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Experimental Physiology 89.1 pp 44-52
DOI: 10.1113/expphysiol.2003.002656
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Festschrift for R. G. O'Regan - Sensing and adaptation to alterations in respiratory gases: oxygen and carbon dioxide

Effects of chronic intermittent asphyxia on haematocrit, pulmonary arterial pressure and skeletal muscle structure in rats

Aidan Bradford

Department of Physiology, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland


   Abstract
Top
 Abstract
Introduction
 References
 
Sleep-disordered breathing in humans is a common condition associated with serious cardiovascular and other abnormalities. The prevalence and pathogenesis of increased haematocrit and pulmonary hypertension is controversial and it has been suggested that these changes only occur in patients who also have daytime continuous hypoxaemia. The hypothesis tested here is that the chronic intermittent hypoxia and asphyxia associated with sleep-disordered breathing causes erythropoiesis and pulmonary hypertension and that this occurs in the absence of periods of continuous hypoxia. In humans and animals with obstructive sleep apnoea, there are abnormalities of upper airway muscle structure that have been ascribed to increased load placed on these muscles. An alternative hypothesis is that chronic intermittent hypoxia and asphyxia cause changes in upper airway muscle structure and function. To test these hypotheses, rats were exposed to intermittent hypoxia and asphyxia for 8 h per day for 5 weeks. This caused an increase in haematocrit, right ventricular weight and pulmonary arterial pressure. There were only slight changes in diaphragm, upper airway and limb muscle structure and force production but in general, muscle fatigability was increased. In conclusion chronic intermittent hypoxia and asphyxia cause an increase in haematocrit and pulmonary arterial pressure in the absence of periods of continuous hypoxia. Chronic intermittent hypoxia and asphyxia have little effect on skeletal muscle structure and force production but increase muscle fatigue. Increased upper airway muscle fatigue could lead to a vicious cycle of further compromise in upper airway patency and further hypoxia and asphyxia.

(Received 23 September 2003; accepted after revision 30 September 2003)
Corresponding author A. Bradford: Department of Physiology, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland. Email: abradfor{at}rcsi.ie


   Introduction
Top
 Abstract
 Introduction
References
 
Sleep-disordered breathing is an extremely common condition, affecting perhaps 1–4% of adults (Young et al. 1993). The prevalence depends upon the criteria used to define it (Kripke et al. 1997) but a major criterion is the apnoea–hypopnoea index which is defined as the number of periods of apnoea or hypopnoea that occur per hour during sleep. This is because sleep-disordered breathing is characterized by multiple episodes of hypopnoea or apnoea. The periods of hypopnoea and apnoea are caused by either intermittent collapse of the upper airway (UA), called obstructive sleep apnoea (OSA) or an intermittent reduction in the central drive to breath, known as central apnoea (McNicholas, 1990). Obstructive sleep apnoea is the commonest form, affecting approximately 20% and 10% of middle aged men and women, respectively (Kripke et al. 1997).

Since periods of apnoea and hypopnoea occur intermittently, the condition is associated with chronic intermittent hypoxia (CIH) or asphyxia (CIA). In normal individuals, intermittent hypoxia or asphyxia can occur in severe exercise (Dempsey et al. 1984), air travel (Cottrell, 1986), diving (Elsner, 1989), exposure to altitude (Hurtado, 1960) and during sleep, particularly in neonates (Thach, 1985). Intermittent hypoxia is common during sleep in a large variety of respiratory diseases and postoperatively (Marshall & Wyche, 1972) and it is used in training for sports (Bernardi, 2001) and in the treatment of a variety of clinical conditions (Serebrovskya, 2002).

Despite the considerable relevance of CIH and CIA to humans in health and disease, and although a great deal is known about the physiological effects of chronic continuous hypoxia, it is only in recent years that the physiological effects of CIH and CIA have begun to be studied. In these studies, the patterns of CIH and CIA that have been induced experimentally have varied greatly but there have been few studies that have attempted to mimic the cyclical blood gas changes associated with sleep-disordered breathing. Foremost among these studies has been the experiments of Fletcher and colleagues that have examined the effects of intermittent hypoxia and asphyxia on systemic blood pressure (Fletcher et al. 1992a,b,c, 1995; Fletcher & Bao, 1996; Bao et al. 1997). These authors developed a technique that exposed rats to hypoxia or asphyxia twice per minute for 6–8 h per day for several weeks. The timing and the blood gas values achieved mimic the blood gas changes that occur in human OSA. These studies clearly demonstrated that CIH and CIA caused an increase in systemic arterial blood pressure. The importance of this observation relates to the association of sleep apnoea and hypertension. More than 50% of sleep apnoea patients have systemic hypertension (Guilleminault et al. 1976) and approximately 30% of patients with primary hypertension have sleep apnoea (Lavie et al. 1985). The rat model of human OSA supports the hypothesis that it is the CIH and CIA associated with OSA that cause sustained systemic hypertension.

However, there is the potential to study the pathophysiological effects of CIH and CIA on a variety of other variables and systems with this model. We have developed a similar model to that of Fletcher and colleagues and have used it to study the effects of CIH and CIA on haematocrit, right ventricular weight and pulmonary arterial pressure (McGuire & Bradford, 1999, 2001), skeletal muscle structure and function (McGuire et al. 2002a,b, 2003), the control of diaphragm and upper airway muscle activity (O'Halloran et al. 2002), medullary respiratory neurone activity (Martial et al. 2003), platelet function (Dunleavy et al. 2003) and cardiac arrhythmias (Dunleavy & Bradford, 2003). The present review will confine itself to the effects of CIH and CIA on haematocrit, pulmonary arterial pressure and skeletal muscle structure and function.

Effects of CIH and CIA on haematocrit and pulmonary arterial pressure

To induce CIH, animals are placed in restrainers with their heads in hoods. A steady flow of room air is delivered to the hoods for 15s followed by 100% nitrogen for 15 s in order to reduce hood oxygen concentration to a minimum of value of 6–8%. This is followed by removal of the nitrogen, reintroduction of air and recovery of hood oxygen concentration to room air values. This reduces arterial blood PO2 to a minimum value of approximately 55–65 mmHg (McGuire & Bradford, 1999). This cycle is repeated for 7–8 h per day for several weeks. To induce CIA, 100% carbon dioxide as well as nitrogen are delivered to the hoods to achieve a maximal hood carbon dioxide concentration of 10–14%. This results in a mean maximal end-tidal carbon dioxide value of approximately 64 mmHg (McGuire & Bradford, 2001). In all experiments, age- and weight-matched control animals are placed in identical restrainers and hoods but receive air, which is switched (using identical solenoid valves) to air from a separate source every 15 s using the same flow rates as for the CIH and CIA animals.

When we initially developed these techniques, we wished to use some simple measurements such as haematocrit and heart weight to verify that the animals were responding to the treatments. It is well known that chronic continuous hypoxia increases haematocrit and right ventricular weight but the effects of CIH were unclear. Haematocrit and right ventricular weight are increased by hypoxia for 1–2 h per day for several weeks (Nattie & Doble, 1984) and by alternating 30-min periods of hypoxia and normoxia for 8 h per day for several weeks (Moore-Gillon & Cameron, 1985). However, in general, Fletcher and coworkers found that haematocrit and right ventricular weight were not affected (Fletcher et al. 1992a, 1995) although in some experiments, they did report an increase in either haematocrit without any change in right ventricular weight (Fletcher et al. 1992b) or an increase in right ventricular weight without any change in haematocrit (Fletcher et al. 1992c).

We found that there was an unequivocal increase in haematocrit (44.3 ± 2.0% at day 0; 50.3 ± 1.3% at day 35, Fig. 1A) and right ventricular weight (right ventricular/body weight ratio at day 35: control, 0.55 ± 0.07; CIH, 0.67 ± 0.05 mg g–1; Fig. 1B) in response to CIH (McGuire & Bradford, 1999). The increase in haematocrit was present after 1 week of treatment and remained elevated for the 5-week duration of treatment with intermittent hypoxia. The increase in right ventricular weight suggests that there is also an increase in pulmonary arterial pressure in these animals (Rabinovitch et al. 1979). In mice, it was shown recently that CIH increases haematocrit, right ventricular weight and right ventricular systolic pressure, an index of pulmonary arterial pressure (Fagan, 2001). The relevance of this to OSA is that the prevalence and pathogenesis of raised haematocrit and pulmonary hypertension in OSA is a matter of some debate and the numbers of OSA patients reported with elevated haematocrit and pulmonary arterial pressure are variable (Bradley et al. 1985; Weitzenblum et al. 1988; Goldman et al. 1991; Hoffstein et al. 1994; Laks et al. 1995; Chaouat et al. 1996; Sanner et al. 1997). One possible explanation for this variability could be the confounding effect of hypercapnia because hypoxia is sometimes accompanied by hypercapnia during apnoeas. In our experiments, the animals were hypoxic but this was accompanied by hypocapnia rather than hypercapnia as a result of reflex hyperventilation in response to the hypoxia. Since chronic continuous hypercapnia prevents the increase in haematocrit and pulmonary arterial pressure caused by chronic continuous hypoxia (Ooi et al. 2000), it is possible that CIA might not cause an increase in haematocrit and pulmonary arterial pressure due to a protective effect of intermittent hypercapnia. However, when we repeated these experiments with CIA, we found that CIA also caused an increase in haematocrit (45.2 ± 1.0% at day 0; 51.5 ± 1.5% at day 35, Fig. 2A), red blood cell count (7.9 ± 0.4 x 106 mm–3 at day 0; 11.1 ± 0.4 x 106 mm–3 at day 21), haemoglobin concentration (14.5 ± 0.2 g% at day 0; 16.5 ± 0.5 g% at day 35) and right ventricular weight (right ventricular/body weight ratio at day 35: control, 0.53 ± 0.05 mg g–1; CIA, 0.63 ± 0.01 mg g–1, Fig. 2B) in a manner similar to that for CIH (McGuire & Bradford, 2001). We also measured pulmonary arterial pressure (Fig. 2C) and found that this too was elevated (control, 20.7 ± 6.8; CIA, 31.3 ± 7.2 mmHg, McGuire & Bradford, 2001). It has been suggested that increased haematocrit and pulmonary hypertension only occur in OSA patients who also have daytime hypoxaemia (Chaouat et al. 1996). However, there have been reports of raised haematocrit and pulmonary arterial pressure in OSA patients with little or no daytime hypoxia (Sajkov et al. 1994; Laks et al. 1995) and the present results show that CIH and CIA cause erythropoiesis, right ventricular hypertrophy and pulmonary hypertension in the absence of intervening periods of continuous hypoxia.



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  		Figure 1.  Effect of chronic intermittent hypoxia on haematocrit and right ventricular weight/body weight ratio
Effect of chronic intermittent hypoxia (CIH) on haematocrit (A) and right ventricular weight/body weight (RV/BW) ratio (B). A, lines indicate values (mean ±S.D.) for haematocrit at day 0, 7, 14, 21, 28 and 35 of the treatment period for control (–{square}–, n= 16) and for CIH (–{blacksquare}–, n= 16). B, values are means ±S.D. for control({square}, n= 16) and CIH ({blacksquare}, n= 16). *Significantly different from control. (Figure modified from McGuire M & Bradford A. (1999)Respir Physiol 117, 53–58 with permission from Elsevier).

 


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  		Figure 2.  Effect of chronic intermittent asphyxia on haematocrit, right ventricular weight/body weight ratio and pulmonary arterial pressure
Effect of chronic intermittent asphyxia (CIA) on haematocrit (A), right ventricular weight/body weight (RV/BW) ratio (B) and pulmonary arterial pressure (C). A, lines indicate values (mean ± S.D.) for haematocrit at day 0, 7, 14, 21, 28 and 35 of the treatment period for control (–{square}–, n= 16) and for CIA (–{blacksquare}–, n= 13). B, values are means ±S.D. for control({square}, n= 16) and CIA ({blacksquare}, n= 13). C, values are means ±S.D. for control({square}, n= 16) and CIA ({blacksquare}, n= 13). *Significantly different from control. (Figure modified from McGuire M & Bradford A. (2001)Eur Respir J 18, 279–285 with permission from European Respiratory Journal).

 
Effect of CIH and CIA on skeletal muscle structure and contractile properties

In OSA, the UA collapses during inspiration because of a failure of UA muscles to dilate and stabilize the UA (Remmers et al. 1978; Brouillette & Thach, 1979; McNicholas, 1990). The reasons for this failure are probably multifactorial, involving factors such as reduced central drive to UA muscles (Remmers et al. 1978) and abnormal reflex control of UA patency (McNicholas et al. 1984, 1987). However, there is also evidence for UA muscle structural abnormalities in humans with OSA (Stauffer et al. 1999; Series et al. 1995, 1996) and in the English bulldog, an animal model of OSA (Petrof et al. 1994). We wondered whether these structural changes manifested themselves as alterations in function and whether these changes were a cause or an effect of OSA. In general, the reported structural changes involved an increase in fast-twitch fibres (Petrof et al. 1994; Series et al. 1995, 1996; Stauffer et al. 1999). It has been suggested that this is due to increased UA muscle load and drive (Petrof et al. 1994; Series et al. 1995). However, although the effects of chronic continuous hypoxia on skeletal muscle structure are controversial, it has been reported to increase fast fibres in rat limb muscles (Bigard et al. 1991). Furthermore, muscle oxidative capacity and mitochondial volume density is low following long-term exposure to hypobaric hypoxia in low-landers and in high-landers permanently exposed to hypobaric hypoxia (see Hoppeler et al. 2003). Perhaps this low oxidative capacity and mitochondrial volume density is due to a hypoxia-induced transition to fast fibres because fast fibres have low oxidative capacity and low mitochondrial volume density. This raises the possibility that CIH and CIA could be responsible for the changes in UA muscle structure observed in OSA. Therefore, we set out to determine the effects of 5 weeks of intermittent hypoxia and asphyxia on UA muscle (geniohyoid and sternohyoid muscle) structure and function. We chose these two muscles as representative UA muscles because they play an important role in determining UA patency (Brouillette & Thach, 1979), because they are anatomically readily accessible and have fibres running in a uniform direction and because both muscles have been shown to have abnormal morphology in the English bulldog (Petrof et al. 1994)

We found (McGuire et al. 2002a) that CIH had no effect on geniohyoid (Fig. 3A) or sternohyoid (Fig. 3B) fibre-type distribution or on force production (Figs 4A and 5A), but caused an increase in fatigability of both muscles (Figs 4B and C, and 5B and C; geniohyoid muscle tension decreased to 46.4 ± 2.1% of initial tension after 5 min of fatigue for control and to 41.5 ± 3.3% for CIH, and sternohyoid muscle tension decreased to 33.5 ± 1.7% of initial tension after 5 min of fatigue for control and to 27.2 ± 2.9% for CIH). CIA caused a small increase in fast fibres in the geniohyoid (Fig. 6A) but reduced fast fibres in the sternohyoid (Fig. 6B). It had no effect on force production in either muscle but increased geniohyoid fatigability (Fig. 7A and B, tension decreased to 50.5 ± 6.6% of initial tension after 5 min of fatigue for control and to 43.6 ± 5.8% for CIA) and decreased sternohyoid fatigability (Fig. 7C and D, tension decreased to 31.5 ± 5.2% of initial tension after 5 min of fatigue for control and to 37.8 ± 6.0% for CIH) (McGuire et al. 2002b).



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  		Figure 3.  Effect of chronic intermittent hypoxia on geniohyoid and sternohyoid fibre-type distribution
Effect of chronic intermittent hypoxia on geniohyoid (A) and sternohyoid (B) fibre-type distribution. Values are means ±S.D. for control ({square}, n = 8) and chronic intermittent hypoxia ({blacksquare}, n= 8). (Figure reproduced from McGuire M et al. (2002)Chest 122, 1012–1017 with permission from Chest).

 


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  		Figure 4.  Effect of chronic intermittent hypoxia on geniohyoid muscle contractile properties
A, tension–frequency relationship; B, fatigue; C, recovery from fatigue. Lines indicate values expressed as means ±S.D. for control (–{square}–, n= 16) and for chronic intermittent hypoxia (–{blacksquare}–, n= 16). *Significant difference between control and chronic intermittent hypoxia. (Figure reproduced from McGuire M et al. (2002)Chest 122, 1012–1017 with permission from Chest).

 


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  		Figure 5.  Effect of chronic intermittent hypoxia on sternohyoid muscle contractile properties
A, tension–frequency relationship; B, fatigue; C, recovery from fatigue. Lines indicate values expressed as means ±S.D. for control (–{square}–, n= 16) and for chronic intermittent hypoxia (–{blacksquare}–, n= 16). *Significant difference between control and chronic intermittent hypoxia. (Figure reproduced from McGuire M et al. (2002)Chest 122, 1012–1017 with permission from Chest).

 


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  		Figure 6.  Effect of chronic intermittent asphyxia on geniohyoid and sternohyoid fibre-type distribution
Effect of chronic intermittent asphyxia on geniohyoid (A) and sternohyoid (B) fibre-type distribution. Values are means ±S.D. for control ({square}) and chronic intermittent asphyxia ({blacksquare}). (Figure reproduced from McGuire M et al. (2002)Chest 122, 1400–1406 with permission from Chest).

 


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  		Figure 7.  Effect of chronic intermittent asphyxia on fatigue and recovery from fatigue in the geniohyoid and sternohyoid muscles
Effect of chronic intermittent asphyxia on geniohyoid fatigue (A) and recovery from fatigue (B) and sternohyoid fatigue (C) and recovery from fatigue (D). Lines indicate values expressed as means ±S.D. for control (–{square}–) and for chronic intermittent asphyxia (–{blacksquare}–). *Significant difference between control and chronic intermittent asphyxia. (Figure reproduced from McGuire M et al. (2002)Chest 122, 1400–1406 with permission from Chest).

 
In the English bulldog, whilst UA muscle structure is abnormal, it has been reported that limb muscle morphology is unchanged (Petrof et al. 1994). This suggests that changes in UA muscle activation are responsible for the structural changes, that is, limb muscle activation is presumably normal in these animals and therefore, morphology is unaffected. Similarly, in our experiments, CIH and CIA would also be associated with increased drive to the UA muscles but would not be expected to affect neural drive to limb muscles. We questioned whether the changes in UA muscle structure and function that we observed were due to this increased activation or to some other effect of the intermittent blood gas changes. We therefore compared the effects of CIA on diaphragm and limb muscles since the former, but not the latter, would encounter a chronic intermittent increase in activity. In general, the findings showed a similar pattern to those for CIH and CIA on UA muscle, namely that there were little or no changes in extensor digitorum longus (Fig. 8A) and soleus (Fig. 8B) muscle structure or force production but that there was an increase in diaphragm (Fig. 9A and B, tension decreased to 54.2 ± 3.9% of initial tension after 5 min of fatigue for control and to 48.0 ± 3.9% for CIA), extensor digitorum longus (Fig. 10A and B, tension decreased to 49.1 ± 2.1% of initial tension after 5 min of fatigue for control and to 44.0 ± 3.0% for CIA) and soleus (Fig. 10C and D, tension decreased to 59.2 ± 3.1% of initial tension after 5 min of fatigue for control and to 49.0 ± 2.0% for CIA) muscle fatigue (McGuire et al. 2003).



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  		Figure 8.  Effect of chronic intermittent asphyxia on extensor digitorum longus and soleus fibre-type distribution
Effect of chronic intermittent asphyxia on extensor digitorum longus (A) and soleus (B) fibre-type distribution. Values are means ±S.D. for control ({square}) and chronic intermittent asphyxia ({blacksquare}). (Figure reproduced from McGuire M et al. (2003)Chest 123, 875–881 with permission from Chest).

 


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  		Figure 9.  Effect of chronic intermittent asphyxia on diaphragm fatigue and recovery from fatigue
Effect of chronic intermittent asphyxia on diaphragm fatigue (A) and recovery from fatigue (B). Lines indicate values expressed as means ±S.D. for control (–{square}–) and for chronic intermittent asphyxia (–{blacksquare}–). *Significant difference between control and chronic intermittent asphyxia. (Figure reproduced from McGuire M et al. (2003)Chest 123, 875–881 with permission from Chest).

 


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  		Figure 10.  Effect of chronic intermittent asphyxia on fatigue and recovery from fatigue in extensor digitorum longus and soleus muscles
Effect of chronic intermittent asphyxia on extensor digitorum longus fatigue (A) and recovery from fatigue (B) and soleus fatigue (C) and recovery from fatigue (D). Lines indicate values expressed as means ±S.D. for control (–{square}–) and for chronic intermittent asphyxia (–{blacksquare}–). *Significant difference between control and chronic intermittent asphyxia. (Figure modified from McGuire M et al. (2003)Chest 123, 875–881 with permission from Chest).

 
In summary, CIH and CIA cause only minor changes in UA, diaphragm and limb muscle structure and force production but reduce muscle endurance. This is a generalized effect of chronic intermittent fluctuations in blood gases and suggests that it is not due to increased neural activation of the muscles. Although we do not know if these effects can be extrapolated to humans, if they were to occur, they might be a factor in the subjective feeling of fatigue reported by OSA patients (Vgontzas et al. 2000). Increased UA fatigue and slow recovery from fatigue might make the UA more vulnerable to collapse and lead to a vicious cycle of more hypoxia or asphyxia and more vulnerability to UA collapse.


   Footnotes
 
Presented at a meeting of the Physiological Society at Trinity College Dublin in July 2003.


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