Oxygen therapy

Oxygen, properly administered, often is a valuable therapeutic agent in many conditions such as hemorrhage, heart disease, respiratory diseases, anemia, shock, infection with fever and others in which there is direct or indirect interference with normal oxygenation of tissues. In severe heart disease or acute respiratory conditions, administration of oxygen under pressure may be necessary in order to deliver the required amount to the tissues in want. For conditions in which oxygen want is less critical, 50 per cent concentration of the gas in the inspired atmosphere is effective and more easily carried out. Patients with chronic heart disease may be greatly helped by taking oxygen at home under the direction of a physician.     

The respiratory responses of Carcinus maenas (L.) to changes in environmental salinity

Exposure of Carcinus to a reduction in salinity is accompanied by an increase in oxygen consumption. The highest rates of oxygen consumption are found during the first 2–3 h after a reduction in salinity, after which oxygen consumption then declines, but to a higher than ‘normal’ level which is maintained throughout the period of exposure to low salinity. This augmented rate of oxygen consumption persists even after 3–4 days in water of reduced salinity and indicates that the respiratory rate of Carcinus does not acclimate rapidly to reduced salinity. The increased oxygen consumption is associated with an increase in ventilation volume resulting from an increase in the rate of beating of the scaphognathites, while oxygen utilization remains at a low level. Since the oxygen-transporting properties of the blood of Carcinus show little change under conditions of reduced salinity, the increased oxygen demand of the tissues is met by a rise in cardiac output resulting mainly from an increase in heart rate.     

Effects of tocopheryl quinone on the heart: model experiments with xanthine oxidase, heart mitochondria, and isolated perfused rat hearts

It is generally accepted that the protection effect of biological tissues by vitamin E is due to its radical scavenging potency in membranes, thereby being transformed to a vitamin E radical. A deficiency of appropriate reductants, which recycle vitamin E radicals back to its antioxidative active form, causes an irreversible degradation of vitamin E leading to tocopheryl quinone (TQ). TQ-like compounds were shown to result from both vitamin E and corresponding hydrophilic analogues of this antioxidant in vitro. In vivo elevated concentrations of tocopheryl quinones were detected after oxidative stress and TQ supplementation as well. Quinones in general are known to be efficient one-electron donors and acceptors. Therefore the question arises whether TQ-like compounds can undergo redox-cycling in conjunction with redox-active enzymes in the heart, thereby producing harmful oxygen radicals, or whether these compounds exhibit antioxidant properties. In order to elucidate this question we focused our interest on the interaction of TQ and a corresponding short-chain homologue (TQ(0)) with xanthine oxidase and heart mitochondria. Furthermore, we tested the influence of TQ on the recovery of isolated perfused rat hearts after ischemia/reperfusion. Our experiments revealed that hydrophilic TQ(0) was univalently reduced by xanthine oxidase (XOD) yielding semiquinone radicals in the absence of oxygen. However, under aerobic conditions TQ(0) enhanced the O(2)(*)(-) radical output of XOD. In the mitochondrial respiratory chain TQ was shown to interact with high potential cytochrome b in the bc(1) complex specifically. In contrast to the system XOD/TQ(0), lipophilic TQ in submitochondrial particles decreased the O(2)(*)(-) radical release during regular respiration possibly due to its interaction with b-cytochromes in the mitochondrial respiratory chain. In isolated rat hearts perfused with liposomes containing lipophilic TQ, it was efficiently accumulated in the heart tissue. When hearts were subjected to conditions of ischemia/reperfusion, infusion of TQ prior to ischemia significantly improved the recovery of hemodynamic parameters. Our results demonstrate that TQ derivatives may induce pro-oxidative and antioxidative effects depending on the distribution of TQ derivatives in the heart tissue and the interacting redox system.     

Mitochondrial respiration at low levels of oxygen and cytochrome c

In the intracellular microenvironment of active muscle tissue, high rates of respiration are maintained at near-limiting oxygen concentrations. The respiration of isolated heart mitochondria is a hyperbolic function of oxygen concentration and half-maximal rates were obtained at 0.4 and 0.7 microM O(2) with substrates for the respiratory chain (succinate) and cytochrome c oxidase [N,N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride (TMPD)+ascorbate] respectively at 30 degrees C and with maximum ADP stimulation (State 3). The respiratory response of cytochrome c-depleted mitoplasts to external cytochrome c was biphasic with TMPD, but showed a monophasic hyperbolic function with succinate. Half-maximal stimulation of respiration was obtained at 0.4 microM cytochrome c, which was nearly identical to the high-affinity K(')(m) for cytochrome c of cytochrome c oxidase supplied with TMPD. The capacity of cytochrome c oxidase in the presence of TMPD was 2-fold higher than the capacity of the respiratory chain with succinate, measured at environmental normoxic levels. This apparent excess capacity, however, is significantly decreased under physiological intracellular oxygen conditions and declines steeply under hypoxic conditions. Similarly, the excess capacity of cytochrome c oxidase declines with progressive cytochrome c depletion. The flux control coefficient of cytochrome c oxidase, therefore, increases as a function of substrate limitation of oxygen and cytochrome c, which suggests a direct functional role for the apparent excess capacity of cytochrome c oxidase in hypoxia and under conditions of intracellular accumulation of cytochrome c after its release from mitochondria.     

Physical work capacity of Alpinists under conditions of extremely low pO2 in inspired air

It is shown that high-trained Alpinists retain relatively high working capacity under conditions of extremely low piO2. Maximal oxygen uptake with extremely low piO2 decreases in high-trained Alpinists less than the working capacity which under conditions of extremely low piO2, is, mainly, limited by decreased potentiality to utilize oxygen by cardiac and skeletal muscles because of paO2 and pvO2 fall below critical values. Low paO2 promotes a decrease in the rate of oxygen diffusion from blood of capillaries into cells, fall of oxygen tension in tissues and lowering of the oxidative processes' rate. Changes in the working capacity of high-trained Alpinists under conditions of extremely low piO2 depend on individual peculiarities of the organism, alpinist length of training which promote high reactivity of the respiration in response to low piO2, economization of the respiration function, development of adaptation mechanisms to low pO2 in the cerebral tissues, skeletal muscles and heart.     

Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation

Reactive oxygen species are a by-product of mitochondrial oxidative phosphorylation, derived from a small quantity of superoxide radicals generated during electron transport. We conducted a comprehensive and quantitative study of oxygen consumption, inner membrane potentials, and H₂O₂ release in mitochondria isolated from rat brain, heart, kidney, liver, and skeletal muscle, using various respiratory substrates (α-ketoglutarate, glutamate, succinate, glycerol phosphate, and palmitoyl carnitine). The locations and properties of reactive oxygen species formation were determined using oxidative phosphorylation and the respiratory chain modulators oligomycin, rotenone, myxothiazol, and antimycin A and the uncoupler CCCP. We found that in mitochondria isolated from most tissues incubated under physiologically relevant conditions, reactive oxygen release accounts for 0.1–0.2% of O₂ consumed. Our findings support an important participation of flavoenzymes and complex III and a substantial role for reverse electron transport to complex I as reactive oxygen species sources. Our results also indicate that succinate is an important substrate for isolated mitochondrial reactive oxygen production in brain, heart, kidney, and skeletal muscle, whereas fatty acids generate significant quantities of oxidants in kidney and liver. Finally, we found that increasing respiratory rates is an effective way to prevent mitochondrial oxidant release under many, but not all, conditions. Altogether, our data uncover and quantify many tissue-, substrate-, and site-specific characteristics of mitochondrial ROS release.     

Effects of aging and caloric restriction on mitochondrial energy production in gastrocnemius muscle and heart

Mitochondria are chronically exposed to reactive oxygen intermediates. As a result, various tissues, including skeletal muscle and heart, are characterized by an age-associated increase in reactive oxidant-induced mitochondrial DNA (mtDNA) damage. It has been postulated that these alterations may result in a decline in the content and rate of production of ATP, which may affect tissue function, contribute to the aging process, and lead to several disease states. We show that with age, ATP content and production decreased by approximately 50% in isolated rat mitochondria from the gastrocnemius muscle; however, no decline was observed in heart mitochondria. The decline observed in skeletal muscle may be a factor in the process of sarcopenia, which increases in incidence with advancing age. Lifelong caloric restriction, which prolongs maximum life span in animals, did not attenuate the age-related decline in ATP content or rate of production in skeletal muscle and had no effect on the heart. 8-Oxo-7,8-dihydro-2'-deoxyguanosine in skeletal muscle mtDNA was unaffected by aging but decreased 30% with caloric restriction, suggesting that the mechanisms that decrease oxidative stress in these tissues with caloric restriction are independent from ATP availability. The generation of reactive oxygen species, as indicated by H2O2 production in isolated mitochondria, did not change significantly with age in skeletal muscle or in the heart. Caloric restriction tended to reduce the levels of H2O2 production in the muscle but not in the heart. These data are the first to show that an age-associated decline in ATP content and rate of ATP production is tissue specific, in that it occurs in skeletal muscle but not heart, and that mitochondrial ATP production was unaltered by caloric restriction in both tissues.     

Influence of hypoxia and of hypoxemia on the development of cardiac activity in zebrafish larvae

Cardiac activity and anaerobic metabolism were analyzed in zebrafish larvae raised under normoxia (PO(2) = 20 kPa) and under chronic hypoxia (PO(2) = 10 kPa) at three different temperatures (25, 28, and 31 degrees C). Heart rate increased with development and with temperature. Under normoxia, cardiac output increased significantly at high temperature (31 degrees C), but not at 28 or at 25 degrees C. Under chronic hypoxia, however, heart rate as well as cardiac output increased at all temperatures in larvae at about hatching time or shortly thereafter. Cardiac activity of larvae raised for 2 wk after fertilization with a reduced hemoglobin oxygen-carrying capacity in their blood (hypoxemia; due to the presence of CO or of phenylhydrazine in the incubation water) was not different from control animals. Whole body lactate content of these animals did not increase. Thus there was no indication of a stimulated anaerobic energy metabolism. The increase in cardiac activity observed during hypoxia suggests that at about hatching time receptors are present that sense hypoxic conditions, and this information can be used to induce a stimulation of convective oxygen transport to compensate for a reduction in bulk oxygen diffusion in the face of a reduced oxygen gradient between environmental water and tissues. Under normoxia, however, the PO(2) gradient between environmental water and tissues and diffusional oxygen transport assure sufficient oxygen supply even if hemoglobin oxygen transport in the blood is severely impaired. Thus, under normoxic conditions and with a normal metabolic rate of the tissues, convective oxygen transport is not required until approximately 2 wk after fertilization.     

Enhancement of Anaerobic Respiration in Root Tips of Zea mays following Low-Oxygen (Hypoxic) Acclimation

Root tips (10-millimeter length) were excised from hypoxically pretreated (HPT, 4% [v/v] oxygen at 25°C for 16 hours) or nonhypoxically pretreated (NHPT, 40% [v/v] oxygen) maize (Zea mays) plants, and their rates of respiration were compared by respirometry under aerobic and anaerobic conditions with exogenous glucose. The respiratory quotient under aerobic conditions with 50 millimolar glucose was approximately 1.0, which is consistent with glucose or other hexose sugars being utilized as the predominant carbon source in glycolysis. Under strictly anaerobic conditions (anoxia), glycolysis was accelerated appreciably in both HPT and NHPT root tips, but the rate of anaerobic respiration quickly declined in NHPT roots. [U-¹⁴C]Glucose supplied under anaerobic conditions was taken up and respired by HPT root tips up to five times more rapidly than by NHPT roots. When anaerobic ethanol production was measured with excised root tips in 50 millimolar glucose, HPT tissues consistently produced ethanol more rapidly than NHPT tissues. These data suggest that a period of low oxygen partial pressure is necessary to permit adequate acclimation of the root tip of maize to subsequent anoxia, resulting in more rapid rates of fermentation and generation of ATP.     

Changes in pulmonary gas exchange during resistive loading that do not cause a sense of shortness of breath

It is known that hypoxic hypometabolism occurs as a result of reduced delivery of oxygen to tissues. We have shown earlier that this response may be observed during latent hypoxia, when blood oxygen saturation (SpO₂) is reduced to 95%. There is a hypothesis that the body can prevent a disturbance of the balance between oxygen delivery and consumption by developing a protective response to reduce oxygen demand. To test the hypothesis, a study was carried out under normal oxygenation conditions, in which a weak additional resistance of 0.4 cm H₂O L^?1 s was used as a trigger. The study sample comprised 14 healthy subjects of both sexes. Gas exchange parameters under normal and combined resistive loading conditions were studied. It was found that the respiratory rate was reduced by 8%, and the tidal volume was increased by 12%. At the same time, oxygen consumption and carbon dioxide production were significantly decreased by 9 and 10%, respectively. These findings suggest that a decrease in the rates of oxygen consumption and carbon dioxide production is a nonspecific protective response to prevent the disturbance of the balance between oxygen delivery and consumption.     

Oxygen-sensing neurons in the central nervous system.

This mini-review summarizes the present knowledge regarding central oxygen-chemosensitive sites with special emphasis on their function in regulating changes in cardiovascular and respiratory responses. These oxygen-chemosensitive sites are distributed throughout the brain stem from the thalamus to the medulla and may form an oxygen-chemosensitive network. The ultimate effect on respiratory or sympathetic activity presumably depends on the specific neural projections from each of these brain stem oxygen-sensitive regions as well as on the developmental age of the animal. Little is known regarding the cellular mechanisms involved in the chemotransduction process of the central oxygen sensors. The limited information available suggests some conservation of mechanisms used by other oxygen-sensing systems, e.g., carotid body glomus cells and pulmonary vascular smooth muscle cells. However, major gaps exist in our understanding of the specific ion channels and oxygen sensors required for transducing central hypoxia by these central oxygen-sensitive neurons. Adaptation of these central oxygen-sensitive neurons during chronic or intermittent hypoxia likely contributes to responses in both physiological conditions (ascent to high altitude, hypoxic conditioning) and clinical conditions (heart failure, chronic obstructive pulmonary disease, obstructive sleep apnea syndrome, hypoventilation syndromes). This review underscores the lack of knowledge about central oxygen chemosensors and highlights real opportunities for future research.     

A system architecture for genomic data analysis

MOTIVATION: Most of diseases are caused by a set of gene defects, which occur in a complex association. The association scheme of expressed genes can be modelled by genetic networks. Genetic networks are efficiently facilities to understand the dynamic of pathogenic processes by modelling molecular reality of cell conditions. In this sense a genetic network consists of first, a set of genes of specified cells, tissues or species and second, causal relations between these genes determining the functional condition of the biological system, i. e. under disease. A relation between two genes will exist if they both are directly or indirectly associated with disease [8]. Our goal is to characterize diseases (especially autoimmune diseases like chronic pancreatitis CP, multiple sclerosis MS, rheumatoid arthritis RA) by genetic networks generated by a computer system. We want to introduce this practice as a bioinformatic approach for finding targets.     

Polymerized bovine hemoglobin decreases oxygen delivery during normoxia and acute hypoxia in the rat

Hemoglobin-based oxygen carriers (HBOC) have been primarily studied for blood loss treatment. More recently infusions of HBOC in euvolemic subjects have been proposed for a wide variety of potential therapies in which increased tissue oxygenation would be beneficial. However, compared with the exchange transfusion models to study blood loss, less is known about HBOC oxygen delivery and vasoacitvity when it is infused in euvolemic subjects. We hypothesized that HBOC [polymerized bovine hemoglobin (PBvHb)] infusion creating hypervolemia would increase oxygen delivery to tissues during acute global hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused with 3 ml of either lactated Ringer or PBvHb solution (13 g/dl, 1.3 g/kg) during acute hypoxia (FIO2 = 10%, 4 h) or normoxia (FIO2 = 21%) exposure. Our data demonstrated that compared with Ringer-infused animals, in hypoxia and normoxia, PBvHb treatment improved oxygen content but raised mean arterial pressure, lowered stroke volume, heart rate, and cardiac index, which resulted in a net reduction in blood flow and oxygen delivery to the tissues. The PBvHb vasoactive effect was similar in magnitude and direction as to the Ringer-infused animals treated with a nitric oxide synthase inhibitor nitro-l-arginine, suggesting the PBvHb effect is mediated via nitric oxide scavenging. We conclude that infusion of PBvHb is not likely to be useful in treating global hypoxia under these conditions.     

Suppression of mycelia formation by NO produced endogenously in Candida tropicalis

In the experiments reported here we found that enzymatic NO synthesis in the yeast Candida tropicalis resembles the one in animal tissues with respect to the substrate arginine as well as its sensitivity to potential competitive inhibitors. Both, NO produced by the yeast's nitric oxide synthase and NO derived from an artificial donor, suppressed the formation of pseudomycelia. These results suggest to make use of NO as a tool in elucidating the mechanism controlling mycelia generation in this yeast. The apparent K(m) towards oxygen of the yeast's nitric oxide synthase (about 50 microM) was found to be high as compared to the apparent K(m) value of the yeast's respiratory chain (about 170 nM). From this observation it may be concluded that under conditions of little oxygen supply the nitric oxide synthase will unsuccessfully compete for oxygen with respiration. Therefore, the formation of mycelia spontaneously occurring in yeast cultures grown in sealed chambers can be attributed to a reduced internal NO level rather than limited respiratory activity.     

Cytoglobin is a respiratory protein in connective tissue and neurons, which is up-regulated by hypoxia

Cytoglobin is a recently discovered vertebrate globin distantly related to myoglobin, and its function is unknown. Here we present the first detailed analysis of the distribution and expression of cytoglobin. Northern and Western blotting experiments show the presence of cytoglobin mRNA and protein in a broad range of tissues. Quantitative PCR demonstrates an up-regulation of cytoglobin mRNA levels in rat heart and liver under hypoxic conditions (22 and 44 h of 9% oxygen). Immunofluorescence studies with three antibodies directed against different epitopes of the protein consistently show cytoglobin in connective tissue fibroblasts as well as in hepatic stellate cells. Cytoglobin is also present in chondroblasts and osteoblasts and shows a decreased level of expression upon differentiation to chondrocytes and osteocytes. Cytoglobin is located in the cytoplasm of these cell types. Evidence against an exclusively nuclear localization of cytoglobin, as recently proposed, is also provided by transfection assays with green fluorescent protein fusion constructs, which demonstrates the absence of an active nuclear import. The differential expression of cytoglobin argues against a general respiratory function of this molecule, but rather indicates a connective tissue-specific function. We hypothesize that cytoglobin may be involved in collagen synthesis. Cytoglobin expression was also observed in some neuronal subpopulations of the central and the peripheral nervous systems. Surprisingly, cytoglobin is localized in both the cytoplasm and nucleus of neurons, indicating a possible additional role of this protein in neuronal tissues.     

Kynurenines and the respiratory parameters on rat heart mitochondria

It has been shown recently that the L-kynurenine metabolite kynurenic acid lowers the efficacy of mitochondria ATP synthesis by significantly increasing state IV, and reducing respiratory control index and ADP/oxygen ratio of glutamate/malate-consuming heart mitochondria. In the present study we investigated the effect of L-tryptophan (1.25 microM to 5 mM) and other metabolites of L-kynurenine as 3-hydroxykynurenine (1.25 microM to 2.5 mM), anthranilic acid (1.25 microM to 5 mM) and 3-hydroxyanthranilic acid (1.25 microM to 5 mM) on the heart mitochondria function. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mM), succinate (10 mM) or NADH (1 mM) in the presence or absence of L-tryptophan metabolites. Among tested substances, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and anthranilic acid but not tryptophan affected the respiratory parameters dose-dependently, however at a high concentration, of a micro molar range. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid lowered respiratory control index and ADP/oxygen ratio in the presence of glutamate/malate and succinate but not with NADH. While, anthranilic acid reduced state III oxygen consumption rate and lowered the respiratory control index only of glutamate/malate-consuming heart mitochondria. Co-application of anthranilic acid and kynurenic acid (125 or 625 microM each) to glutamate/malate-consuming heart mitochondria caused a non-additive deterioration of the respiratory parameters determined predominantly by kynurenic acid. Accumulated data indicate that within L-tryptophan metabolites kynurenic acid is the most effective, followed by anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid to influence the respiratory parameters of heart mitochondria. Present data allow to speculate that changes of kynurenic acid and/or anthranilic acid formation in heart tissue mitochondria due to fluctuation of L-kynurenine metabolism may be of functional importance for cardiovascular processes. On the other hand, beside the effect of 3-hydroxyanthranilic acid and 3-hydroxykynurenine on respiratory parameters, their oxidative reactivity may contribute to impairment of mitochondria function, too.     

肺心病患者血清甲状腺激素的变化

本文分析30例慢性肺心病心衰并呼衰患者(心衰并呼衰组)及30例慢性肺心病心衰无呼衰患者(心衰无呼哀组)和慢性肺心病死亡组的血清甲状腺激素水平。结果表明心衰并呼衰组T_3、T_4水平均值显著低于心衰无呼衰组和健康组,心衰无呼衰组T_3水平均值显著低于健康组,肺心病死亡组T_3、T_4水平均值显著低于存活组,并发现血清T_3、T_4水平与动脉血氧分压(PaO_2)呈正相关。作者认为T_3明显降低是重症肺心病的损伤性结果,预示病情严重,预后差。而T_4明显下降,可能是死亡的信号之一。     

Effect of hypoxia on the concentration of nicotinamide coenzymes in the tissues of newborn rats]

The content of nicotinamide coenzymes (NAD, NAD-H, NADP, NADP-H) was studied in the brain, heart and liver tissue of the newborn rats kept in hypoxic gaseous medium with a 4% oxygen content for 2 1/2 hours. There was a marked reduction of NAD content, an accumulation of NAD-H and a more than two-fold fall of the NAD/NAD-H ratio particularly marked in the brain and heart. A reduction of the NADP-H values chiefly in the liver and of the general pool of NAD-phosphates in the tissues of the newborn rats under study occurred under the same conditions. The data obtained led to the conclusion that oxygen deficiency had a significant influence on the concentration and the ratio of the nicotinamide coenzymes in the tissues of newborn rats, that in its turn led to the changes in the level and the direction of the redox processes under the conditions of hypoxia.     

The Challenges of Living in Hypoxic and Hypercapnic Aquatic Environments

Organisms living in coastal waters, and especially estuaries,have long been known to have behavioral or physiological mechanismsthat enable them toexist in water containing low amounts ofoxygen. However, the respiratory consumption of oxygen thatgenerates hypoxia is also responsible for producing significantamounts of carbon dioxide. An elevation of carbon dioxide pressurein water will cause a significant acidosis in most aquatic organisms.Thus, the combination of low oxygen and elevated carbon dioxidethat occurs in estuaries represents a significant environmentalchallenge to organisms living in this habitat. Organisms maymaintain oxygen uptake in declining oxygen conditions by usinga respiratory pigment and/or by making adjustments in the convectiveflow of water and blood past respiratory surfaces (i.e., increasecardiac output and ventilation rate). Severe hypoxia may resultin an organism switching partially or completely to anaerobicbiochemical pathways to sustain metabolic rate. There is alsoevidence to suggest that organisms lower their metabolism duringhypoxic stress. Elevated water CO₂ (hypercapnia) produces anacidosis in the tissues of organisms that breathe it. This acidosismay be wholly or partially compensated (i.e., mechanisms returnpH to pre-exposure levels), or may be uncompensated. Some studieshave examined the effects on organisms of exposure simultaneouslyto hypoxia and hypercapnia. This article reviews some of thespecific adaptations and responses of organisms to low oxygen,to high carbon dioxide, and to the cooccurrence of low oxygenand high carbon dioxide