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Themed Issue Papers |
1 Department of Integrative Physiology, University of North Texas Health Science Center, Fort Worth, TX, USA
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(Received 26 September 2006;
accepted after revision 9 November 2006; first published online 10 November 2006)
Corresponding author M. L. Smith: Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Email: msmith{at}hsc.unt.edu
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Introduction |
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In patients with chronic OSA, there are significant elevations of production and circulation of catecholamines during sleep and wakefulness (Fletcher et al. 1987; Carlson et al. 1993; Marrone et al. 1993; Somers et al. 1995; Garcia-Rio et al. 2000). Marrone et al. (1993) illustrated that both noradrenaline and adrenaline were elevated in patients with sleep apnoea and that urinary adrenaline secretion decreased in the absence of apnoeas. Fletcher et al. (1987) and Carlson et al. (1993) both demonstrated elevated noradrenaline levels in OSA patients during the daytime, suggesting a physiological adaptation to hypoxia and apnoeas during sleep. Relative to a potential role of the chemoreceptors, it is not known whether patients were hypoxaemic during wakefulness. In most OSA patients, however, hypoxaemia during wakefulness is normally uncommon and mild; therefore, these data would suggest either that the chemoreflex control of sympathetic activity becomes tonically active at rest (normoxia), or that other mechanisms (e.g. sleep deprivation) contribute to the chronic elevation of sympathetic tone. Similarly, Garcia-Rio et al. (2000) found elevated nocturnal adrenaline levels that were correlated with the pressor response to hypoxia. Together, these data suggest that the elevated catecholamine concentrations found in this population may be mediated in part by the nighttime apnoeas, but also by altered autonomic control throughout the day.
Numerous studies also have shown that directly measured muscle sympathetic nerve activity (MSNA) is elevated during normal wakeful breathing and during episodes of sleep apnoea in OSA patients (Carlson et al. 1993; Leuenberger et al. 1995; Somers et al. 1995; Saito et al. 1988). Narkiewicz & Somers (1997) compared MSNA in normal-weight subjects, obese subjects without OSA and obese subjects with OSA. During normal daytime breathing, the obese OSA subjects had significantly higher resting MSNA than the normal-weight subjects and obese subjects without OSA. These results strongly suggest that the increase in basal MSNA is independent of obesity in this population. Collectively, these studies imply that the high incidence of hypertension among OSA patients is, in part, due to chronically elevated MSNA. In this light, considerable attention has focused on the role of chemoreflex function, or dysfunction, in both the acute and chronic responses to sleep apnoea, and its potential role in imparting an increased risk of hypertension.
As noted, the majority of investigations into OSA and sympathetic tone and its control focus on microneurographic measures of MSNA. This measurement is thought to be reflective of normal reflex control of vascular beds which determine systemic vascular resistance and thus, arterial pressure. Thus, these studies address effects of apnoea and hypoxia on altered reflex control of sympathetic tone which would be expected to affect long-term arterial pressure and its control.
Chemoreceptors and OSA
Chemoreflex control of sympathetic activity. Until recently, the investigation of the physiological role of the chemoreceptors has generally been focused on the control of respiration. However, a growing body of evidence has shown that disturbed blood gases, whether acute, chronic or intermittent, can affect autonomic and cardiovascular function as well. Activation of the chemoreceptors by acute exposure to either hypoxia or hypercapnia is known to provoke a sympathoexcitatory response in humans (Xie et al. 2000; Shoemaker et al. 2002; Cutler et al. 2004b; Leuenberger et al. 2005). The effects appear to be more sensitive to hypoxia than to hypercapnia, and growing evidence suggests that the hypoxic stimulus is the principal stimulus for sympathoexcitation during episodes of apnoea. When breathing a hypoxic gas, these sympathoexcitatory responses occur in the face of a modulatory effect of associated increased ventilation responses (Somers et al. 1989a). Despite the significance of hypoxia as a chemoreflex-mediated stimulus for sympathoexcitation during apnoea, the concomitant hypercapnia and apnoea itself also contribute to this response (Somers et al. 1989b; Morgan et al. 1995; Tamisier et al. 2004). Hypercapnia and hypoxia are known to act synergistically to augment both ventilatory and sympathetic neural responses (Somers et al. 1989b).
Chemoreflex control in OSA. It is well documented that OSA is characterized by increased MSNA compared with baseline during acute bouts of hypoxia during wakefulness when subjects are breathing normally, and this abnormal response is independent of the ventilatory response (Hedner et al. 1992b; Leuenberger et al. 1995; Somers et al. 1995). In addition, it has been demonstrated that patients with sleep apnoea exhibit enhanced ventilatory and pressor responses to hypoxia when compared with normal subjects. Accumulating data suggest that the peripheral chemoreceptors (via sensitivity to hypoxia) are responsible for these augmented MSNA, pressor and ventilatory responses observed in OSA (Narkiewicz et al. 1999; Iturriaga et al. 2005). These data point to the hypoxia stimulus as the primary drive for these adapted responses in OSA patients; however, both the intermittent interruption of respiration and hypercapnia are also likely to contribute to this adaptation of the reflex, as noted above. Other studies further support the idea that chemoreceptor control of MSNA is exaggerated in patients with OSA. Leuenberger et al. (1995) studied OSA patients during episodes of hypoxia at night and observed marked increases in muscle sympathetic nerve activity. Smith et al. (1996) reported that transient bouts of hypoxaemia provoked sympathetic stimulation in OSA patients during wakefulness, although the response was less than that observed during episodes of hypoxaemia during sleep. They also demonstrated that this response was greater in OSA patients than in non-OSA weight-matched control subjects.
The increased MSNA observed during sleep apnoeic events can be explained by the repetitive bouts of hypoxia, hypercapnia and apnoea. In contrast, the mechanism by which sympathetic outflow is increased in sleep apnoea patients during wakefulness remains to be elucidated. It has been postulated that tonic peripheral chemoreceptor activation contributes to the increased MSNA observed during wakefulness in this population (Narkiewicz et al. 1998; Cutler et al. 2004a). Moreover, several studies examining the effects of sustained and intermittent hypoxia in rats concluded that continuous exposure to hypoxia did not elicit an enhanced sensory response by the chemoreceptors, whereas intermittent hypoxia produced an enhanced chemosenstivity (Fletcher et al. 1992b; Fletcher, 2001; Peng et al. 2003; Peng & Prabhakar, 2004). The seminal studies of Fletcher and colleagues demonstrated that chronic intermittent hypoxia can lead to development of hypertension, and that this effect is prevented by denervation of the chemoreceptors (Fletcher et al. 1992a,,b). These results strongly suggest that in a rat model: (1) the intermittent nature of the stimulus is key to these pathology-induced changes; and (2) the chemoreceptors can mediate physiological changes resulting in hypertension. However, the relative contribution of intermittent versus sustained hypoxia to changes in autonomic function and the link between chemoreflex dysfunction and hypertension remain inconclusive in humans and merit further investigation.
Four studies addressed the hypothesis that short-term interventions akin to sleep apnoea can evoke an adaptation of chemoreflex control of MSNA. Morgan et al. (1996) and Xie et al. (2000) observed a sustained elevation of MSNA after 20 min of intermittent asphyxia (hypercapnic hypoxia). The basal MSNA remained elevated for at least 20 min after the asphyxic stimulus had subsided. Using a similar study design, Cutler et al. (2004a,b) demonstrated in healthy subjects that 20 min of intermittent hypoxia lead to sustained elevation in MSNA even after hypoxic bouts were terminated. These responses and the associated time course of adaptation were similar to 20 min of intermittent apnoea. Thus, they concluded that this prolonged elevation postconditioning stimulus was mediated by hypoxia and that the chemoreceptors played an integral role in this outcome. The fact that intermittent hypoxia or apnoea produces altered chemoreflex control of MSNA that is sustained well beyond the period of the intervention supports the hypothesis that impaired chemoreflex function may have long-term effects on haemodynamic control and thus, the risk of hypertension.
The hypothesis that chemoreflex input may contribute to the sustained elevation of MSNA during wakefulness implies that the chemoreceptors are tonically active during normal wakeful breathing. Studies in which the effect of hyperoxia on MSNA was assessed support this premise. Leuenberger et al. (1995) showed that breathing 100% oxygen produced a modest reduction in MSNA in OSA subjects, thereby suggesting that the chemoreflex was actively controlling MSNA even under normoxic conditions. Similarly, Narkiewicz et al. (1998) deactivated the chemoreflex by having subjects breathe 100% oxygen and found that MSNA was attenuated in obese subjects with OSA but not in obese subjects without OSA. In a preliminary study, we assessed the MSNA response to 60 s periods of gradations of hypoxia induced by an initial breath of nitrogen followed by an hypoxic gas mixture. In nine OSA patients, the mildest hypoxia (producing O2 saturations of 93 ± 1%) elicited a significant increase in MSNA (
28 ± 15%), whereas weight-matched control subjects without OSA showed no change in MSNA (–6 ± 11%) with similar hypoxia (92 ± 1%). Collectively, these studies support the tenet that the chemoreflex control of MSNA is active under normoxic conditions in OSA patients, but is not in healthy control subjects.
Cardiovascular responses to hypoxia. Ultimately, if we are to determine a mechanistic link between OSA and hypertension, the link must involve net effects on the cardiovascular system. The changes in chemoreflex control of MSNA discussed above may be implicated; however, the question also remains whether those changes affect the determinants of arterial pressure, namely, cardiac output and systemic vascular resistance. The majority of the literature offers data suggesting that pressor responses to hypoxia are exaggerated in subjects with OSA. Narkiewicz et al. (1999) found significant increases in heart rate, blood pressure and ventilation during hypoxic breathing in OSA patients compared with control subjects. In addition, the authors demonstrated that the MSNA response to hypoxia that is normally attenuated by the compensatory increases in heart rate, ventilation and blood pressure in healthy subjects was sustained in the OSA patients. Thus, the chemoreflex seems to be an important mediator in the exaggerated cardiovascular responses observed in this population (Narkiewicz et al. 1999). Narkiewicz et al. (1998) demonstrated that hyperoxic conditions decrease blood pressure in normoxic OSA patients but not in normal control subjects. The authors postulated that tonic activation of chemoreceptors could partly account for the increase in blood pressure, again consistent with the observations of chemoreflex control of MSNA noted above. Hedner et al. (1992a) demonstrated that OSA patients have an exaggerated pressor and ventilatory response to hypoxia compared with normal subjects, and that both responses were not different between normotensive and hypertensive OSA patients. These results suggest the possibility of greater peripheral chemosensitivity in the OSA patients; however, the reason for the lack of difference between normotensive and hypertensive OSA patients remains unclear. In addition, the authors found that ventilatory and pressor increases were positively correlated. These data suggest the presence of an excessive vasoconstriction mediated by the chemoreflex during hypoxia. The relationship between the ventilatory and pressor response is debatable. Not all OSA patients had high ventilatory responses that accompany a high pressor response; likewise, some normal control subjects with no pressor responses display exaggerated ventilatory responses (Hedner et al. 1992a). Beyond these studies, there is now growing evidence to suggest that vascular function is adversely impacted by OSA. These effects are discussed in the associated reviews in this themed issue (see Foster et al. and Weiss et al.).
The chemoreceptor reflex and hypertension
Evidence suggests that in humans with early and mild hypertension, sympathetic neural activity is increased (Trzebski et al. 1982; Anderson et al. 1989; Matsukawa et al. 1991; Floras & Hara, 1993; Grassi et al. 2000). In turn, it is hypothesized that this elevation of MSNA is causally related to the hypertension. One hypothesized mechanism by which this augmentation occurs involves altered peripheral chemoreceptor control of MSNA.
Carotid body morphology. Why might the chemoreflex contribute to development of hypertension? One reason could be that changes in the chemoreceptor structure may adversely impact upon receptor function. Morphological studies that examined the anatomical and vascular characteristics of the carotid bodies in hypertension disclosed another possible explanation for the augmented chemoreflex response observed in hypertension. Since the carotid bifurcation (Howe & Neil, 1972) is very susceptible to atherosclerosis (Friedman et al. 1975), several autopsy studies examined the arteries that feed into the carotid bodies in order to understand the possible relationship of carotid body pathology to hypertension. For example, Habeck et al. (1983), Habeck (1986), Przybylski & Trzebski (1980) and Przybylski (1981) observed atherosclerosis of the glomic arteries and thus a decreased blood flow to the carotid bodies of hypertensive subjects. Along these lines, Kluge (1985) examined the vascularization of dissected carotid bodies from deceased patients with hypertension. There was a significant difference in the vascularization of the carotid bodies between the hypertensives and the control group such that the patients with hypertension had a lower number of arteries supplying the carotid bodies. Kluge concluded that the difference in the number of arteries may be genetically determined and that the carotid bodies may play an important role in the pathogenesis of hypertension. It has been proposed that chronic ischaemia of the carotid bodies leads to chronic stimulation of the chemoreceptors and subsequent hypertrophy (Przybylski & Trzebski, 1980; Przybylski, 1981). Morphological studies suggest that there is in fact hypertrophy and hyperplasia of the carotid bodies in hypertensive humans. One study examined the histology of the carotid bodies in deceased cases with myocardial hypertrophy secondary to both systemic hypertension and hypoxaemia. The authors found a higher cell count, increased weight and a greater diameter of the carotid bodies in those with systemic hypertension (Smith et al. 1982). In a follow-up study, the authors conclude that the type of cell that proliferates and causes hyperplasia and hypertrophy is the elongated sustentacular type II cell (Heath et al. 1982). Taken together, these findings suggest an important relationship between abnormalities of the carotid bodies and systemic hypertension. However, caution is warranted when interpreting any results from morphological studies of the carotid bodies because it is likely that the subjects suffered from several diseases; thus it is difficult to characterize the relationship between the anatomical changes found in the carotid bodies and systemic hypertension independent of important systemic vascular abnormalities, cardiac disease and other comorbidities. Whether hypertension precedes carotid body ischaemia and hyperplasia or whether in fact ischaemia, chronic stimulation and subsequent hyperplasia of the carotid bodies causes hypertension remains unclear. These changes are likely not to be the principal cause in many aetiologies of essential hypertension, but may be contributory to the facilitation of disease progression.
Chemoreflex resetting and chemoreceptor hyperactivity. Data that demonstrate the role of chemoreflex dysfunction in OSA and its association with the development of systemic hypertension have only recently been uncovered and are limited at best. Nevertheless, several human studies have attempted to clarify this association. As postulated above, an increased chemoreflex gain and threshold for activation of MSNA supports the view that the chemoreflex may contribute to chronic elevation of MSNA. Two other possibilities that have been proposed are chemoreflex resetting and chemoreflex hyperactivity.
First, although not extensively researched, the concept of chemoreflex resetting has been postulated by few researchers and warrants evaluation. Hedner et al. (1992a) suggested that as a result of chronic episodic hypoxia, the chemoreflex may reset to a higher level. Trzebski (1992) hypothesized that recurrent apnoeas as seen in OSA reset the chemoreflex to a higher level, thus increasing sympathetic outflow during normoxia or mild hypoxia and initiating hypertension. Tafil-Klawe et al. (1991) found a decrease in ventilation after inactivation of the carotid chemoreceptors in hypertensive OSA patients, thus indicating an increase in resting peripheral chemoreceptor drive in this population. Although these studies are limited, there is the suggestion that a process of resetting may also occur with sleep apnoea (Garcia-Rio et al. 2000). Whether this occurs in the chemoreflex control of MSNA remains to be determined, and this hypothesis needs further investigation.
Second, as mentioned earlier, patients with OSA exhibit elevated MSNA and catecholamine levels during wakefulness, which may result in part from the hyperactivity of the chemoreceptors. Loredo et al. (2001) found that hypertensive OSA patients had higher tonic chemoreceptor activity than OSA normotensives. They concluded that tonic chemoreceptor activity has some role in the development of systemic hypertension in OSA patients. The mechanism that would lead to a chronic hyperactivity of the chemoreceptors is unknown, and this outcome could be a manifestation of resetting and/or a change in the threshold or gain of the control system.
Conclusion
It is well established that there is a link between OSA and hypertension; however, the physiological mechanism(s) explaining this relationship remains unclear. A growing body of evidence supports the premise that a chemoreflex-mediated elevation of basal sympathetic activity may play an important role in the pathogenesis of hypertension among OSA patients. A chronic elevation of sympathetic activity would logically lead to vascular remodelling and sustained changes in vascular reactivity and tone, which are hallmark manifestations of essential hypertension. Nevertheless, further investigation into these potential links and mechanisms are needed, and many are addressed in the accompanying review papers in this journal.
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