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This work presents a mathematical model of the human respiratory control system, based on physiological knowledge. It includes three compartments for gas storage and exchange (lungs, brain tissue and other body tissues), and various kinds of feedback mechanisms. These comprehend peripheral chemoreceptors in the carotid body, central chemoreceptors in the medulla and a central ventilatory depression. The latter acts by reducing the response of the central neural system to the afferent peripheral chemoreceptor activity during prolonged hypoxia of the brain tissue. Furthermore, the model considers local blood flow adjustments in response to O2 and CO2 arterial pressure changes. In this study, the model has been validated by simulating the response to square changes in alveolar PCO2, performed at different constant levels of alveolar PO2. A good agreement with data reported in the literature has been checked. Subsequently, a sensitivity analysis on the role of the main feedback mechanisms on ventilation response to CO2 has been performed. The results suggest that the ventilatory response to CO2 challenges during hyperoxia can be almost completely ascribed to the central chemoreflex, while, during normoxia, the peripheral chemoreceptors provide a modest contribution too. By contrast, the response to hypercapnic stimuli during hypoxia involves a complex superimposition among different factors with disparate dynamics. Hence, results suggest that the ventilatory response to hypercapnia during hypoxia is more complex than that provided by simple empirical models, and that discrimination between the central and peripheral components based on time constants may be misleading.
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PMID:An integrated model of the human ventilatory control system: the response to hypercapnia. 1144 78

To examine the process of spontaneous autoresuscitation and the recovery of the hypoxic ventilatory response (HVR) after prolonged anoxia, we monitored respiratory frequency (f, by body plethysmography) and heart rate (HR, by ECG) in intact newborn rats (n = 12, day 2-4) before, during, and after 100% N2 exposure. The rat before anoxia showed signs of HVR: f changes at acute hypoxia (10% O2) and hyperoxia (100% O2). During anoxia, the spontaneous respiratory movement "gasping" appeared for 21 min (mean). At O2 restoration (with 100% O2), gasping stopped and no respiratory flow was detected for 1 min. One rat failed to autoresuscitate and had heart arrhythmia during the transient apnea, but 11 rats recovered respiration after the HR acceleration. Despite the successful autoresuscitation, the rats did not show HVR at 10 min into the recovery period and the recovery of HVR required more than 30 min. The results indicate that O2 inhalation is useful to trigger autoresuscitation even when the rat has already been in a state of profound hypoxic depression, but the rat becomes transiently insensitive to HVR after autoresuscitation. We estimate that reform of the respiratory control system in newborn rats is not yet firmly established to track HVR early in the recovery phase after prolonged anoxia.
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PMID:The process of cardiorespiratory autoresuscitation in intact newborn rats. 1182 39

Hypoxia disturbs Ca(2+) regulation and increases the intracellular Ca(2+) concentration ([Ca(2+)](i)), which may in turn activate the nitric oxide synthase (NOS) regulated by [Ca(2+)](i). Since nitric oxide (NO) reduces the isometric contractility of rat diaphragm in vitro, we hypothesized that NO contributes to the impaired force generation of an hypoxic diaphragm. The effects of different concentrations of the NOS inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), the NO scavenger haemoglobin (150 micro mol.l(-1)) and the NO donor spermine NONOate (Sp-NO; 1 mmol.l(-1)) were determined on isometric contractility during hypoxia [partial pressure of oxygen, PO(2), about 7 kPa (about 54 mmHg)] and hyperoxia [ PO(2) about 83 kPa (about 639 mmHg)]. Hypoxia significantly reduced maximal twitch force ( F(t)), and submaximal tetanic force (30 Hz, F(30)) in all L-NMMA groups. A low concentration of L-NMMA (30 micromol.l(-1)) increased F(30) but a high concentration (1,000 micromol.l(-1)) reduced F(30) during hypoxia. The effects of L-NMMA on force generation were more pronounced during hypoxia compared to hyperoxia. Peak increases in F(30) and F(t) were observed at a concentration of 30 micromol.l(-1) L-NMMA during hypoxia, but with 10 micromol.l(-1) L-NMMA during hyperoxia. The same concentration of haemoglobin increased F(30) and F(t) less during hypoxia compared to hyperoxia. The Sp-NO reduced F(t), F(30) and maximal tetanic force (F(0)) during hypoxia; these effects were abolished in the presence of haemoglobin. The Sp-NO did not alter F(t), F(30) and F(0)during hyperoxia. We conclude that NO plays a more prominent role during hypoxia and that NO contributes to the depression of force generation in the hypoxic rat diaphragm in vitro. This change may be related to an elevated NO generation within the hypoxic diaphragm.
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PMID:Role of nitric oxide in isometric contraction properties of rat diaphragm during hypoxia. 1252 72

Current evidence suggests that a modulatory action on O(2)-dependent EPO secretion is exerted by the erythroid/precursor cell population in the erythropoietic organs through a negative feedback system. The hypothesis is based on studies of stimulated-EPO secretion performed in mice in whom the erythropoietic rates were either enhanced or depressed in the presence of normal plasma EPO half-lives. Since erythropoietic depression was elicited by cyclophosphamide administration, which could have altered EPO production directly, the aim of the present investigation was to estimate hypoxia-stimulated EPO secretion in a mouse model of functional depressed erythropoiesis induced by exposure to normobaric hyperoxia. Females CF#1 mice aged 70 d were divided into control (C) and experimental (E) groups. The former was maintained in plastic cages in a normal environment, while the latter was placed in an environment of 60% O(2)/40% N(2) in an 85-dm(3) atmospheric chamber with air flow of 1 L/min. Erythropoiesis was evaluated by either 24-h RBC-(59)Fe uptake or iron kinetics performed 3 h after IV injection of a tracer dose of (59)Fe. Both indexes of the red cell production rate were significantly depressed in E mice. Plasma disappearance of exogenous EPO in C mice, as well as in E mice exposed to hyperoxia for 4 d, was estimated by injecting (125)I-rHuEPO intravenously. Linear regression analysis indicated that neither the differences between the slopes of both curves nor the Y-intercepts were significant. Hypobaric hypoxemia was used as stimulus for EPO production. Plasma immuno-EPO titer after a 4-h exposure to hypobaric air was 73% higher in mice with hyperoxia-induced hypoerythropoiesis than in control mice with normal erythropoiesis. Data support the concept that the rate of erythropoiesis, perhaps through the number of the erythroid progenitor/precursor cell population, modulates O(2)-dependent EPO secretion.
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PMID:Enhanced hypoxia-stimulated erythropoietin production in mice with depression of erythropoiesis induced by hyperoxia. 1271 14

The aim of this study was to examine the response of phrenic and hypoglossal motor outputs to hyperoxia and 11% hypoxia during picrotoxin-induced seizures. Adult rats were anesthetized with a mixture of urethane with alpha-chloralose. The animals were bilaterally vagotomized, paralyzed, and artificially ventilated. Picrotoxin was administered intravenously in a cumulative dose until seizures occurred. The response to changes in oxygen tension was studied after the convulsive dose of picrotoxin and compared with the baseline level. The results show that the picrotoxin-induced seizures evoked a complex respiratory response that consisted of an augmentation of phrenic and hypoglossal nerve activities and irregular disturbances in phasic respiratory discharges. The excitation of the hypoglossal activity appeared earlier and showed a more irregular pattern than that of the phrenic activity. Hyperoxia elicited a similar decrease in neural respiratory outputs during the control and seizure conditions, suggesting the unaltered peripheral chemoreceptor mechanism. In the pre-seizure condition, hypoxia caused an initial excitation of the phrenic and hypoglossal outputs followed by some decline of the effect. During seizures, the striking effect of hypoxia was a decrease of the respiratory rate. A biphasic response to hypoxia was maintained in the hypoglossal activity due to stimulation of the hypoglossal amplitude. In contrast, in the phrenic activity the excitatory phase of hypoxia was absent and depression ensued. The mechanism underlying the facilitation of hypoxic respiratory depression during seizures is discussed.
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PMID:Hypoglossal and phrenic nerve responses to changes in oxygen tension during picrotoxin-induced seizures in the rat. 1561 91

Inspiratory hypoglossal motoneurons (IHMNs) maintain upper airway patency. However, this may be compromised during sleep and by sedatives, potent analgesics, and volatile anesthetics by either depression of excitatory or enhancement of inhibitory inputs. In vitro data suggest that serotonin (5-HT), through the 5-HT2A receptor subtype, plays a key role in controlling the excitability of IHMNs. We hypothesized that in vivo 5-HT modulates IHMNs activity through the 5-HT2A receptor subtype. To test this hypothesis, we used multibarrel micropipettes for extracellular single neuron recording and pressure picoejection of 5-HT or ketanserin, a selective 5-HT2A receptor subtype antagonist, onto single IHMNs in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs. Drug-induced changes in neuronal discharge frequency (F(n)) and neuronal discharge pattern were analyzed using cycle-triggered histograms. 5-HT increased the control peak F(n) to 256% and the time-averaged F(n) to 340%. 5-HT increased the gain of the discharge pattern by 61% and the offset by 34 Hz. Ketanserin reduced the control peak F(n) by 68%, the time-averaged F(n) by 80%, and the gain by 63%. These results confirm our hypothesis that in vivo 5-HT is a potent modulator of IHMN activity through the 5-HT2A receptor subtype. Application of exogenous 5-HT shows that this mechanism is not saturated during hypercapnic hyperoxia. The two different mechanisms, gain modulation and offset change, indicate that 5-HT affects the excitability as well as the excitation of IHMNs in vivo.
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PMID:Serotonergic modulation of inspiratory hypoglossal motoneurons in decerebrate dogs. 1649 64

Inhalation of high concentration of oxygen produces oxidative stress in men and experimental animals. Our previous experiments showed that the cough reflex is suppressed in guinea pigs after exposure to 100% O(2) for 60 hours. The aim of this study was to determine the effects of dietary antioxidant supplementation with vitamins C and E on hyperoxia-induced oxidative stress in airway and lung tissues directed on cough reflex. The experimental group (T-H, n=8) was pretreated with vitamins C (500 mg/kg) and E (300 mg/kg) for 4 weeks and subsequently exposed to 100% O(2) for 60 hours. Hyperoxic group (H, n=8) received saline instead of antioxidants and then inhaled 100% O(2) for 60 hours. Cough was induced by inhalation of citric acid aerosol in gradually increased concentration (0.05-1.6 M) at the end of antioxidant therapy and then at the end of exposure to 100% O(2). Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals just 1 hour after the end of oxygen exposure. Our results showed a tendency to a decrease in citric acid-induced cough in hyperoxic animals and an increase in animals with antioxidant therapy after hyperoxia. Antioxidant therapy significantly unblocked hyperoxia-induced down-regulation of cough (P=0.004). Significant changes also were obtained from mechanically-induced TBr cough [2.5(1-4) vs. 1.0(1-2); P<0.01] between the experimental and hyperoxic (control) animals. In conclusion, our results indicate a protective effect of antioxidant supplementation on oxidant-mediated cough depression.
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PMID:The interaction of dietary antioxidant vitamins and oxidative stress on cough reflex in guinea-pigs after long term oxygen therapy. 1707 29

The objective was to determine the impact of intact normoxic and hyperoxia-exposed (95% O(2) for 48 h) bovine pulmonary arterial endothelial cells in culture on the redox status of the coenzyme Q(10) homolog coenzyme Q(1) (CoQ(1)). When CoQ(1) (50 microM) was incubated with the cells for 30 min, its concentration in the medium decreased over time, reaching a lower level for normoxic than hyperoxia-exposed cells. The decreases in CoQ(1) concentration were associated with generation of CoQ(1) hydroquinone (CoQ(1)H(2)), wherein 3.4 times more CoQ(1)H(2) was produced in the normoxic than hyperoxia-exposed cell medium (8.2 +/- 0.3 and 2.4 +/- 0.4 microM, means +/- SE, respectively) after 30 min. The maximum CoQ(1) reduction rate for the hyperoxia-exposed cells, measured using the cell membrane-impermeant redox indicator potassium ferricyanide, was about one-half that of normoxic cells (11.4 and 24.1 nmol x min(-1) x mg(-1) cell protein, respectively). The mitochondrial electron transport complex I inhibitor rotenone decreased the CoQ(1) reduction rate by 85% in the normoxic cells and 44% in the hyperoxia-exposed cells. There was little or no inhibitory effect of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors on CoQ(1) reduction. Intact cell oxygen consumption rates and complex I activities in mitochondria-enriched fractions were also lower for hyperoxia-exposed than normoxic cells. The implication is that intact pulmonary endothelial cells influence the redox status of CoQ(1) via complex I-mediated reduction to CoQ(1)H(2), which appears in the extracellular medium, and that the hyperoxic exposure decreases the overall CoQ(1) reduction capacity via a depression in complex I activity.
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PMID:Role of mitochondrial electron transport complex I in coenzyme Q1 reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia. 1760 93

Cortical spreading depression (CSD), a transient neuronal and glial depolarization that propagates slowly across the cerebral cortex, is the putative electrophysiological event underlying migraine aura. It negatively impacts tissue injury during stroke, cerebral contusion and intracranial hemorrhage. Susceptibility to CSD has been assessed in several experimental animal models in vivo, such as after topical KCl application or cathodal stimulation. Various combinations of anesthetics and ambient conditions have been used by different laboratories making comparisons problematic and differences in data difficult to reconcile. We systematically studied CSD susceptibility comparing commonly used experimental anesthetics (isoflurane, alpha-chloralose, and urethane) with or without N(2)O or normobaric hyperoxia (100% O(2) inhalation). The frequency of evoked CSDs, and their propagation speed, duration, and amplitude were recorded during 2 h topical KCl (1 M) application. We found that N(2)O reduced CSD frequency when combined with isoflurane or urethane, but not alpha-chloralose; N(2)O also decreased CSD propagation speed and duration. Urethane anesthesia was associated with the highest CSD frequency that was comparable to pentobarbital. Inhalation of 100% O(2) did not alter CSD frequency, propagation speed or duration in combination with any of the anesthetics tested. Our data show anesthetic modulation of CSD susceptibility in an experimental model of human disease, underscoring the importance of proper study design for hypothesis testing as well as for comparing results between studies.
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PMID:The impact of anesthetics and hyperoxia on cortical spreading depression. 1850 48

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q(1) (CoQ(1)) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O(2) for 48 h) rats. CoQ(1) or its hydroquinone (CoQ(1)H(2)) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ(1)H(2) and CoQ(1) were measured. CoQ(1)H(2) appeared in the venous effluent when CoQ(1) was infused, and CoQ(1) appeared when CoQ(1)H(2) was infused. In normoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ(1)H(2) oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ(1) reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ(1) during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ(1) to CoQ(1)H(2) due to a depression in complex I activity.
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PMID:Coenzyme Q1 redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia. 1870 62


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