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We have previously reported that chronic intermittent hypoxia (CIH), a central feature of human sleep-disordered breathing, causes respiratory instability in sleeping rats (Edge D, Bradford A, O'halloran KD. Adv Exp Med Biol 758:359-363, 2012). Long term facilitation (LTF) of respiratory motor outputs following exposure to episodic, but not sustained, hypoxia has been described. We hypothesized that CIH would enhance ventilatory LTF during sleep. We examined the effects of 3 and 7 days of CIH exposure on the expression of ventilatory LTF in sleeping rats. 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 per day for 3 or 7 consecutive days (CIH, N = 7 per group). Corresponding sham groups (N = 7 per group) were subjected to alternating cycles of air under identical experimental conditions in parallel. Following gas exposures, breathing during sleep was assessed in unrestrained, unanaesthetized animals using the technique of whole-body plethysmography. Rats were exposed to room air (baseline) and then to an acute IH (AIH) protocol consisting of alternating periods of normoxia (7 min) and hypoxia (FiO(2) 0.1, 5 min) for 10 cycles. Breathing was monitored during the AIH exposure and for 1 h in normoxia following AIH exposure. Baseline ventilation was elevated after 3 but not 7 days of CIH exposure. The hypoxic ventilatory response was equivalent in sham and CIH animals after 3 days but ventilatory responses to repeated hypoxic challenges were significantly blunted following 7 days of CIH. Minute ventilation was significantly elevated following AIH exposure compared to baseline in sham but not in CIH exposed animals. LTF, determined as the % increase in minute ventilation from baseline following AIH exposure, was significantly blunted in CIH exposed rats. In summary, CIH leads to impaired ventilatory responsiveness to AIH. Moreover, CIH blunts ventilatory LTF. The physiological significance of ventilatory LTF is context-dependent but it is reasonable to consider that it can potentially destabilize respiratory control, in view of the potential for LTF to give rise to hypocapnia. CIH-induced blunting of LTF may represent a compensatory mechanism subserving respiratory homeostasis. Our results suggest that CIH-induced increase in apnoea index (Edge D, Bradford A, O'halloran KD. Adv Exp Med Biol 758:359-363, 2012) is not related to enhanced ventilatory LTF. We conclude that the mature adult respiratory system exhibits plasticity and metaplasticity with potential consequences for the control of respiratory homeostasis. Our results may have implications for human sleep apnoea.

Duchenne muscular dystrophy (DMD) is a genetic disease caused by defects in the dystrophin gene resulting in loss of the structural protein dystrophin. Patients have reduced diaphragm functional capacity due to progressive muscle weakness. Respiratory morbidity in DMD is further characterised by hypoxaemic periods due to hypoventilation. DMD patients die prematurely due to respiratory and cardiac failure. In this study, we examined respiratory function in young adult male mdx (dystrophin deficient) mice (C57BL/10ScSn-Dmd(mdx)/J; n = 10) and in wild-type controls (WT; C57BL/10ScSnJ; n = 11). Breathing was assessed in unrestrained, unanaesthetised animals by whole-body plethysmography. Ventilatory parameters were recorded during air breathing and during exposure to acute hypoxia (F(i)O(2) = 0.1, 20 min). Data for the two groups of animals were compared using Student's t tests. During normoxic breathing, mdx mice had reduced breathing frequency (p = 0.011), tidal volume (p = 0.093) and minute ventilation (p = 0.033) compared to WT. Hypoxia increased minute ventilation in WT and mdx animals. Mdx mice had a significantly increased ventilatory response to hypoxia which manifest as an elevated % change from baseline for minute ventilation (p = 0.0015) compared to WT. We conclude that mdx mice have impaired normoxic ventilation suggestive of hypoventilation. Furthermore, mdx mice have an enhanced hypoxic ventilatory response compared to WT animals which we speculate may be secondary to chronic hypoxaemia. Our results indicate that a significant respiratory phenotype is evident as early as 8 weeks in the mdx mouse model of DMD.

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.

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.

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.

Obstructive sleep apnoea is characterized by chronic intermittent hypoxia (CIH) due to recurrent apnoea. We have developed a rat model of CIH, which shows evidence of impaired respiratory muscle function. In this study, we wished to characterize the ventilatory effects of CIH in conscious male and female animals. Adult male (n=14) and female (n=8) Wistar rats were used. Animals were placed in chambers daily for 8 h with free access to food and water. The gas supply to one half of the chambers alternated between air and nitrogen every 90 s, for 8 h per day, reducing ambient oxygen concentration in the chambers to 5% at the nadir (intermittent hypoxia; n=7 male, n=4 female). Air supplying the other chambers was switched every 90 s to air from a separate source, at the same flow rates, and animals in these chambers served as controls (n=7 male, n=4 female). Ventilatory measurements were made in conscious animals (typically sleeping) after 10 days using whole-body plethysmography. Normoxic ventilation was increased in both male and female CIH-treated rats compared to controls but this did not achieve statistical significance. However, ventilatory drive was increased in CIH-treated rats of both sexes as evidenced by significant increases in mean and peak inspiratory flow. Ventilatory responses to acute hypoxia (F(I)O(2) = 0.10; 6 min) and hyperoxic hypercapnia (F(I)CO(2) = 0.05; 6 min) were unaffected by CIH treatment in male and female rats (P>0.05, ANOVA). We conclude that CIH increases respiratory drive in adult rats. We speculate that this represents a form of neural plasticity that may compensate for respiratory muscle impairment that occurs in this animal model.