Sleep Apneas
An Oxidative Stress?

Nanduri R. Prabhakar, Ph.D.

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio

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Sleep apneas (obstructive or central) are one of the most commonly encountered respiratory disorders in humans. More importantly, epidemiologic, retrospective, and cross-sectional studies on sleep apnea patients have identified strong associations between apneas and serious cardiovascular disturbances. For example, there is a strong linkage between the development of hypertension and the severity of sleep apneas (number of apneas or near apneas/hour) (1). Sleep apnea patients are also prone to myocardial infarctions, pulmonary hypertension, and stroke (2). In a large population of patients (Sleep Heart Health study), sleep-disordered breathing is more strongly associated with heart failure and stroke than coronary heart disease (3). Treatment with continuous positive airway pressure reverses hypertension in sleep apnea patients (4).

Apneas are associated not only with periodic decreases in arterial oxygen (hypoxia) but also simultaneous increases in arterial carbon dioxide (hypercapnia). Therefore, one fundamental question that often surfaces is whether hypoxia or hypercapnia underlies the pathophysiology of sleep apneas. This question has been recently addressed in animal models of episodic hypoxia. Fletcher (5) exposed rats to episodic hypoxia (using a paradigm of intermittent hypoxia without hypercapnia) and found development of hypertension and increased sympathetic activity after 30 days. Moreover, when hypoxia was combined with hypercapnia using a similar paradigm, the magnitude of hypertension was nearly the same, suggesting that episodic hypoxia contributes more to the cardiovascular abnormalities than hypercapnia.

Development of animal models of intermittent hypoxia has greatly facilitated our understanding of the mechanisms associated with recurrent apneas. Hypertension caused by intermittent hypoxia is due to enhanced reflex drive from peripheral chemoreceptors, especially the carotid bodies (see Ref. 6 for references). Recent studies on a rat model of intermittent hypoxia suggest that enhanced peripheral chemoreceptor drive as well as the development of hypertension critically depends on the pattern of hypoxia (6). Thus, exposing rats to 10 days of intermittent hypoxia (15 seconds 5% O₂ followed by 21% O₂ for 5 minutes; 8 hours/day) resulted in marked enhancement of peripheral chemoreceptor activity, increased blood pressure, and sympathetic activity. In sharp contrast, such cardiovascular changes were not elicited by exposing animals to cumulative comparable duration of sustained hypoxia. Similarly, exposing cell cultures to intermittent hypoxia using the protocols similar to experimental animals increased c-fos protooncogene expression, whereas the cumulative comparable duration of sustained hypoxia had little effect (6). These studies suggest that intermittent hypoxia is a more potent stimulus than sustained hypoxia and also emphasize that the pattern of hypoxia, i.e., repetitive or continuous, have profoundly different effects.

The major difference between intermittent and continuous hypoxia is the episodic re-oxygenation in the former but not the latter. In this respect, intermittent hypoxia seems to resemble ischemia-reperfusion. Several lines of evidence suggest that ischemia-reperfusion represents an oxidative stress causing increased generation of reactive oxygen species, especially superoxide anions (O₂^· ). Therefore, the cardiorespiratory alterations evoked by intermittent hypoxia are likely due to increased generation of O₂^· . Such a possibility is supported by the finding that administration of manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (5 mg/kg/day in animal studies; 50 µM in cell studies), a potent scavenger of O₂^· , prevented intermittent hypoxia-evoked changes in the cardiorespiratory system as well as gene expression (6).

Based on the findings from experimental studies, it has been proposed that intermittent hypoxia, such as that seen in sleep apneas, represents a form of oxidative stress leading to increased generation of reactive oxygen species. Such an idea seems to be supported by a recent study by Shultz and coworkers (7), who reported increased O₂^· generation from neutrophils in patients with obstructive sleep apnea, and treatment with continuous positive airway pressure led to rapid decrease in O₂^· generation. Circulating nitric oxide levels, measured by serum nitrite/nitrate, are decreased in patients with sleep apnea and the levels were restored after treatment with continuous positive airway pressure (8). These studies suggest that intermittent hypoxia represents a form of oxidative stress. However, the association between increased generation of reactive oxygen species and pathogenesis in patients with sleep apnea has not been explored. In this issue of the AJRCCM, Dyugovskaya and colleagues (pp. 934-939) examined generation of reactive oxygen species and adhesion molecule expression in neutrophils from patients with sleep apnea (9). Their results showed increased expression of CD15 and CD11c in monocytes from the patients, which were correlated with increased intracellular production of reactive oxygen species. Furthermore, alterations in adhesion molecule expression and levels of reactive oxygen species were associated with increased adherence of monocytes to human endothelial cells in cell cultures. More importantly, treatment with continuous positive airway pressure down-regulated the adhesion molecule expression and decreased basal production of reactive oxygen species in CD11c monocytes. Because increased expression of adhesion molecules contributes to atherogenesis, the findings of Dyugovskaya and associates (9) are important in that they link the oxidative stress caused by recurrent apneas to the pathogenesis of the vascular disease.

Several mechanisms contribute to endogenous generation of reactive oxygen species. For instance, NADPH oxidases produce O₂^· via protein kinase C (PKC)-dependent mechanism. The data presented by Dyugovskaya and colleagues (9) suggest that increased generation of reactive oxygen species involves PKC-dependent NADPH oxidase activation because they observed a marked enhancement of O₂^· generation with phorbol ester, a potent activator of PKC. However, it remains to be determined whether increased reactive oxygen species in patients with obstructive sleep apnea is due to upregulation of NADPH-oxidases and/or PKC-dependent phosphorylation. Reactive oxygen species could also be generated when mitochondrial oxidative metabolism is perturbed at the level of complexes I or III. Hopefully, future studies will provide further insight as to the effects of intermittent hypoxia on NADPH oxidases and/or mitochondrial function and their respective contributions to oxidative stress in recurrent apneas.

Thus, both experimental and human studies seem to be consistent with the idea that intermittent hypoxia, associated with recurrent apneas, represents a form of oxidative stress. More importantly, whatever the source of reactive oxygen species, these studies beg the question of whether scavengers can be used as an effective therapeutic intervention in alleviating the cardiovascular disturbances associated with recurrent apneas.

	References

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5. Fletcher EC. Effect of episodic hypoxia on sympathetic activity and blood pressure. Respir Physiol 2000; 119: 189-197 [Medline].

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7. Schultz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger F. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Am J Respir Crit Care Med 2000; 162: 566-570 [Abstract/Free Full Text].

8. Ip MSM, Lam B, Chan LY, Zheng L, Tsang KWT, Fung PC, Lam WK. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000; 162: 2166-2171 [Abstract/Free Full Text].

9. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002; 165: 934-939 [Abstract/Free Full Text].