until the onset of convulsions. Only the rats which suffered from HBO convulsions were found to have alterations in renal function. It was observed that 4 hr after convulsions, there was a decrease in urinary excretion of urea and creatinine, which resulted in an elevation of blood urea nitrogen (BUN) and creatinine. Clearances of inulin and p-aminohippuric acid showed a decrease in the glomerular filtration rate and effective renal blood flow 4 hr after HBO convulsions. These parameters nearly returned to normal in 24 hr after convulsions. The renal handling of a large volume of infused saline was also retarded 4 hr after HBO convulsions, but by the end of 24 hr after HBO convulsions, it was much improved. Therefore, it was concluded that the renal function was altered after HBO convulsions, but nearly recovered in 24 hr.     

Similar but not the same: normobaric and hyperbaric pulmonary oxygen toxicity, the role of nitric oxide

Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O(2) at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O(2) pressures, 2-3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral transection of the vagus nerve. We propose that extrapulmonary, neurogenic events predominate in the pathogenesis of acute pulmonary oxygen toxicity in hyperbaric oxygenation, as nNOS activity drives lung injury by modulating the output of central autonomic pathways.     

BRAIN ENERGETICS IN OXYGEN-INDUCED CONVULSIONS

Mice were exposed to 6 ATA of 100% oxygen. The effect of high oxygen pressure (OHP), disulphiram and both disulphiram and oxygen as a function of the length of oxygen exposure on cerebral cortical ATP, phosphocreatine, lactate, pyruvate and glucose was determined. Neither OHP nor disulphiram altered ATP prior to the onset of convulsions. The combination of OHP and disulphiram appeared to elevate cerebral ATP, particularly during the early exposure period. OHP had no effect on phosphocreatine, however, disulphiram, both alone and in combination with OHP increased cerebral cortical phosphocreatine. ATP and phosphocreatine were unchanged in mice sacrificed either at the onset or 9 s after the onset of oxygen convulsions. Lactate and pyruvate increased as the length of time the mice were exposed to OHP increased although neither lactate nor pyruvate levels differed significantly from control levels at either the onset or 9 s after the onset of convulsions. Disulphiram by itself lowered cerebral lactate, and prevented the increase in lactate and pyruvate in mice exposed to OHP. OHP and disulphiram increased cerebral glucose with the combination of both OHP and disulphiram appearing to have an additive effect. Glucose also remained elevated at the onset or 9 s after the onset of oxygen convulsions.     

Brain oxygenation and CNS oxygen toxicity after infusion of perfluorocarbon emulsion

Intravenous perfluorocarbon (PFC) emulsions, administered with supplemental inspired O(2), are being evaluated for their ability to eliminate N(2) from blood and tissue prior to submarine escape, but these agents can increase the incidence of central nervous system (CNS) O(2) toxicity, perhaps by enhancing O(2) delivery to the brain. To assess this, we infused a PFC emulsion (Oxycyte, 6 ml/kg iv) into anesthetized rats and measured cerebral Po(2) and regional cerebral blood flow (rCBF) in cortex, hippocampus, hypothalamus, and striatum with 100% O(2) at 1, 3, or 5 atmospheres absolute (ATA). At 1 ATA, brain Po(2) stabilized at >20 mmHg higher in animals infused with PFC emulsion than in control animals infused with saline, and rCBF fell by ~10%. At 3 ATA, PFC emulsion raised brain Po(2) >70 mmHg above control levels, and rCBF decreased by as much as 25%. At 5 ATA, brain Po(2) was ≥159 mmHg above levels in control animals for the first 40 min but then rose sharply; rCBF showed a similar profile, reflecting vasoconstriction followed by hyperemia. Conscious rats were also pretreated with PFC emulsion at 3 or 6 ml/kg iv and exposed to 100% O(2) at 5 ATA. At the lower dose, 80% of the animals experienced seizures by 33 min compared with 50% of the control animals. At the higher dose, seizures occurred in all rats within 25 min. At these doses, administration of PFC emulsion poses a clear risk of CNS O(2) toxicity in conscious rats exposed to hyperbaric O(2) at 5 ATA.     

Alteration of Striatal Dopamine Levels Under Various Partial Pressure of Oxygen in Pre-convulsive and Convulsive Phases in Freely-Moving rats

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5 ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5 ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1 week rest, awaked rats were exposed to oxygen–nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5 ATA. DA level was monitored continuously (every 3 min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1 ATA to 4 ATA (?15 % at 1 ATA, ?30 % at 2 ATA, ?40 % at 3 ATA, ?45 % at 4 ATA), without signs of oxygen toxicity. At 5 ATA, DA level strongly decreases (?75 %) before seizure which occurred after 27 min ± 7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.     

Humidity does not affect central nervous system oxygen toxicity.

Central nervous system (CNS) oxygen toxicity can occur as convulsions and loss of consciousness when hyperbaric oxygen is breathed in diving and hyperbaric medical therapy. Lin and Jamieson (J Appl Physiol 75: 1980-1983, 1993) reported that humidity in the inspired gas enhances CNS oxygen toxicity. Because alveolar gas is fully saturated with water vapor, we could not see a cause and effect and surmised that other factors, such as metabolic rate, might be involved. Rats were exposed to 507- and 608-kPa O(2) in dry (31 or 14%) or humid (99%) atmosphere until the appearance of the first electrical discharge preceding the clinical convulsions. Each rat served as its own control. A thermoneutral temperature (28 +/- 0.4 degrees C) yielded resting CO(2) production of 0.81 +/- 0.06 ml x g(-1) x h(-1). Latency to the first electrical discharge was not affected by humidity. At 507-kPa O(2), latency was 23 +/- 0.4 and 22 +/- 0.7 min in dry and humid conditions, respectively, and, at 608-kPa O(2), latency was 15 +/- 4 and 14 +/- 3 min in dry and humid conditions, respectively. When no effects of CO(2) and metabolic rate are present, humidity does not affect CNS oxygen toxicity. Relevance of the findings to diving and hyperbaric therapy is discussed.     

Hyperoxia increases H2O2 production by brain in vivo

Hyperoxia and hyperbaric hyperoxia increased the rate of cerebral hydrogen peroxide (H2O2) production in unanesthetized rats in vivo, as measured by the H2O2-mediated inactivation of endogenous catalase activity following injection of 3-amino-1,2,4-triazole. Brain catalase activity in rats breathing air (0.2 ATA O2) decreased to 75, 61, and 40% of controls due to endogenous H2O2 production at 30, 60, and 120 min, respectively, after intraperitoneal injection of 3-amino-1,2,4-triazole. The rate of catalase inactivation increased linearly in rats exposed to 0.6 ATA O2 (3 ATA air), 1.0 ATA O2 (normobaric 100% O2) and 3.0 ATA O2 (3 ATA 100% O2) compared with 0.2 ATA O2 (room air). Catalase inactivation was prevented by pretreatment of rats with ethanol (4 g/kg), a competitive substrate for the reactive catalase-H2O2 intermediate, compound I. This confirmed that catalase inactivation by 3-amino-1,2,4-triazole was due to formation of the catalase-H2O2 intermediate, compound I. The linear rate of catalase inactivation allows estimates of the average steady-state H2O2 concentration within brain peroxisomes to be calculated from the formula: [H2O2] = 6.6 pM + 5.6 ATA-1 X pM X [O2], where [O2] is the concentration of oxygen in ATA that the rats are breathing. Thus the H2O2 concentration in brains of rats exposed to room air is calculated to be about 7.7 pM, rises 60% when O2 tension is increased to 100% O2, and increases 300% at 3 ATA 100% O2, where symptoms of central nervous system toxicity first become apparent. These studies support the concept that H2O2 is an important mediator of O2-induced injury to the central nervous system.     

Prevention of H2O2 generation by monoamine oxidase protects against CNS O2 toxicity.

Toxicity to the central nervous system (CNS) by hyperbaric oxygen (HBO) presumably relates to increased production of reactive oxygen species. The sites of generation of reactive oxygen species during HBO, however, have not been fully characterized in the brain. We investigated the relationship between regional generation of hydrogen peroxide (H2O2) in the brain in the presence of an irreversible inhibitor of catalase, aminotriazole (ATZ), and protection from CNS O2 toxicity by a monoamine oxidase (MAO) inhibitor, pargyline. At 6 ATA of oxygen, pargyline significantly protected rats from CNS O2 toxicity whereas ATZ enhanced O2 toxicity. In animals pretreated with ATZ, HBO inactivated 21-40% more catalase than air exposure in the six brain regions studied. Because ATZ-mediated inactivation of catalase was H2O2 dependent, the decrease in catalase activity during hyperoxia was proportional to the intracellular production of H2O2. Pargyline, administered 30 min before HBO, inhibited MAO by greater than 90%, prevented ATZ inhibition of catalase activity during HBO, and reversed the augmentation of CNS O2 toxicity by ATZ. These findings indicate that H2O2 generated by MAO during hyperoxia is important to the pathogenesis of CNS O2 toxicity in rats.     

Effects of Variations in Glutamic Acid Decarboxylase Activity on Acute Oxygen Poisoning

Abstract— A study was made to test the influence of rapid variations in glutamic acid decarboxylase (GAD) activity on the susceptibility of rats to hyperbaric oxygen (HBO). GAD was inhibited by the convulsant drug unsymmetrical dimethylhydrazine (UDMH) and reactivated by pyridoxine (PYR) after onset of convulsive activity. There was a relatively long induction period after UDMH injection until the onset of convulsions and the predictable interictal periods between successive periodic convulsions made it possible to study the impact of variations in GAD activity on survival rates, suspectibility to HBO and brain glycogen levels in a time sequence after UDMH administration. The experiments showed that UDMH interferes with aerobic metabolism in brain in such a way that profound alterations in resistance to acute oxygen poisoning resulted. An accumulation of substrate proximal to the enzyme block is assumed to develop during UDMH poisoning. The protective effect against HBO toxicity that was achieved after reactivation of GAD by PYR injection, as well as the rapid re-establishment of glycogen levels, is believed to speak in favour of this hypothesis.     

The acute antinociceptive effect of hyperbaric oxygen is not accompanied by an increase in markers of oxidative stress

Aims

Exposure to hyperbaric oxygen (HBO₂) causes an antinociceptive response in mice. However, breathing oxygen (O₂) at an elevated pressure can potentially cause oxygen toxicity. The aim of this study was to identify the determinants of HBO₂ antinociception and the toxicity profile of HBO₂.

Main methods

Male NIH Swiss mice were assessed for acute antinociceptive responsiveness under room air or 100% O₂ at 1.0 or 3.5 atmospheres absolute (ATA), using the acetic acid-induced abdominal constriction test. For the oxygen toxicity test, mice were exposed to 3.5 ATA oxygen for 11 min, 60 min, and 60 min daily for 2 days (120 min) or 60 min daily for 4 days (240 min), then assessed by analyzing the levels of two oxidative stress markers, MDA (malondialdehyde) and protein carbonyl in brain, spinal cord and lung.

Key findings

Only the combination of 100% O₂ and 3.5 ATA caused significant antinociception. The antinociceptive effect of 100% O₂ was pressure-dependent up to 3.5 ATA. In the oxygen toxicity test, mice exposed to HBO₂ for different time intervals had levels of brain, spinal cord and lung MDA and protein carbonyl that were comparable to that of control animals exposed to room air.

Significance

Treatment with 100% O₂ evokes a pressure-dependent antinociceptive effect. Since there was no significant increase in levels of the oxidative stress markers in the tested tissues, it is concluded that HBO₂ at 3.5 ATA produces antinociception in the absence of oxidative stress in mice.     

Evidence that Alterations in γ-Aminobutyric Acid and Acetylcholine in Rat Striata and Cerebella Are Not Related to Soman-Induced Convulsions

Many reports have suggested that gamma-aminobutyric acid (GABA) may play a role in organophosphate-induced convulsions. The balance between GABA and acetylcholine (ACh) in the brain also has been suggested by some investigators to be related to brain excitability. We examined these questions by studying the levels of GABA and ACh and the ratios of GABA to ACh in rat striata and cerebella (two major motor control areas in the CNS) after the administration of soman, an organophosphate acetylcholinesterase inhibitor also known as nerve gas. Male Sprague-Dawley rats weighing 250-300 g were injected subcutaneously with three different doses of soman: a subconvulsive dose of 40 micrograms/kg (approximately 30% of the ED50 for convulsions in rats), a convulsive dose of 120 micrograms/kg (approximately one ED50 for convulsions), and a higher convulsive dose of 150 micrograms/kg (approximately 120% of the ED50 for convulsions). The incidence and severity of convulsions were monitored in individual rats until they were sacrificed by focused microwave irradiation of the head at the following time points after soman administration: 4 min, a time prior to the onset of convulsions; 10 min, the time of onset of convulsions; 1 h, the time of peak convulsive activity; and 6 h, a time at which rats were recovering from convulsions. Results showed that in rat striata and cerebella, neither changes in levels of GABA and ACh nor changes in ratios of GABA to ACh were related to soman-induced convulsions, i.e., none of the changes in either levels or ratios of these two neurotransmitters were related to the initiation of, maintenance of, or recovery from soman-induced convulsions.     

Optimization of oxygen tolerance extension in rats by intermittent exposure.

Optimization of oxygen tolerance extension by intermittent exposure was studied in groups of 20 rats exposed to systematically varied patterns of alternating oxygen and normoxic breathing periods at 4.0, 2.0, and 1.5 ATA. Oxygen periods of 20, 60, and 120 min were alternated with normoxic intervals that provided oxygen-to-normoxia ratios of 4:1, 2:1, 1:1, and 1:3. In general, median survival times had nearly linear relationships to increasing normoxic intervals with oxygen period held constant. Exceptions occurred at 4.0 and 2.0 ATA where a 5-min normoxic interval was too short for adequate recovery even with a 20-min oxygen period, and an oxygen period of 120 min was too long even with a normoxic interval of 30 min. These exceptions did not occur at 1.5 ATA. Survival time for many intermittent exposure patterns was equivalent to that for continuous exposure to an oxygen pressure definable as a time-weighted average of the alternating oxygen and normoxia periods. However, this predictive method underestimated the degree of protection achieved by several of the intermittent exposure patterns, especially those performed at 4.0 ATA. Results provided guidance for selection of intermittent exposure patterns for direct evaluation in humans breathing oxygen at 2.0 ATA. Definition of intermittent exposure patterns and conditions that produced prominent gains in oxygen tolerance can also facilitate the performance of future experiments designed to study potential mechanisms for oxygen tolerance extension by intermittent exposure. Heat shock and oxidation-specific stress proteins that are induced by exposure to oxidant injury are suggested for emphasis in such investigations.     

Effects of acute and chronic hypercapnia on oxygen tolerance in rats

Groups of 16-52 normal or CO2-adapted rats were exposed top 100% O2 or to O2 with 60 Torr PICO2 (O2-CO2) at pressures of 1.0, 1.5, 2.0, 3.0, and 4.0 ATA. Exposure durations for 50% mortality (LD50) in normal rats at 4.0, 3.0, 2.0, 1.5, and 1.0 ATA O2 were 6.3, 9.3, 17.2, 27.4, and 76.1 h, respectively. Corresponding LD50 values for normal rats exposed to O2-CO2 were 2.0, 2.9, 16.3, 24.8, and 74.8 h. Survival times of CO2-adapted rats exposed to O2 were nearly identical to those of normal rats. LD50 values for CO2-adapted rat exposed to O2-CO2 were 4.1, 7.5, 17.9, 23.6, and 65.4 h, respectively. These data confirm acceleration of O2 intoxication by acute hypercapnia at 4.0 and 3.0 ATA, but they show less prominent effects at 2.0, 1.5, and 1.0 ATA. Hypercapnia adaptation clearly has a protective effect in rats exposed to O2-CO2 at 4.0 and 3.0 ATA. At 2.0, 1.5, and 1.0 ATA, where acute hypercapnia has less effect, the effects of CO2 adaptation are also less prominent. The observed changes in oxygen tolerance can be explained by cerebral vasodilation with increased brain oxygenation in acute hypercapnia and by significant amelioration of this response during chronic hypercapnia.     

Effect of exposure to high pressure on subsequent spatial learning and memory in rats

The effects of high helium pressure on the subsequent acquisition of spatial memory were studied in male rats. Thirty-two rats were exposed to 65 ATA helium-oxygen pressure for 4.2 days, decompressed (total time in chamber 5 days), and then tested in an eight-arm radial maze. Thirty-two control rats were exposed in the chamber to 1 ATA air. Each rat had 20 sessions in the maze (2 sessions/day for 10 days), and the number of correct (visiting an arm not previously visited to obtain the reward pellet) and incorrect choices (visiting a previously visited arm) were recorded. Statistical analysis showed that the rats exposed to 65 ATA performed significantly better than 1-ATA controls during the first 8 of 20 sessions. This effect was most pronounced in sessions 5-8. Results for sessions 9-20 showed that the pressure-treated rats still made more correct choices but to an extent that did not always reach statistical significance. Possible explanations include the pressure-treated rats performing better because of hunger after a lower food consumption at pressure. Alternatively, pressure itself may enhance proposed mechanisms of spatial memory such as long-term potentiation.