Endothelial NOS expression and ischemia-reperfusion in isolated working rat heart from hypoxic and hyperoxic conditions

Induction of endothelial nitric oxide synthase (eNOS) contributes to the mechanism of heart protection against ischemia-reperfusion damage. We analyzed the effects of hypoxia and hyperoxia on eNOS expression in isolated working rat hearts after ischemia-reperfusion damage. Adult male Wistar rats were submitted to chronic hypoxia (2 weeks) and hyperoxia (72 h). The hearts were submitted to 15 min of ischemia and reperfused for 60 min, then we evaluated hemodynamic parameters and creatine phosphokinase (CPK) release. eNOS expression was estimated by RT-PCR; enzyme localization was evaluated by immunohistochemistry and the eNOS protein levels were detected by Western blot. All hemodynamic parameters in hypoxic conditions were better with respect to other groups. The CPK release was lower in hypoxic (P<0.01) than in normoxic and hyperoxic conditions. The eNOS deposition was significantly higher in the hypoxic group versus the normoxic or hyperoxic groups. The eNOS protein and mRNA levels were increased by hypoxia versus both other groups. Chronic hypoxic exposure may decrease injury and increase eNOS protein and mRNA levels in heart subjected to ischemia-reperfusion.     

Effects of hypoxia or hyperoxia on the lung of the chick embryo

Newborn mammals in chronic hypoxia or hyperoxia experience, respectively, an increase or decrease in lung weight:body weight ratios, possibly because of the mechanical effect on the lung accompanying the ventilatory response. Because the avian lung does not expand or contract with the breathing cycle, we asked whether or not qualitatively similar changes could be observed in the lung of chick embryos incubated in hypoxic or hyperoxic conditions. Hypoxic embryos (10% O2, days 14-18) were smaller than controls incubated in normoxia, with higher hematocrit values and larger lung weight:body weight ratios (both wet and dry). Both the total pulmonary DNA (reflecting the cellular component) and the DNA concentration were decreased in hypoxia. Hyperoxic embryos (50% O2, days 7-18 or days 14-18) had lower hematocrit values and smaller dry lung weight:body weight ratios than controls, with similar DNA concentrations. In general, the differences from controls were more apparent in those embryos hyperoxic from day 14 to 18 of incubation than from day 7 to 18. We conclude that changes in lung weights qualitatively similar to those occurring in the chronically hypoxic or hyperoxic newborn mammal can also be observed in the hypoxic or hyperoxic chick embryo, suggesting that they are not necessarily caused by changes in mechanical stretch on the lung.     

Peripheral chemoreceptor contributions to sympathetic and cardiovascular responses during hypercapnia

We tested the hypothesis that integrated sympathetic and cardiovascular reflexes are modulated by systemic CO2 differently in hypoxia than in hyperoxia (n = 7). Subjects performed a CO2 rebreathe protocol that equilibrates CO2 partial pressures between arterial and venous blood and that elevates end tidal CO2 (PET(CO2)) from approximately 40 to approximately 58 mmHg. This test was repeated under conditions where end tidal oxygen levels were clamped at 50 (hypoxia) or 200 (hyperoxia) mmHg. Heart rate (HR; EKG), stroke volume (SV; Doppler ultrasound), blood pressure (MAP; finger plethysmograph), and muscle sympathetic nerve activity (MSNA) were measured continuously during the two protocols. MAP at 40 mmHg PET(CO2) (i.e., the first minute of the rebreathe) was greater during hypoxia versus hyperoxia (P < 0.05). However, the increase in MAP during the rebreathe (P < 0.05) was similar in hypoxia (16 +/- 3 mmHg) and hyperoxia (17 +/- 2 mmHg PET(CO2)). The increase in cardiac output (Q) at 55 mmHg PET(CO2) was greater in hypoxia (2.61 +/- 0.7 L/min) versus hyperoxia (1.09 +/- 0.44 L/min) (P < 0.05). In both conditions the increase in Q was due to elevations in both HR and SV (P < 0.05). Systemic vascular conductance (SVC) increased to similar absolute levels in both conditions but rose earlier during hypoxia (> 50 mmHg PET(CO2)) than hyperoxia (> 55 mmHg). MSNA increased earlier during hypoxic hypercapnia (> 45 mmHg) compared with hyperoxic hypercapnia (> 55 mmHg). Thus, in these conscious humans, the dose-response effect of PET(CO2) on the integrated cardiovascular responses was shifted to the left during hypoxic hypercapnia. The combined data indicate that peripheral chemoreceptors exert important influence over cardiovascular reflex responses to hypercapnia.     

Respiratory and cardiovascular responses to acute hypoxia and hyperoxia in internally pipped chicken embryos.

During the first day of hatching, the developing chicken embryo internally pips the air cell and relies on both the lungs and chorioallantoic membrane (CAM) for gas exchange. Our objective in this study was to examine respiratory and cardiovascular responses to acute changes in oxygen at the air cell or the rest of the egg during internal pipping. We measured lung (VO2(lung)) and CAM (VO2(CAM)) oxygen consumption independently before and after 60 min exposure to combinations of hypoxia, hyperoxia, and normoxia to the air cell and the remaining egg. Significant changes in VO2(total) were only observed with combined egg and air cell hypoxia (decreased VO2(total)) or egg hyperoxia and air cell hypoxia (increased VO2(total)). In response to the different O2 treatments, a change in VO2(lung) was compensated by an inverse change in VO2(CAM) of similar magnitude. To test for the underlying mechanism, we focused on ventilation and cardiovascular responses during hypoxic and hyperoxic air cell exposure. Ventilation frequency and minute ventilation (V(E)) were unaffected by changes in air cell O2, but tidal volume (V(T)) increased during hypoxia. Both V(T) and V(E) decreased significantly in response to decreased P(CO2). The right-to-left shunt of blood away from the lungs increased significantly during hypoxic air cell exposure and decreased significantly during hyperoxic exposure. These results demonstrate the internally pipped embryo's ability to control the site of gas exchange by means of altering blood flow between the lungs and CAM.     

Hyperoxia and recovery from hypoxia alter collagen in peripheral pulmonary arteries similarly

Chronic hypoxia causes pulmonary hypertension, the mechanism of which includes altered collagen metabolism in the pulmonary vascular wall. This chronic hypoxic pulmonary hypertension is gradually reversible upon reoxygenation. The return to air after the adjustment to chronic hypoxia resembles in some aspects a hyperoxic stimulus and we hypothesize that the changes of extracellular matrix proteins in peripheral pulmonary arteries may be similar. Therefore, we studied the exposure to moderate chronic hyperoxia (FiO2 = 0.35, 3 weeks) in rats and compared its effects on the rat pulmonary vasculature to the effects of recovery (3 weeks) from chronic hypoxia (FiO2 = 0.1, 3 weeks). Chronically hypoxic rats had pulmonary hypertension (Pap = 26 +/- 3 mm Hg, controls 16 +/- 1 mm Hg) and right ventricular hypertrophy. Pulmonary arterial blood pressure and right ventricle weight normalized after 3 weeks of recovery in air (Pap = 19 +/- 1 mm Hg). The rats exposed to moderate chronic hyperoxia also did not have pulmonary hypertension (Pap = 18 +/- 1 mm Hg, controls 17 +/- 1 mm Hg). Collagenous proteins isolated from the peripheral pulmonary arteries (100-300 microm) were studied using polyacrylamide gel electrophoresis. A dominant low molecular weight peptide (approx. 76 kD) was found in hypoxic rats. The proportion of this peptide decreases significantly in the course of recovery in air. In addition, another larger peptide doublet was found in rats recovering from chronic hypoxia. It was localized in polyacrylamide gels close to the zone of alpha2 chain of collagen type I. It was bound to anticollagen type I antibodies. An identically localized peptide was found in rats exposed to moderate chronic hyperoxia. The apparent molecular weight of this collagen fraction suggests that it is a product of collagen type I cleavage by a rodent-type interstitial collagenase (MMP-13). We conclude that chronic moderate hyperoxia and recovery from chronic hypoxia have a similar effect on collagenous proteins of the peripheral pulmonary arterial wall.     

Augmentation of hypoxic respiration after brief hyperoxia in the anesthetized cat: Putative function of GABA<Subscript>A</Subscript> neurotransmission

In this study, we attempted to determine the role of GABA neurotransmission in augmentation of hypoxic respiration by antecedent hyperoxic breathing. The experiments were performed in anesthetized, paralyzed and vagotomized cats divided into control and bicuculline (a GABA_A receptor blocker)-injected groups. The experimental protocol consisted of exposing the animals to successive hypoxic-hyperoxic-hypoxic conditions. Respiration was assessed using phrenic electroneurograms, from which the peak phrenic height, a surrogate of the tidal volume component, and respiratory rate were obtained, and their product, the respiratory minute output, was calculated. We found that prior hyperoxic ventilation increased the subsequent respiratory response to hypoxia by an average of 23.5%, compared with the preoxygen response. This increase was driven by volume respiration. The biphasic character of the hypoxic respiratory response, consisting of stimulatory and depressant phases, was sustained. Bicuculline abolished the augmentative effect on hypoxic respiration of prior hyperoxia, which suggests that oxygenation induces GABA_A-mediated hyperexcitability of respiratory neurons, possibly by the liberation of reactive oxygen species. We concluded that GABA neurotransmission is pertinent to the effect of hyperoxia on hypoxic respiratory reactivity.     

Aminophylline effects on ventilatory response to hypoxia and hyperoxia in normal adults

In 10 normal young adults, ventilation was evaluated with and without pretreatment with aminophylline, an adenosine blocker, while they breathed pure O2 1) after breathing room air and 2) after 25 min of isocapnic hypoxia (arterial O2 saturation 80%). With and without aminophylline, 5 min of hyperoxia significantly increased inspiratory minute ventilation (VI) from the normoxic base line. In control experiments, with hypoxia, VI initially increased and then declined to levels that were slightly above the normoxic base line. Pretreatment with aminophylline significantly attenuated the hypoxic ventilatory decline. During transitions to pure O2 (cessation of carotid bodies' output), VI and breathing patterns were analyzed breath by breath with a moving-average technique, searching for nadirs before and after hyperoxia. On placebo days, at the end of hypoxia, hyperoxia produced nadirs that were significantly lower than those observed with room-air breathing and also significantly lower than when hyperoxia followed normoxia, averaging, respectively, 6.41 +/- 0.52, 8.07 +/- 0.32, and 8.04 +/- 0.39 (SE) l/min. This hypoxic depression was due to significant decrease in tidal volume and prolongation of expiratory time. Aminophylline partly prevented these alterations in breathing pattern; significant posthypoxic ventilatory depression was not observed. We conclude that aminophylline attenuated hypoxic central depression of ventilation, although it does not affect hyperoxic steady-state hyperventilation. Adenosine may play a modulatory role in hypoxic but not in hyperoxic ventilation.     

Ventilation in the shore crab Carcinus maenas (L.) as a function of ambient oxygen and carbon dioxide: Field and laboratory studies

Ventilatory responses of crabs Carcinus maenas (L.) to changes in ambient oxygen and carbon dioxide were studied in field and laboratory experiments, over a range of Pw_O2 and Pw_co2 conditions encompassing natural variations observed in intertidal rock-pools. Ventilatory activity was assessed by recording gill chamber hydrostatic pressure and estimating the specific ventilation, Vw/M_O2, the reciprocal of the difference of oxygen concentrations in inspired and expired waters.

Variations in ambient oxygenation always induced large changes of ventilatory activity, hyperventilation in hypoxia, hypoventilation in hyperoxia. Conversely, Pw_CO2 changes either at constant P_O2 or in combination with different P_O2 values (hypoxic hypercapnia or hyperoxic hypocapnia) led only to small or even non-significant ventilatory responses. In the field, strong hyperventilation developed during tidal exposure at night, when the pool water became hypoxic and hypercapnic, whereas during the day the animals hypoventilated in progressively more hyperoxic and hypocapnic conditions.

Thus, in a typical intertidal animal such as C. maenas, the only ventilatory stimulus of ecological significance appears to be the ambient water oxygenation.     

Effects of acute hypoxia and hyperoxia on respiratory rate in albino rats chronically exposed to hypoxia

Changes in respiratory frequencies with hypoxic or hyperoxic exposure were studied in: 12 normoxic control rats (N) born and raised in normoxic environment at sea level; 12 rats (A) born and raised in normoxic environment at sea level exposed to normobaric hypoxia (10% O2 in N2) as adults; 12 rats of first generation (G1) raised in the above mentioned hypoxic environment since a few hours after birth; 12 rats of third generation (G3) conceived and born in the hypoxic environment of hypoxic parents of second generation and maintained continuously under hypoxic conditions until their utilization. The response of A rats to 10% O2 and 7% O2 breathing was elevated (57% and 86% over air breathing). The mean respiratory frequency of A rats exposed to 7% O2 rose to a greater extent than did that of N rats. The G1 and G3 rats were less responsive to 7% O2 (64% and 37% over air breathing, respectively) than N and A rats; however, in G1 rats the exposure to 7% O2 produced a greater rise of frequency than in G3 rats. Furthermore A rats, G1 rats and G3 rats were less responsive to 97% O2 breathing (19%, 19% and 11% below air breathing, respectively). Comparing these data with previous findings we suggest that, with chronic exposure to hypoxia, changes in ventilatory response to hypoxia and hyperoxia occur in the following manner: I) loss of response to hypoxia if chronic exposure is begun in the immediate postnatal period; 2) degree of response to hypoxia or hyperoxia influenced by duration of chronic exposure.     

Pulmonary vascular responses to surgical chemodenervation and chemical sympathectomy in dogs

We investigated the effects of surgical peripheral chemoreceptor denervation, chemical sympathectomy with 6-hydroxydopamine (6-OHDA), and the peripheral chemoreceptor stimulant almitrine on multipoint pulmonary arterial pressure-cardiac index (PAP/Q) plots in 30 pentobarbital sodium-anesthetized dogs ventilated alternatively in hyperoxia [fraction of inspired O2, (FIO2) = 0.4] and hypoxia (FIO2 = 0.1). A hypoxic pulmonary vasoconstriction (HPV), i.e., a hypoxia-induced increase in PAP over the entire range of Q studied, from 2 to 5 l.min-1.m-2, was elicited in all the animals. Surgical denervation of the carotid and aortic chemoreceptors in a first group of nine dogs increased PAP at the lowest Q of 2 and 3 l.min-1.min-2 in hyperoxia and increased PAP at all levels of Q in hypoxia, so that HPV was enhanced. Chemical sympathectomy in a second group of eight dogs increased PAP at all levels of Q to a comparable extent in hyperoxia and hypoxia so that HPV remained unchanged. Almitrine (8 micrograms.kg-1.min-1 iv) in a third group of eight dogs increased PAP at all levels of Q in hyperoxia but had no effect on PAP/Q plots in hypoxia, so that HPV was inhibited. Almitrine had these same pulmonary vascular effects when administered to the chemodenervated and the sympathectomized dogs. Sham operation and a 2-h delay in a final group of five dogs had no effect on hyperoxic or hypoxic PAP/Q plots. We conclude that in intact dogs 1) the sympathetic nervous system reduces both hyperoxic and hypoxic pulmonary vascular tone, 2) stimulation of the peripheral chemoreceptors inhibits HPV, and 3) almitrine has direct pulmonary vasoconstricting effects in hyperoxia but not hypoxia.     

Cerebral blood flow responses to changes in oxygen and carbon dioxide in humans

This study characterized cerebral blood flow (CBF) responses in the middle cerebral artery to PCO2 ranging from 30 to 60 mmHg (1 mmHg = 133.322 Pa) during hypoxia (50 mmHg) and hyperoxia (200 mmHg). Eight subjects (25 +/- 3 years) underwent modified Read rebreathing tests in a background of constant hypoxia or hyperoxia. Mean cerebral blood velocity was measured using a transcranial Doppler ultrasound. Ventilation (VE), end-tidal PCO2 (PETCO2), and mean arterial blood pressure (MAP) data were also collected. CBF increased with rising PETCO2 at two rates, 1.63 +/- 0.21 and 2.75 +/- 0.27 cm x s(-1) x mmHg(-1) (p < 0.05) during hypoxic and 1.69 +/- 0.17 and 2.80 +/- 0.14 cm x s(-1) x mmHg(-1) (p < 0.05) during hyperoxic rebreathing. VE also increased at two rates (5.08 +/- 0.67 and 10.89 +/- 2.55 L min(-1) m mHg(-1) and 3.31 +/- 0.50 and 7.86 +/- 1.43 L x min(-1) x mmHg(-1)) during hypoxic and hyperoxic rebreathing. MAP and PETCO2 increased linearly during both hypoxic and hyperoxic rebreathing. The breakpoint separating the two-component rise in CBF (42.92 +/- 1.29 and 49.00 +/- 1.56 mmHg CO2 during hypoxic and hyperoxic rebreathing) was likely not due to PCO2 or perfusion pressure, since PETCO2 and MAP increased linearly, but it may be related to VE, since both CBF and VE exhibited similar responses, suggesting that the two responses may be regulated by a common neural linkage.     

Poly(ADP-ribose) polymerase activity in the cat carotid body in hypoxia and hyperoxia.

Reactive oxygen species (ROS) induce DNA damage with the ensuing activation of the chromosomal repair enzyme poly(ADP-ribose) polymerase (PARP). ROS also interact with the function of carotid body chemoreceptor cells. The possibility arises that PARP is part of the carotid chemosensing process. This study seeks to determine the presence of PARP and its changes in response to contrasting chemical stimuli, hypoxia and hyperoxia, both capable of generating ROS, in cat carotid bodies. The organs were dissected from anesthetized cats exposed in vivo to acute normoxic (PaO2 approximately 90 mmHg), hypoxic (PaO2 approximately 25 mmHg), and hyperoxic (PaO2 > 400 mmHg) conditions. Carotid body homogenate was the source of PARP and [adenine 14C] NAD was the substrate in the assay. Specimens of the superior cervical ganglion and brainstem were used as reference tissues. We found that PARP activity amounted to 27 pmol/mg protein/min in the normoxic carotid body. The activity level more than doubled in both hypoxic and hyperoxic carotid bodies. Changes of PARP in the reference tissues were qualitatively similar. We conclude that PARP is present in the carotid body but the augmentation of the enzyme activity in both hypoxia and hyperoxia reflects DNA damage, induced likely by ROS and being universal for neural tissues, rather than a specific involvement of PARP in the chemosensing process.     

Heart rate responses to altered ambient oxygen in early (days 3–9) chick embryos in the intact egg

Normal heart rate (HR), and the HR responses to hypoxia and hyperoxia during early heart development in chick embyros have not been studied in detail, particularly in undisturbed embryos within the intact egg. HR was measured in day 3–9 chick embryos at 38 °C using relatively noninvasive impedance cardiography. Embryos were exposed to air (control) and to hypoxic (10% O₂) or hyperoxic (100% O₂) gas for a 2-h or 4-h period, during which HR was continually monitored. Control (normoxic) HR increased from about 150 beats per min (bpm) on day 3 to about 240 bpm on days 7–9. HR in very early embryos showed a variety of moderate responses to hypoxia (all survived), but as development progressed beyond day 6, hypoxic exposure induced a profound bradycardia that frequently terminated in death before the end of the measurement period. In contrast to the marked developmental changes in hypoxic sensitivity, HR showed little response to hyperoxia throughout development, suggesting no “hypoxic drive” to HR. We speculate that hypoxia has little effect early in development because of the embryo's small absolute O₂ demand, but as the embryo grows, hypoxia represents a progressively more severe perturbation. Although general trends were identified, there was considerable variation in both HR and HR responses to ambient O₂ changes between individuals of the same developmental stage. Accepted: 16 December 1998     

Responses of type II pneumocyte antioxidant enzymes to normoxic and hyperoxic culture

Summary Cultured type II pneumocyte responses to in vitro normoxia (95% air: 5% CO₂) or hyperoxia (95% O₂:5% CO₂) were quantified. Normoxic culture (0 to 96 h) of rabbit type II cells resulted in enhanced cell-monolayer protein and DNA content. During this same time, cellular activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH Px) decreased. Compared to cultures maintained in normoxia, hyperoxic exposure of cultures resulted in decreased cell-associated protein and DNA content. Exposure to hyperoxia also resulted in cytotoxicity as demonstrated by elevated cellular release of DNA, lactate dehydrogenase (LDH), and preincorporated 8-[¹⁴C]adenine. Cellular catalase and GSH Px activities in hyperoxic cells decreased similarly to normoxic controls. In contrast, cellular SOD activity in hyperoxic cells decreased less than in normoxic cultures. Cellular SOD activity in hyperoxic cultures, when normalized for cellular protein, but not DNA, was greater than normoxic values after 24 to 96 h of exposure. Unlike the decrease in cellular antioxidant enzymes during normoxic and hyperoxic culture, cellular LDH activity increased during both these exposures. Cellular LDH activity in 24 to 96 h hyperoxia-exposed cells increased to a lesser extent than normoxic controls. The extent of depression in LDH activity was dependent on whether the activity was normalized for cellular protein or DNA. Type II pneumocytes, which normally undergo hyperplasia and hypertrophy during hyperoxia in vivo, exhibited oxygen sensitivity in vitro. Exposure of type II cells to hyperoxia in vitro resulted in alterations in cellular SOD and LDH activities, but recognition of such changes were dependent on whether enzymatic activities were normalized for cellular DNA or protein. This work was supported by a grant from the Health Effects Institute, grant HL40458 from the National Institutes of Health, Bethesda, MD, and a grant from the American Lung Association, New York, NY.     

慢性低氧对豚鼠右室心肌细胞钙、钾电流的影响

采用全细胞膜片箝技术,分别记录并比较正常对照组与慢性低氧组豚鼠单个右室心肌细胞的膜电容、L型钙电流和延迟整流钾电流峰值和电流-电压关系曲线,以探讨慢性低氧对豚鼠右室心肌细胞L型钙电流和延迟整流钾电流的影响。结果表明,上述两组细胞膜电容分别为（155±13．2）pF、（179±14,8）pF,低氧组显著大于正常对照组（P＜0．01）;L型钙电流峰值分别为（1．07±0．21）nA和（0．99±0．17）nA,两组之间无显著差异;在-20mV至＋20mV,慢性低氧组L型钙电流密度较正常对照组显著下降（P＜0．05）。在＋月mV至＋60mV之间,慢性低氧组豚鼠右室心肌细胞延迟整流钾电流幅度均小于正常对照组;在-20mV至＋60mV之间,慢性低氧组豚鼠右室心肌细胞延迟整流钾电流密度明显低于正常对照组。可见慢性低氧能使豚鼠右室心肌细胞膜电容增加,L型钙电流幅度不变,但L型钙电流密度下降;同时慢性低氧降低豚鼠右室心肌细胞延迟整流钾电流幅度和密度。     

Dependency of hypoxic chemotransduction in cat carotid body on voltage-gated calcium channels.

The hypothesis that the entry of extracellular calcium ions into some compartment, quite possibly the type I cells, through voltage-gated calcium channels (VGCC) is essential for hypoxic chemotransduction in the cat carotid body was tested using an in situ perfusion technique. The neural output of the carotid body of anesthetized, paralyzed, and artificially ventilated cats in response to perfusions with Krebs-Ringer bicarbonate solution (KRB), calcium-free KRB, KRB containing calcium channel blockers, or KRB containing BAY K 8644 was recorded. Selective perfusion of the carotid body with hypoxic calcium-free KRB significantly decreased carotid chemoreceptor activity, suggesting that extracellular calcium is essential for hypoxic chemotransduction. Selective perfusion of the carotid body with hypoxic KRB containing verapamil (10-100 microM), diltiazem (10-100 microM), or nifedipine (10-100 microM) dose dependently attenuated the increase in chemoreceptor activity produced by hypoxia, suggesting that VGCC need to be activated for hypoxic chemotransduction. The carotid body response to hyperoxic KRB containing the calcium channel agonist BAY K 8644 (10 microM) was 267 +/- 87% of hyperoxic control KRB, suggesting that an enhanced influx of calcium ions through VGCC stimulates carotid chemoreceptor activity. Selective perfusion of the carotid body with severely hypoxic KRB containing BAY K 8644 did not increase chemoreceptor activity above that produced by severe hypoxia alone. This suggests that severe hypoxia increases intracellular calcium in some compartment of the carotid body to achieve stimulatory maximum response and that further increase in intracellular calcium does not produce further elevation of neural activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of acute hypoxia on respiratory muscle fatigue in healthy humans

Background

Greater diaphragm fatigue has been reported after hypoxic versus normoxic exercise, but whether this is due to increased ventilation and therefore work of breathing or reduced blood oxygenation per se remains unclear. Hence, we assessed the effect of different blood oxygenation level on isolated hyperpnoea-induced inspiratory and expiratory muscle fatigue.

Methods

Twelve healthy males performed three 15-min isocapnic hyperpnoea tests (85% of maximum voluntary ventilation with controlled breathing pattern) in normoxic, hypoxic (SpO₂ = 80%) and hyperoxic (FiO₂ = 0.60) conditions, in a random order. Before, immediately after and 30 min after hyperpnoea, transdiaphragmatic pressure (P_di,tw ) was measured during cervical magnetic stimulation to assess diaphragm contractility, and gastric pressure (P_ga,tw ) was measured during thoracic magnetic stimulation to assess abdominal muscle contractility. Two-way analysis of variance (time x condition) was used to compare hyperpnoea-induced respiratory muscle fatigue between conditions.

Results

Hypoxia enhanced hyperpnoea-induced P_di,tw and P_ga,tw reductions both immediately after hyperpnoea (P_di,tw : normoxia -22 ± 7% vs hypoxia -34 ± 8% vs hyperoxia -21 ± 8%; P_ga,tw : normoxia -17 ± 7% vs hypoxia -26 ± 10% vs hyperoxia -16 ± 11%; all P < 0.05) and after 30 min of recovery (P_di,tw : normoxia -10 ± 7% vs hypoxia -16 ± 8% vs hyperoxia -8 ± 7%; P_ga,tw : normoxia -13 ± 6% vs hypoxia -21 ± 9% vs hyperoxia -12 ± 12%; all P < 0.05). No significant difference in P_di,tw or P_ga,tw reductions was observed between normoxic and hyperoxic conditions. Also, heart rate and blood lactate concentration during hyperpnoea were higher in hypoxia compared to normoxia and hyperoxia.

Conclusions

These results demonstrate that hypoxia exacerbates both diaphragm and abdominal muscle fatigability. These results emphasize the potential role of respiratory muscle fatigue in exercise performance limitation under conditions coupling increased work of breathing and reduced O₂ transport as during exercise in altitude or in hypoxemic patients.     

Postnatal development of the denervated lung in normoxia, hypoxia, or hyperoxia.

We asked whether lung innervation was essential for the normal postnatal development of the lung in conditions of normoxia, hypoxia, or hyperoxia. Litters of newborn rats were assigned to a normoxic [inspired oxygen partial pressure (PIO2) = 150 Torr, eight litters], hypoxic (PIO2 = 100 Torr, nine litters), or hyperoxic (PIO2 = 360 Torr, nine litters) group. Each litter consisted of 12 pups. Two days after birth, one-third of the litter had the vagus and sympathetic trunk cut in the neck on the left side [left denervated (L)], one-third was denervated on the right side (R), and one-third was sham-operated (S). From day 3, all pups were exposed to the designed PIO2, until day 8 or days 21-22. Almost all rats, whether S, R, or L, survived in normoxia and hyperoxia, whereas in hypoxia survival at day 22 of R and L was approximately 60-65%. Body growth was the same in S, R, and L and less in hypoxia than in normoxia or hyperoxia. At days 8 and 22, hematocrit and hemoglobin concentration, heart and lung dry and wet weights, and lung DNA content did not differ among S, R, and L, whether the pups were raised in normoxia, hypoxia, or hyperoxia. At days 21-22, aerobic metabolism and breathing pattern, both measured during air breathing, as well as compliance of isolated lungs, were also similar among S, R, and L for each of the conditions in which the pups were raised.(ABSTRACT TRUNCATED AT 250 WORDS)     

Asymmetric development of mitochondrial activity in rat embryos as a determinant of the defect patterns induced by exposure to hypoxia, hyperoxia, and redox cyclers in vitro

Previous study has shown that midorganogenesis-stage rat embryos exposed to strong redox cyclers under moderate hypoxia in vitro develop severe necrotic defects on the right side. Similar effects can be produced by exposure to severe hypoxia alone. Studies presented here indicate that exposure to severe but survivable hyperoxia induces comparable necrotic degeneration on the left sides of all embryos. We hypothesize that the basis of these axially asymmetric defects is relatively precocious mitochondrial maturity on the left side of the embryo. In order to investigate this hypothesis, we compared mitochondrial oxygen utilization (NADH oxidase activities) on either side of rat embryos between days 11 and 14 of gestation. Activities were consistently higher on the left side during this period and significantly higher on day 11. We also found that the asymmetric embryotoxicity induced by niridazole, a strong redox cycler, could be attenuated by prior culture under hyperoxic conditions. We propose that mitochondrial immaturity on the right results in inadequate energy generation under hypoxic conditions, either directly or as a result of redox cycling. On the other hand, necrosis associated with hyperoxic conditions results from "leakage" of superoxide from functionally mature mitochondria on the left side.