Optical Sensor for Real-Time pH Monitoring in Human Tissue.

This article reports on a fiber-based ratiometric optical pH sensor for use in real-time and continuous in vivo pH monitoring in human tissue. Stable hybrid sol-gel-based pH sensing material is deposited on a highly flexible plastic optical fiber tip and integrated with excitation and detection electronics. The sensor is extensively tested in a laboratory environment before it is applied in vivo in a human model. The pH sensor performance in the laboratory environment outperforms the state-of-the-art reported in the current literature. It exhibits the highest sensitivity in the physiological pH range, resolution of 0.0013 pH units, excellent sensor to sensor reproducibility, long-term stability, short response time of <2 min, and drift of 0.003 pH units per 22 h. The sensor also exhibits promising performance in in vitro whole blood samples. In addition, human evaluations conducted under this project demonstrate successful short-term deployment of this sensor in vivo.

Improved tolerance of acute severe hypoxic stress in chronic hypoxic diaphragm is nitric oxide-dependent.

The effects of chronic hypoxia (CH) on respiratory muscle performance have hardly been investigated, despite clinical relevance. Results from recent studies are indicative of unique adaptive strategies in hypoxic diaphragm. Respiratory muscle tolerance of acute severe hypoxic stress was examined in normoxic and CH diaphragm in the presence and absence of a nitric oxide (NO) synthase inhibitor. We tested the hypothesis that improved tolerance of severe hypoxic stress in CH diaphragm is NO-dependent. Wistar rats were exposed to normoxia (sea-level, n = 6) or CH (ambient pressure = 380 mmHg, n = 6) for 6 weeks. Diaphragm muscle functional properties were determined ex vivo under severe hypoxic conditions (gassed with 95%N2/5% CO2) with and without 1 mM L-N(G)-nitroarginine (L-NNA, nNOS inhibitor). Fatigue tolerance, but not force, was significantly improved in CH diaphragm (p = 0.008). CH exposure did not affect diaphragm muscle fibre oxidative capacity determined from cluster analysis of area-density plots of muscle fibre succinate dehydrogenase activity. Acute NOS inhibition reduced diaphragm peak tetanic force (p = 0.018), irrespective of gas treatment, and completely reversed improved fatigue tolerance of the CH diaphragm. We conclude that CH exposure improves fatigue tolerance during acute severe hypoxic stress in an NO-dependent manner, independent of muscle fibre oxidative capacity.

Effect of chronic intermittent hypoxia on the reflex recruitment of the genioglossus during airway obstruction in the anesthetized rat.

We sought to test the hypothesis that chronic intermittent hypoxia (CIH)-a feature of sleep-disordered breathing in humans-impairs reflex recruitment of the genioglossus (GG, pharyngeal dilator) during obstructive airway events. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O2 at nadir) per hour, 8h a day for 7 days (CIH, N=7). The sham group (N=7) were exposed to normoxia in parallel. Following gas treatments, rats were anesthetized with an i.p. injection of urethane (1.5g/kg; 20%, w/v). Fine concentric needle electrodes were inserted into the GG and the costal diaphragm. Discriminated GG motor unit potentials and whole electromyograph (EMG), together with arterial blood pressure and arterial O2 saturation, were recorded during quiet basal breathing and during nasal airway occlusion. Airway occlusion significantly increased GG EMG activity in all animals; but there was no difference in the reflex response to airway occlusion between sham and CIH-treated animals (+105±22% vs. +105±17%, mean±SEM for area under the curve of integrated GG EMG, % increase from baseline, p=0.99). Occluded breaths were characterized by a significant increase in the firing frequency of phasically active units and the recruitment of large motor units that were quiescent under basal conditions. Though there are reports of impaired control of the upper airway following CIH in the rat, we conclude that reflexly evoked motor discharge to the GG is not affected by 7 days of CIH, a paradigm that we have shown increases apnea index in sleeping rats.

Reactive oxygen species mediated diaphragm fatigue in a rat model of chronic intermittent hypoxia.

Respiratory muscle dysfunction documented in sleep apnoea patients is perhaps due to oxidative stress secondary to chronic intermittent hypoxia (CIH). We sought to explore the effects of different CIH protocols on respiratory muscle form and function in a rodent model. Adult male Wistar rats were exposed to CIH (n = 32) consisting of 90 s normoxia-90 s hypoxia (either 10 or 5% oxygen at the nadir; arterial O2 saturation ∼ 90 or 80%, respectively] for 8 h per day or to sham treatment (air-air, n = 32) for 1 or 2 weeks. Three additional groups of CIH-treated rats (5% O2 for 2 weeks) had free access to water containing N-acetyl cysteine (1% NAC, n = 8), tempol (1 mM, n = 8) or apocynin (2 mM, n = 8). Functional properties of the diaphragm muscle were examined ex vivo at 35 °C. The myosin heavy chain and sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform distribution, succinate dehydrogenase and glyercol phosphate dehydrogenase enzyme activities, Na(+)-K(+)-ATPase pump content, concentration of thiobarbituric acid reactive substances, DNA oxidation and antioxidant capacity were determined. Chronic intermittent hypoxia (5% oxygen at the nadir; 2 weeks) decreased diaphragm muscle force and endurance. All three drugs reversed the deleterious effects of CIH on diaphragm endurance, but only NAC prevented CIH-induced diaphragm weakness. Chronic intermittent hypoxia increased diaphragm muscle myosin heavy chain 2B areal density and oxidized glutathione/reduced glutathione (GSSG/GSH) ratio. We conclude that CIH-induced diaphragm dysfunction is reactive oxygen species dependent. N-Acetyl cysteine was most effective in reversing CIH-induced effects on diaphragm. Our results suggest that respiratory muscle dysfunction in sleep apnoea may be the result of oxidative stress and, as such, antioxidant treatment could prove a useful adjunctive therapy for the disorder.

Effects of sustained hypoxia on sternohyoid and diaphragm muscle during development.

Sustained hypoxia is a dominant feature of respiratory disease. Despite the clinical significance, the effects of sustained hypoxia on the form and function of respiratory muscle during development are relatively underexplored. Wistar rats were exposed to 1 week of sustained hypoxia (ambient pressure 450 mmHg) or normoxia at various time points during development. Sternohyoid and diaphragm muscle contractile and endurance properties were assessed in vitro. Muscle succinate dehydrogenase and myosin heavy chain composition were determined. The role of reactive oxygen species in hypoxia-induced muscle remodelling was assessed. Sustained hypoxia increased sternohyoid muscle force and fatigue in early but not late development, effects that persisted after return to normoxia. Hypoxia-induced sternohyoid muscle fatigue was not attributable to fibre type transitions or to a decrease in oxidative capacity. Chronic supplementation with the superoxide scavenger tempol did not prevent hypoxia-induced sternohyoid muscle fatigue, suggesting that mechanisms unrelated to oxidative stress underpin hypoxia-induced maladaptation in sternohyoid muscle. Sustained hypoxia had no effect on diaphragm muscle fatigue. We conclude that there are critical windows during development for hypoxia-induced airway dilator muscle maladaptation. Sustained hypoxia-induced impairment of upper airway muscle endurance may persist into later life. Upper airway muscle dysfunction could have deleterious consequences for the control of pharyngeal airway calibre in vivo.

Diaphragm muscle remodeling in a rat model of chronic intermittent hypoxia.

Respiratory muscle remodeling occurs in human sleep apnea--a common respiratory disorder characterized by chronic intermittent hypoxia (CIH) due to recurrent apnea during sleep. We sought to determine if CIH causes remodeling in rat sternohyoid (upper airway dilator) and diaphragm muscles. Adult male Wistar rats were exposed to CIH (n=8), consisting of 90 sec of hypoxia (5% at the nadir; SaO2 ~80%)/90 sec of normoxia, 8 hr per day, for 7 consecutive days. Sham animals (n=8) were exposed to alternating air/air cycles in parallel. The effect of CIH on myosin heavy-chain (MHC) isoform (1, 2a, 2x, 2b) distribution, sarcoplasmic reticulum calcium ATPase (SERCA) isoform distribution, succinate dehydrogenase activity, glycerol phosphate dehydrogenase activity, and Na⁺/K⁺ ATPase pump content was determined. Sternohyoid muscle structure was unaffected by CIH treatment. CIH did not alter oxidative/glycolytic capacity or the Na⁺/K⁺-ATPase pump content of the diaphragm. CIH significantly increased the areal density of MHC 2b fibers in the rat diaphragm, and this was associated with a shift in SERCA proteins from SERCA2 to SERCA1. We conclude that CIH causes a slow-to-fast fiber transition in the rat diaphragm after just 7 days of treatment. Respiratory muscle functional remodeling may drive aberrant functional plasticity such as decreased muscle endurance, which is a feature of human sleep apnea.

Chronic intermittent hypoxia alters genioglossus motor unit discharge patterns in the anaesthetized rat.

The respiratory control system is subject to diverse and considerable plasticity in health and disease. Intermittent hypoxia elicits expression of intrinsic plasticity within sensory and motor pathways involved in the control of breathing with potentially adaptive and maladaptive consequences for respiratory homeostasis. We and others have shown that chronic intermittent hypoxia (CIH) - a major feature of sleep-disordered breathing - has deleterious effects on rat upper airway dilator muscle contractile function and motor control. In the present study, we sought to test the hypothesis that CIH alters genioglossus (pharyngeal dilator) motor unit properties during basal breathing and obstructive airway events. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O(2) at nadir; SaO(2) ∼ 80%) per hour, 8 h a day for 7 days (CIH, N = 5). The sham group (N = 5) were subject to alternating cycles of air under identical experimental conditions in parallel. Following gas treatments, rats were anaesthetized with an i.p injection of urethane (1.5 g/kg; 20% w/v). Fine concentric needle electrodes were inserted into the genioglossus and the costal diaphragm. Genioglossus motor unit potentials, together with arterial blood pressure, tracheal pressure and arterial O(2) saturation were recorded during quiet basal breathing and nasal airway occlusion. During basal breathing, the amplitude of genioglossus motor units was significantly different in sham vs. CIH-treated rats (313 ± 32 µV vs. 430 ± 46 µV; mean ± SEM, Student's t test, p = 0.0415). The most common instantaneous firing frequency of individual units determined from auto correlograms was also significantly different in the two groups (53 ± 6 Hz vs. 37 ± 3 Hz; sham vs. CIH p = 0.0318). In addition, the amplitude of motor units recruited during airway obstruction was significantly decreased in CIH-treated rats (939 ± 102 µV vs. 619 ± 75 µV; sham vs. CIH p = 0.0267). Our results indicate that CIH causes remodelling in the central respiratory motor network with potentially maladaptive consequences for the physiological control of upper airway patency. We conclude that CIH could serve to exacerbate and perpetuate obstructive events in patients with sleep-disordered breathing.

Chronic intermittent hypoxia increases apnoea index in sleeping rats.

Intermittent hypoxia (IH) is the dominant feature of sleep-disordered breathing which is very common. It is recognized that IH elicits plasticity in the respiratory control system. Recently it was reported in humans that IH destabilizes breathing during sleep increasing the susceptibility to apnoea. Many forms of respiratory plasticity are dependent upon reactive oxygen species (ROS), and NADPH oxidase has been identified as an important source of ROS necessary for IH-induced plasticity. In the present study, we sought to examine the effects of chronic IH (CIH) on the propensity for spontaneous apnoea during sleep. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O(2) at nadir; SaO(2) ∼ 80%) per hour, 8 h a day for 7 consecutive days (CIH group, N = 6). The sham group (N = 6) were subject to alternating cycles of air under identical experimental conditions in parallel. Two additional groups of CIH-treated rats were given either the superoxide dismutase mimetic - tempol (1 mM, N = 8), or the NAPDH oxidase inhibitor - apocynin (2 mM, N = 8) in their drinking water throughout the study. Following gas exposures, breathing during sleep was assessed in unrestrained animals using the technique of whole-body plethysmography. CIH significantly increased apnoea index during sleep (4.7 ± 0.8 vs. 11.3 ± 1.6 events/h; mean ± SEM, sham vs. CIH, Student's t test, p = 0.0035). Apnoea duration was unaffected by CIH treatment. The CIH-induced increase in the occurrence of apnoea was completely reversed by antioxidant supplementation (4.9 ± 0.9 events/h for CIH + tempol and 5.6 ± 0.9 events/h for CIH + apocynin). CIH-induced increase in the propensity for apnoea may have clinical relevance and may explain the phenomenon of 'complex' apnoea in sleep apnoea patients. Our results suggest that oxidative stress is implicated in CIH-induced respiratory disturbance during sleep. We conclude that antioxidants may be a realistic adjunct therapy in the treatment of sleep-disordered breathing.

Respiratory control and sternohyoid muscle structure and function in aged male rats: decreased susceptibility to chronic intermittent hypoxia.

Obstructive sleep apnoea syndrome (OSAS) is a common respiratory disorder characterized by chronic intermittent hypoxia (CIH). We have shown that CIH causes upper airway muscle dysfunction in the rat due to oxidative stress. Ageing is an independent risk factor for the development of OSAS perhaps due to respiratory muscle remodelling and increased susceptibility to hypoxia. We sought to examine the effects of CIH on breathing and pharyngeal dilator muscle structure and function in aged rats. Aged (18-20 months), male Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; F(I)O(2)=5% O(2) at nadir) or sham treatment for 8h/day for 9 days. Following CIH exposure, breathing was assessed by whole-body plethysmography. In addition, sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fibre type and cross-sectional area, and the activity of key oxidative and glycolytic enzymes were determined. CIH had no effect on basal breathing or ventilatory responses to hypoxia or hypercapnia. CIH did not alter succinate dehydrogenase or glycerol phosphate dehydrogenase enzyme activities, myosin heavy chain fibre areal density or cross-sectional area. Sternohyoid muscle force and endurance were unaffected by CIH exposure. Since we have established that this CIH paradigm causes sternohyoid muscle weakness in adult male rats, we conclude that aged rats have decreased susceptibility to CIH-induced stress. We suggest that structural remodelling with improved hypoxic tolerance in upper airway muscles may partly compensate for impaired neural regulation of the upper airway and increased propensity for airway collapse in aged mammals.

Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia.

Respiratory muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased sternohyoid muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy.

Antioxidant treatment does not prevent chronic hypoxia-induced respiratory muscle impairment in developing rats.

Litters of rats were exposed to normobaric normoxia or hypobaric hypoxia (P(B)= 450 mmHg) for 7 days at 3 different time points during early development (postnatal day (P)1, P6 & P11). A separate litter exposed to hypoxia at P11 was treated with the antioxidant Tempol (100 mg/kg) given by oral administration daily starting at P8. At P19, sternohyoid and diaphragm muscles were removed and isolated muscle bundles were mounted isometrically in physiological salt solution at 30 degrees C in vitro. Fatigue was assessed in response to repeated stimulation (40 Hz) every 2 s for 5 min. Fatigue index was measured. Chronic hypoxia decreased sternohyoid, but not diaphragm, muscle endurance. Tempol treatment did not prevent hypoxia-induced muscle plasticity, suggesting that reactive oxygen species are not implicated in hypoxia-induced muscle dysfunction.

Respiratory plasticity in the behaving rat following chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH), a feature of obstructive sleep apnoea (OSA) has been shown to have myriad effects on the respiratory control system. The effects on breathing are of great clinical significance for the sleep apnoea patient. We sought to determine the effect of CIH on normoxic ventilation. Both male and female adult Wistar rats were studied due to the evident sex difference in the prevalence of OSA. A role for oxidative stress in respiratory modifications was also explored. Adult male (n = 30) and female (n = 16) rats were exposed to alternating periods of N(2) and O(2) for 90 s each, bringing the ambient oxygen concentration to 5% at nadir (CIH) group. Sham groups were subject to cycles of air/air under identical experimental conditions. A subset of male rats (8 controls, 8 CIH) had free access to water containing 1 mM Tempol (SOD-mimetic) at all times. Treatments were carried out for 8 hours a day for 9 days. Following treatment, normoxic ventilation was assessed by whole body plethysmography in sleeping animals. Baseline normoxic ventilation was increased in both male and female treated rats but this did not achieve statistical significance. However, ventilatory drive (V(T)/Ti) was significantly increased in male rats. Chronic treatment with Tempol abolished this effect. Conversely, CIH had no significant effect on VT/Ti in female rats. Our results indicate subtle effects of intermittent hypoxia on breathing in conscious behaving rats. We speculate the increased ventilatory drive following CIH represents a form a neural plasticity - a ROS dependent phenomenon - with sexual dimorphism.

Intermittent hypoxia impairs pharyngeal dilator muscle function in male but not female rats.

Upper airway muscle dysfunction is implicated in obstructive sleep apnoea syndrome (OSAS), a common respiratory disorder associated with recurrent hypoxaemia. The prevalence of OSAS is higher in males than females. We tested the hypothesis that sex differences exist in the effects of intermittent hypoxia on upper airway muscle function. Adult Wistar rats were exposed to intermittent hypoxia (IH, 90 s air/90 s N(2); 5% O(2) at nadir) or sham treatment for 8 hours/day for 9 days. Following treatments, animals were killed humanely and isometric contractile properties of the sternohyoid (SH) muscle were examined at 35OC in vitro. Force-frequency relationship was determined at stimulus frequencies ranging 10-100 Hz. In male rats, SH peak force was decreased in IH-treated male rats [22.7 +/- 08. vs. 15.9 +/- 0.9 N/cm(2), sham (n = 8) vs. IH (n = 8), p < 0.001 ANOVA]. Conversely, in female rats, IH treatment had no effect on SH peak force [21.0 +/- 1.2 vs. 19.8 +/- 0.8 N/cm(2), sham (n = 8) vs. IH (n = 8), p > 0.05 ANOVA]. We conclude that IH-induced impairment of pharyngeal dilator muscle performance may contribute to OSAS.

Superoxide scavengers improve rat pharyngeal dilator muscle performance.

Obstructive sleep apnea is a common disorder associated with upper airway muscle dysfunction. Agents that improve respiratory muscle performance may be useful as an adjunct therapy. The aim of this study was to examine the effects of antioxidants on rat pharyngeal dilator muscle performance. Adult male Wistar rats were killed humanely and isometric contractile properties of isolated sternohyoid muscle strips were examined in physiological salt solution at 35 degrees C in vitro. Muscle strips were incubated in tissue baths under hyperoxic (95%O(2)/5%CO(2)) or hypoxic (95%N(2)/5%CO(2)) conditions in the absence (control) or presence of the antioxidants: N-acetylcysteine (10 mM), Tiron (10 mM), or Tempol (10 mM). Force-frequency relationship was determined in response to supramaximal stimulation (10-100 Hz in increments of 10-20 Hz, train duration: 300 ms). Isometric force was also recorded during repetitive muscle stimulation (40 Hz, 300 ms every 2 s for 2 min). Under hyperoxic conditions, Tiron and Tempol, but not N-acetylcysteine, significantly increased sternohyoid muscle force and caused a left-shift in the force-frequency relationship. In addition, Tempol had a significant positive inotropic effect over the initial 90 seconds of repeated muscle activation. Hypoxia caused a significant decrease in sternohyoid muscle force. Under hypoxic conditions, Tempol-incubated muscles generated significantly higher forces compared with control muscles and showed improved performance in the early phase of the fatigue trial. This study illustrates that superoxide scavengers increase upper airway muscle force and that this effect persists under hypoxic conditions. We conclude that antioxidant treatment may be beneficial as a therapy in obstructive sleep apnea.

Cyclooxygenase-2-linked attenuation of hypoxia-induced pulmonary hypertension and intravascular thrombosis.

Exogenous prostacyclin is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To explore whether endogenous prostaglandins played a similar role in pulmonary hypertension, we examined the effect of deleting cyclooxygenase (COX)-gene isoforms in a chronic hypoxia model of PH. Pulmonary hypertension, examined by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (n = 8), and hematocrit (n = 3), was induced by 3 weeks of hypobaric-hypoxia in wild-type and COX-knockout (KO) mice. RVESP was increased in wild-type hypoxic mice compared with normoxic controls (24.4 +/- 1.4 versus 13.8 +/- 1.9 mm Hg; n = 8; p < 0.05). COX-2 KO mice showed a greater increase in RVESP following hypoxia (36.8 +/- 2.7 mm Hg; p < 0.05). Urinary thromboxane (TX)B(2) excretion increased following hypoxia (44.6 +/- 11.1 versus 14.7 +/- 1.8 ng/ml; n = 6; p < 0.05), an effect that was exacerbated by COX-2 gene disruption (54.5 +/- 10.8 ng/ml; n = 6). In contrast, the increase in 6-keto-prostacyclin(1alpha) excretion following hypoxia was reduced by COX-2 gene disruption (29 +/- 3 versus 52 +/- 4.6 ng/ml; p < 0.01). Tail cut bleed times were lower following hypoxia, and there was evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The TXA(2)/endoperoxide receptor antagonist ifetroban (50 mg/kg/day) offset the effect of deleting the COX-2 gene, attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis. COX-2 gene deletion exacerbates pulmonary hypertension, enhances sensitivity to TXA(2), and induces intravascular thrombosis in response to hypoxia. The data provide evidence that endogenous prostaglandins modulate the pulmonary response to hypoxia.

Oxidative stress impairs upper airway muscle endurance in an animal model of sleep-disordered breathing.

Obstructive sleep apnoea is characterised by intermittent hypoxia due to recurrent obstructions of the pharyngeal airway during sleep. We have shown that chronic intermittent hypoxia impairs respiratory muscle function and CNS control of upper airway patency. In this study, we tested the hypothesis that disruption of an endogenous antioxidant defence system exacerbates the effects of intermittent hypoxia on upper airway muscle contractile function. Thirty-two male Wistar rats were placed in restrainers with their heads in hoods in which the ambient oxygen concentration could be modified by controlling the gas supply to the hoods. Sixteen rats were exposed to alternating equal periods of hypoxia and normoxia, twice per minute, 8 hours per day for 1 week. The remaining 16 animals were exposed to normoxia continuously under identical experimental conditions. In both groups, half the animals received daily injections of buthionine sulfoxamine (BSO), an inhibitor of the rate-limiting enzyme in glutathione synthesis. The other half received daily vehicle injections. At the end of the 1-week treatment period, the sternohyoid muscles were removed and fatigue characteristics were determined in vitro. Intermittent hypoxia was associated with a decrease in sternohyoid muscle endurance, an effect that was exacerbated by treatment with BSO. In separate experiments, daily treatment with the antioxidant N-acetyl cysteine blocked the deleterious effects of intermittent hypoxia on respiratory muscle function. We suggest that oxidative stress contributes to impaired upper airway muscle endurance in our animal model and that endogenous glutathione may be especially important in limiting free radical-induced muscle dysfunction. Our results may have particular relevance to respiratory disorders associated with recurrent hypoxia, such as the sleep apnoea/hypopnoea syndrome.

Respiratory plasticity in response to changes in oxygen supply and demand.

Aerobic organisms maintain O(2) homeostasis by responding to changes in O(2) supply and demand in both short and long time domains. In this review, we introduce several specific examples of respiratory plasticity induced by chronic changes in O(2) supply (environmental hypoxia or hyperoxia) and demand (exercise-induced and temperature-induced changes in aerobic metabolism). These studies reveal that plasticity occurs throughout the respiratory system, including modifications to the gas exchanger, respiratory pigments, respiratory muscles, and the neural control systems responsible for ventilating the gas exchanger. While some of these responses appear appropriate (e.g., increases in lung surface area, blood O(2) capacity, and pulmonary ventilation in hypoxia), other responses are potentially harmful (e.g., increased muscle fatigability). Thus, it may be difficult to predict whole-animal performance based on the plasticity of a single system. Moreover, plastic responses may differ quantitatively and qualitatively at different developmental stages. Much of the current research in this field is focused on identifying the cellular and molecular mechanisms underlying respiratory plasticity. These studies suggest that a few key molecules, such as hypoxia inducible factor (HIF) and erythropoietin, may be involved in the expression of diverse forms of plasticity within and across species. Studying the various ways in which animals respond to respiratory challenges will enable a better understanding of the integrative response to chronic changes in O(2) supply and demand.

Does episodic hypoxia affect upper airway dilator muscle function? Implications for the pathophysiology of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterised by repetitive collapse of the upper airway during sleep owing to a sleep-related decrement in upper airway muscle activity with consequent failure of the pharyngeal dilator muscles to oppose the collapsing pressure that is generated by the diaphragm and accessory muscles during inspiration. The causes of upper airway obstruction during sleep are multi-factorial but there is evidence implicating intrinsic upper airway muscle function and impaired central regulation of the upper airway muscles in the pathophysiology of OSA. The condition is associated with episodic hypoxia due to recurrent apnoea. However, despite its obvious importance very little is known about the effects of episodic hypoxia on upper airway muscle function. In this review, we examine the evidence that chronic intermittent hypoxia can affect upper airway muscle structure and function and impair CNS control of the pharyngeal dilator muscles. We review the literature and discuss results from our laboratory showing that episodic hypoxia/asphyxia reduces upper airway muscle endurance and selectively impairs pharyngeal dilator EMG responses to physiological stimulation. Our observations lead us to speculate that episodic hypoxia--a consequence of periodic airway occlusion--is responsible for progression of OSA through impairment of the neural control systems that regulate upper airway patency and through altered respiratory muscle contractile function, leading to the establishment of a vicious cycle of further airway obstruction and hypoxic insult that chronically exacerbates and perpetuates the condition. We conclude that chronic intermittent hypoxia/asphyxia contributes to the pathophysiology of sleep-disordered breathing.