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Themed Issue Papers |
Departments of 1 Physiology & Biophysics2 Medicine3 Pathology4 Biochemistry, Case Western School of Medicine, Cleveland, OH, USA
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Abstract |
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(Received 3 November 2006;
accepted after revision 6 November 2006; first published online 23 November 2006)
Corresponding author N. R. Prabhakar: Department of Physiology & Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44109, USA. Email: nrp{at}case.edu
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Introduction |
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Systemic responses to CIH
Effects of CIH on the carotid body. It is well established that patients experiencing CIH as a consequence of obstructive sleep apnoea (OSA) exhibit increased muscle SNA and elevated plasma catecholamines (Kara et al. 2003 for references). In experimental animals, CIH elevates basal SNA and potentiates SNA response to acute hypoxia (Sica et al. 2000; Prabhakar et al. 2005). In OSA patients, SNA activation is depressed in response to brief hyperoxia (Dejour's test, an indirect measure of arterial chemoreceptor sensitivity; Kara et al. 2003). In rodents, CIH-induced sympathetic activation is prevented by carotid body denervation (Lesske et al. 1997; Prabhakar et al. 2005). These observations led to the notion that CIH augments the carotid chemoreceptor response to hypoxia, which in turn leads to reflex sympathetic activation.
Recent studies on experimental animals provide direct evidence for CIH-induced sensitization of the carotid body activity. In rats exposed to CIH, the hypoxic sensory response of the carotid body was augmented, whereas the hypercapnic sensory response was unaltered (Peng & Prabhakar, 2004). A similar increase in the hypoxic sensory response of the carotid body was also reported in cats (Rey et al. 2004) and mice (Peng et al. 2006b) exposed to CIH. These observations demonstrate that CIH leads to selective sensitization of the carotid body response to hypoxia, and support the notion that intermittent hypoxia resulting from sleep-disordered breathing does affect the carotid chemoreceptor activity.
Peng et al. (2003) examined the effects of acute intermittent hypoxia (AIH; 15 s of hypoxia followed by 5 min of reoxygenation, 10 episodes) on carotid body sensory activity in control and CIH-exposed rats. They recorded the sensory response to 10 episodes of AIH and for 60 min during the post-AIH period. In control carotid bodies, sensory activity increased with each episode of hypoxia, returned to baseline after terminating the 10th episode and remained at this level during 60 min post-AIH period. In contrast, in CIH-exposed animals, sensory activity progressively increased with each episode of hypoxia and, more importantly, elevated baseline activity after the 10th episode persisted during the entire 60 min post-AIH period. This long-lasting increase in baseline sensory activity has been termed sensory long-term facilitation (LTF; Peng et al. 2003), because it resembled the time course of LTF of breathing elicited by repetitive hypoxia (see Mitchell & Johnson, 2003 for references). These observations suggest that CIH, in addition to sensitizing the carotid body to hypoxia, also induces a hitherto uncharacterized form of plasticity manifested as sensory LTF.
Characterization of CIH-induced effects on the carotid body revealed that sensory LTF and sensitization of the hypoxic response were not apparent until 3 days of CIH, and the magnitude of the response increased further by the 10th day of CIH (Peng et al. 2003), indicating that the effects of CIH develop over time. When CIH-exposed rats were re-exposed to 10 days of normoxia, neither the sensory LTF nor the augmented hypoxic response was evident, suggesting that CIH-induced effects on the carotid body are reversible. The reversible nature of the CIH responses might be of considerable clinical significance, in that it might explain why treating OSA patients with nasal continuous positive pressure, which improves the oxygenation, restores the normal sympathetic nerve activity (Kara et al. 2003). Chronic intermittent hypoxia with a single episode of hypoxia per day (4 h of hypoxia per day) for 10 days instead of 76 episodes of brief hypoxia per day for ten days neither sensitized the hypoxic response nor induced sensory LTF (Peng et al. 2003; Peng & Prabhakar, 2004), suggesting that the frequency of hypoxic cycling is an important factor that contributes to CIH-induced changes in the carotid body function.
What mechanisms might underlie CIH-induced alterations in the carotid body function? Sensitization of the hypoxic response and sensory LTF could be elicited in ex vivo carotid bodies from CIH-exposed rats as well as mice (Peng et al. 2003, 2006b), suggesting that the effects of CIH were not secondary to alterations in blood flow to the glomus tissue, but rather appear to result from a direct effect on the chemoreceptor tissue. Morphometric analysis revealed no significant differences in the total volume of the carotid body, number of glomus cells or glomus cell volume between control and CIH-exposed rats (Peng et al. 2003). A recent study by Rey et al. (2006) suggests that endothelin-1 (ET-1) contributes to CIH-induced sensitization of the carotid body response to hypoxia. 5-Hydroxytryptamine (5-HT) leads to long-term neuronal activation elsewhere in the nervous system (Mauelshagen et al. 1998; Machacek et al. 2001). The carotid body expresses substantial amounts of 5-HT (Jacono et al. 2005), and exogenous spaced application of 5-HT evokes sensory LTF of the carotid body via protein kinase C (PKC)-dependent activation of NADPH oxidase (Peng et al. 2006a). Further studies, however, are needed to demonstrate whether 5-HT contributes to CIH-induced sensory LTF of the carotid body.
In summary, the studies described above demonstrate that CIH exerts two major effects on the carotid body: (a) sensitization of the sensory response to hypoxia; and (b) induction of sensory LTF in response to repetitive hypoxia. What might be the significance of carotid body changes to CIH-induced sympathoexcitation? Acute hypoxia-evoked sympathoexcitation is more pronounced in CIH-exposed rats (Sica et al. 2000). It is possible that sensitization of the carotid body might contribute to augmented sympathetic activity that occurs with each episode of hypoxia, whereas the sensory LTF might contribute to the augmented LTF of sympathetic nerve activity seen after CIH (Peng et al. 2003). Further studies are needed to test these possibilities.
Effect of CIH on processing of chemoreceptor afferent inputs at the central nervous system. Processing of chemoreceptor afferent information at the central nervous system is critical for translation of the sensory information to appropriate changes in the sympathetic motor output. Arterial chemoreceptor afferents make synaptic contacts with neurones in the nucleus tractus solitarii (NTS). Although neurones responding to chemoreceptor afferent stimulation can be found throughout NTS (Mifflin, 1992), the primary site of integration appears to be the commissural part of the NTS (Zhang & Mifflin, 1993; Chitravanshi & Sapru, 1995). This section summarizes the effects of CIH on NTS neurones that receive chemoreceptor afferent inputs.
Expression of c-fos protein, a member of the immediate-early gene family, is often used as an index of neuronal activation. Intermittent hypoxia has been shown to be a potent activator of the c-fos gene (Yuan et al. 2004). Greenberg et al. (1999) reported that CIH upregulates c-fos protein in the commissural part of the NTS, suggesting that CIH activates NTS neurones that process chemoreceptor afferent information. Neuronal activity in NTS is regulated by various neurotransmitters, including glutamate and dopamine. Chronic intermittent hypoxia upregulates NMDA-R1 receptor subunit (Reeves et al. 2003) and downregulates tyrosine hydroxylase (TH; Gozal et al. 2005) in NTS. Dopamine, a product of TH-mediated catalysis, inhibits synaptic transmission at NTS (Kline et al. 2002), possibly by suppressing glutamatergic excitatory transmission as it does elsewhere in the nervous system (Chen et al. 1999). It is therefore likely that CIH facilitates NTS neuronal activity by tilting the balance between the excitatory and inhibitory transmitters.
Neurones in NTS relay chemoreceptor afferent information to sympathoexcitatory sites, including the paraventricular nucleus (PVN) and the rostral ventrolateral medulla (RVLM). Very little information, however, is available concerning whether or not CIH affects neuronal activity in NTS, PVN and RVLM.
Effects of CIH on sympathetic output. Several studies have examined whether repetitive hypoxia also elicits LTF of SNA similar to that reported for breathing (Mitchell & Johnson, 2003). Cutler et al. (2004) reported that voluntary apnoeas evoke LTF of muscle SNA wherein the increase in burst frequency persisted during 180 min of recovery period. These investigators also found that addition of CO2 to the hypoxic stimulus had no significant effect on LTF of muscle SNA, supporting the idea that hypoxia rather than hypercapnia is the primary stimulus for evoking LTF of SNA. Leuenberger et al. (2005) examined the effects of repetitive apnoeas on muscle SNA and arterial pressure in awake and healthy young humans. Following 30 hypoxic apnoeas (O2 saturation nadir 83.1 ± 1.2%), muscle SNA increased and remained elevated while arterial pressure increased only transiently. In contrast, in subjects who performed repetitive voluntary apnoeas (breath holding) during room air exposure (O2 saturation nadir 95.1 ± 0.8%), no changes in arterial pressure and muscle SNA were seen, emphasizing the critical role for hypoxia in evoking SNA. We recently found that acute repetitive hypoxia also evokes LTF of splanchnic SNA in anaesthetized rats, and methysergide, a broad spectrum 5-HT receptor antagonist, prevented the development of LTF of splanchnic SNA (Dick et al. 2006).
Lusina et al. (2006) examined the effects of CIH (10 daily exposures of intermittent hypoxia; 1 h day–1; oxyhaemoglobin saturation, 80%) in healthy human subjects. They reported that CIH augments LTF of muscle SNA, which resulted primarily from increases in the burst frequency rather than the burst amplitude. The LTF of SNA correlated with the augmented hypoxic ventilatory response.
These studies suggest that repetitive hypoxia elicits persistent activation of the sympathetic output.
Effects of CIH on adrenal medulla. Bao et al. (1997) reported that adrenalectomy prevents CIH-induced elevations in the blood pressure, as well as increases in plasma catecholamines (CA), suggesting that the adrenal medulla is important for mediating CIH-induced cardiovascular changes. Kumar et al. (2006) reported that prior exposure to CIH markedly facilitates hypoxia-evoked CA secretion from adrenal medulla. The effects of CIH were selective to the hypoxic stimulus because either isohydric or acidic hypercapnia was ineffective in evoking CA secretion from CIH-exposed adrenal medullae. Hypoxic sensitivity of the adrenal medulla induced by CIH was associated with concomitant downregulation of neurogenic CA secretion, as evidenced by attenuated responses to nicotine and 2-deoxyglucose (Kumar et al. 2006). In contrast, prior exposure to continuous hypoxia for 10 days was ineffective in facilitating hypoxia-evoked CA release from adrenal medulla. These observations suggest that CIH results in functional remodelling of the adrenal medulla, manifested as enhanced hypoxic sensitivity and a loss of neurogenic CA secretion. Such a remodelling might be of considerable functional significance, in that CIH, by downregulating neurogenic CA secretion, prevents depletion of CA stores during persistent sympathetic activation, whereas by inducing hypoxic sensitivity, CIH facilitates CA secretion only during hypoxic episodes (i.e. regulated secretion). These findings provide another example of CIH-induced functional plasticity not only in the SNA but also in the adrenal medulla, another effector of the chemoreceptor reflex pathway.
Systemic responses to CIH described thus far suggest that CIH leads to functional reorganization of the chemoreceptor reflex pathway that includes heightened hypoxic sensitivity and long-lasting activation of the carotid body (sensor), as well as the effectors. The following sections summarize recent studies addressing the cellular and molecular mechanism(s) associated with CIH-induced alterations in chemoreflex-mediated sympathoexcitation.
Cellular mechanism(s): role of reactive oxygen species (ROS)
Chronic exposure to intermittent but not continuous hypoxia evokes functional alterations in the carotid body (Peng et al. 2003; Peng & Prabhakar, 2004) and adrenal medulla (Kumar et al. 2006). What makes CIH a more effective stimulus than the continuous hypoxia? Chronic intermittent hypoxia is characterized by periodic reoxygenations, which are absent with continuous hypoxia. It is possible that ROS might be generated during the reoxygenation phase of CIH, similar to that seen in ischaemia–reperfusion. Recent studies have reported that CIH indeed results in increased generation of ROS in the carotid body (Peng et al. 2003), adrenal medulla (Kumar et al. 2006) and brainstem (Ramanathan et al. 2005). Physiological studies showed that treating CIH-exposed rats with ROS scavengers such as MnTMPyP [manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride, a ·O2– scavenger], as well as NAC (N-acetyl cysteine, a precursor of glutathione) prevent CIH-induced: (a) augmentation of the hypoxic sensory response, as well as the sensory LTF of the carotid body (Peng et al. 2003; Peng & Prabhakar, 2004); (b) functional changes in adrenal medulla; and (c) elevations in plasma catecholamines (index of sympathetic activation) and blood pressure (Kumar et al. 2006). Kolar et al. (2006) reported that CIH increases oxidative stress as evidenced by decreased reduced-to-oxidized glutathione ratio and plays a role in the development of increased cardiac ischaemic tolerance. These observations suggest that ROS-mediated signalling is a major cellular mechanism associated with CIH-induced functional changes in the chemoreceptor reflex pathway. More importantly, increased generation of ROS has been reported in OSA patients (Christou et al. 2003; Suzuki et al. 2006).
What might be the source(s) of CIH-induced ROS generation? Cellular mechanisms of ROS generation involve inhibition of complex I and III of the mitochondrial electron transport chain (Ambrosio et al. 1993), as well as activation of several oxidases (Halliwell & Gutteridge, 1990). Studies by Schumacker and his coworkers suggest that prolonged hypoxia results in increased ROS production via complex III of the mitochondrial electron transport chain (see Guzy & Schumacker, 2006 for references). However, biochemical measurements in CIH-exposed animals showed marked downregulation of mitochondrial complex I, but not complex III, in carotid bodies (Peng et al. 2003), as well as in cell cultures exposed to CIH (Yuan et al. 2004). These observations suggest that, unlike continuous hypoxia, mitochondrial complex I is one of the sources of ROS generation during CIH. The contribution of oxidases (e.g. NADPH oxidase) to ROS generation during CIH remains to be investigated. Furthermore, studies are needed to identify which of the ROS species (i.e. ·O2–, H2O2 or OH–) play a role in CIH-induced changes in the chemoreceptor reflex pathway.
Molecular mechanisms: role of hypoxia-inducible factor-1 (HIF-1)
It is being increasingly recognized that activation of specific genes is an important mechanism by which hypoxia triggers long-term systemic responses. The transcriptional activator HIF-1 is regarded as a master regulator of O2 homeostasis during hypoxia that controls multiple physiological processes and regulates the expression of hundreds of genes (Manalo et al. 2005). Hypoxia-inducible factor-1 is a heterodimeric protein that is composed of a constitutively expressed HIF-1ß subunit and an O2-regulated HIF-1
subunit (Wang et al. 1995). Complete HIF-1 deficiency results in embryonic lethality at mid-gestation, whereas Hif1a+/– heterozygous (HET) mice, which are partially deficient in HIF-1 expression, develop normally and are indistinguishable from wild-type (WT) littermates under normoxic conditions (Iyer et al. 1998; Yu et al. 1998). Interestingly, carotid body responses to hypoxia are selectively impaired in adult HET mice, suggesting an essential role of both HIF-1 in O2 sensing by the carotid body (Kline et al. 2003).
Intermittent hypoxia activates HIF-1-mediated transcription via activation of a novel Ca2+/calmodulin kinase (CaMK)-mediated signalling pathway in cell cultures (Yuan et al. 2005). Peng et al. (2006b) examined whether CIH also activates HIF-1 in mice and, if so, whether HIF-1 contributes to CIH-induced carotid body and cardiorespiratory responses. Wild-type and heterozygous (HET) mice were exposed to either 10 days of CIH or to 10 days of 21% O2 (controls). In CIH-exposed WT mice, the carotid body response to hypoxia was augmented, and AIH induced sensory LTF. In striking contrast, in CIH-exposed HET mice, the hypoxic sensory response was unaffected and sensory LTF was not elicited by AIH. Analysis of cardiorespiratory responses in CIH-exposed WT mice revealed an augmented hypoxic ventilatory response, LTF of breathing, elevated blood pressures and increased plasma noradrenaline, an index of sympathetic activation. In striking contrast, these responses were either absent or attenuated in HET mice exposed to CIH. The findings suggest that even partial deficiency of HIF-1 profoundly impairs CIH-evoked carotid body alterations, as well as the resulting reflex responses.
Since both HIF-1 deficiency and ROS scavengers impair carotid body-mediated reflex responses to CIH, Peng et al. (2006b) examined whether HIF-1 contributes to CIH-induced ROS. They found that ROS were elevated in CIH-exposed WT mice, whereas this response was absent in heterozygous mice exposed to CIH. Interestingly, MnTMPyP, a potent O2.– scavenger, not only prevented CIH-induced increases in ROS but also prevented CIH-evoked HIF-1 upregulation in WT mice, indicating that CIH-induced alterations in the chemoreceptor reflex involve complex positive interactions between HIF-1 and ROS.
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