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Nitric oxide and obstructive sleep apnea
Respiratory Physiology & Neurobiology 184 (2012) 192–196
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Review
Nitric oxide and obstructive sleep apnea夽 J. Woodrow Weiss a,∗ , Yuzhen Liu a , Xianghong Li a , En-sheng Ji b a b
Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States Department of Physiology, Shijiazhuang 050091, Hebei, PR China
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Article history: Accepted 13 August 2012 Keywords: Obstructive sleep apnea Nitric oxide Hypertension
a b s t r a c t Obstructive sleep apnea is a common disease, affecting 16% of the working age population. Although sleep apnea has a well-established connection to daytime sleepiness presumably mediated through repetitive sleep disruption, some other consequences are less well understood. Clinical, epidemiological, and physiological investigations have demonstrated a connection between sleep apnea and daytime hypertension. The elevation of arterial pressure is evident during waking, when patients are not hypoxic, and is mediated by sustained sympathoexcitation and by altered peripheral vascular reactivity. This review summarizes data suggesting that both the sympathoexcitation and the altered vascular reactivity are, at least in part, a consequence of reduced expression of nitric oxide synthase, in neural tissue and in endothelium. Reduced nitric oxide generation in central and peripheral sites of sympathoregulation and in endothelium together may, in part, explain the elevations in waking pressures observed in sleep apnea patients. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Patients with sleep apnea experience repetitive upper airway obstructions during sleep, as each obstruction is terminated by arousal and is accompanied by oxygen desaturation. The Wisconsin Sleep Cohort Study attempted to define the occurrence of obstructive sleep apnea (OSA) in working-age, community dwelling individuals by screening subjects with symptom questionnaires and sleep studies. These investigators measured sleep apnea prevalence, defined as volunteers with positive sleep studies and symptoms of daytime sleepiness, as 4% of working age males, with prevalence in females approximately half as great. If subjects with positive sleep studies who denied symptoms were included, the male prevalence swelled to 24% and female prevalence to 9% for an overall prevalence of 16% (Young et al., 1993). Because of this high prevalence, considerable recent attention has been focused on the consequences of this disease. Repetitive sleep disruption and sleep fragmentation have obvious influences on daytime performance and cognitive function, but there are other systemic consequences that are pertinent to this review. In particular, as detailed below, patients with obstructive sleep apnea
夽 This paper is part of a special issue entitled “Gasotransmitters and Respiration: Consequences in Health and Disease”, guest-edited by Prem Kumar and Chris Peers. ∗ Corresponding author at: 330 Brookline Avenue, Boston, MA 02215, United States. Tel.: +1 617 667 4895; fax: +1 617 667 1604. E-mail addresses: [email protected], [email protected] (J.W. Weiss). 1569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2012.08.011
demonstrate alterations in nitric oxide production in critical areas of sympathoregulation (carotid body and central nervous system) that lead to increased peripheral chemosensitivity and augmented central sympathetic processing. Combined with dysregulation of nitric oxide (NO) production in systemic arteries, the sustained sympathoexcitation displayed by OSA patients produces increases in arterial pressure that persist even during waking. 2. Hypertension as a consequence of OSA Of the different possible cardiovascular consequences experienced by sleep apnea patients, the best documented is systemic arterial hypertension – hypertension that is evident during waking, not just during sleep. Convincing data from both the Wisconsin Sleep Cohort Study (Hla et al., 1994) and the Sleep Heart Health Study (Nieto et al., 2000), a second community-based epidemiologic investigation, have established a link between OSA and systemic elevations in arterial pressure. While these epidemiological studies have linked OSA and hypertension they have not revealed the mechanisms that link nocturnal upper airway obstruction to elevated arterial pressure, but two animal models provided important evidence that links nocturnal hypoxia, rather than sleep disruption or thoracic pressure changes, to altered hemodynamics. The first model represented an attempt to mimic the nocturnal fluctuations in oxygen saturation experienced by sleep apnea patients. In this model, rats were exposed to cyclic intermittent hypocapnic hypoxia (CIH) for 8 h each day induced by alterations in inspired oxygen concentration (Fletcher et al., 1992) – an exposure that results in significant increases in arterial pressure. The second
J.W. Weiss et al. / Respiratory Physiology & Neurobiology 184 (2012) 192–196
model more closely mimicked the thoracic pressure changes and the episodic asphyxia of obstructive sleep apnea. In this model, which used a chronic dog preparation, a computer was used to activate a solenoid valve that occluded a tracheotomy tube whenever the animal slept (Brooks et al., 1997b). The occlusion was released when the animal awakened, mimicking human sleep apnea. Providing strong support for a causal relationship of sleep apnea to hypertension, animals subjected to this protocol for 2 months developed sustained daytime elevations of arterial pressure that resolved when the airway occlusions were halted (Brooks et al., 1997a). Reinforcing the link of nocturnal cyclic intermittent hypoxia to daytime arterial pressure increases, Brooks and colleagues used this model to establish that airway obstructions, but not nocturnal acoustic arousals, lead to the development of hypertension in the animals (Brooks et al., 1997a). Although not yet used to assess hemodynamic consequences of airway obstruction, new models of sleep apnea using induced obstructions in rodents hold promise for future investigations of the mechanisms of OSA hypertension (Schoorlemmer et al., 2011). While it is now accepted that CIH links OSA to hypertension, there is still debate about the mechanisms that provide that link. Two primary mechanisms have been proposed by which the nocturnal cyclic hypoxia of OSA might contribute to increased arterial pressure. The first mechanism that might link OSA and CIH to diurnal hypertension is the development of sustained sympathoexcitation. Although long-term control of arterial pressure has been thought to be regulated through hormonal and renal regulation of intravascular volume, recent animal studies suggest that sympathoexcitation contributes to sustained hypertension in several models including the Spontaneously Hypertensive Rat (SHR) and models of renal insufficiency induced hypertension (Osborn et al., 1997). Significantly, in the model of CIH induced hypertension in rats, the renal sympathetic nervous system is necessary for the change in blood pressure, as section of the renal nerves prior to the exposure to CIH prevents the rise in arterial pressure (Bao et al., 1997). Carlson and colleagues were the first to use peroneal microneurography to assess sympathetic activity in OSA patients (Carlson et al., 1993). These investigators reported marked elevations of muscle sympathetic nerve activity (MSNA) in OSA patients while awake compared to non-apneic controls, a finding now confirmed by others (Waradeker et al., 1996). Further supporting the connection between sleep apnea and sympathetic hyperactivity is the evidence that effective sleep apnea treatment with nasal continuous positive airway pressure (CPAP) results in a decrease in resting sympathetic tone, again assessed with peroneal microneurography (Waradeker et al., 1996). The second mechanism that might link OSA and CIH to diurnal hypertension is through the development of impaired vasodilation. A number of years ago Tahawi et al. (2001) suggested altered vascular function in rats exposed to CIH for 5 weeks. Hedner et al. (1992) showed that OSA patients have an abnormal pressor response when exposed acutely to hypoxia during waking, compared to non-apneic control subjects who maintained or decreased arterial pressure during an identical exposure. Remsberg et al. (1999) used forearm plethysmograpy to demonstrate that OSA patients vasoconstrict during the same hypoxic exposure used by Hedner while non-apneic volunteers routinely vasodilate. Subsequent studies by Kato et al. (2000) and Carlson et al. (1995) established that OSA patients have reduced flow-mediated vasodilation relative to nonapneic control subjects and Imadojemu et al. (2002) has shown that effective CPAP treatment improves flow-mediated dilation in OSA patients. Thus, cyclic intermittent hypoxia in rats and in OSA patients is associated with both sustained sympathoexcitation and impaired vasodilation. To understand the connection of OSA to arterial hypertension we therefore need to understand how exposure
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to CIH causes these apparently unconnected pathophysiological conditions. Although sustained sympathoexcitation and impaired vasodilation might seem unlikely to share a common pathogenesis, we believe evidence suggests that both sympathoexcitation and abnormal vascular reactivity are linked to CIH exposure by decreased nitric oxide bioavailability, in neural tissues and in endothelium.
3. NO and sympathetic outflow in OSA Efferent sympathetic outflow is influenced by peripheral reflex activity (Gujic et al., 2007) and also by central sympathetic processing. Our own and published data suggest that CIH exposure alters both peripheral chemosensitivity and central sympathoregulation. Peng et al. (2001) have reported an increase in carotid sinus nerve activity during both normoxia and during re-challenge to hypoxia in rats previously exposed for 14 days of cyclic hypoxia (20 s every 5 min, 8 h/day). Supporting the hypothesis that untreated OSA may increase chemosensitivity in a recent manuscript which reported that OSA patients treated with nasal continuous positive airway pressure (nasal CPAP) for 3 months demonstrate a decrease in the ventilatory response to progressive hypoxia relative to their untreated baseline (Tun et al., 2000). Interestingly, recent studies suggest increased carotid chemosensitivity may characterize not only OSA hypertension, but other forms of sympathetically mediated hypertension as well (Abdala et al., in press). Although the cause of increased chemosensitivity after CIH exposure is unknown, one possible explanation is altered bioavailability of NO in the carotid body. A number of investigators have explored the role of nitric oxide in altering carotid chemosensitivity. After Wang et al. (1993) demonstrated a plexus of NOS-containing neurons in the carotid body associated with type 1 (glomus) cells with cell bodies located in the petrosal ganglion, Prabhakar et al. (1993) showed that NOS inhibition with N(omega)nitro-l-arginine (l-NNA) increased carotid sinus nerve activity in a dose-dependent manner. Summers et al. (1999) provided evidence that one way in which NO acts on glomus cells is by inhibiting Ltype calcium channels through a mechanism that is at least in part independent of cGMP. In a series of studies, Sun and Schultz applied these findings to a specific disease state, showing that NOS activity is reduced in the carotid bodies of rabbits with pacing-induced congestive heart failure and that NOS inhibition increased baseline carotid sinus nerve activity and chemosensitivity to hypoxia in sham, but not CHF carotid bodies (Sun et al., 1999a,b). This same laboratory later demonstrated that gene transfer of nNOS to carotid bodies of CHF rabbits substantially blunted both the augmented chemosensitivity and the sustained sympathoexcitation that occur in CHF. Although these studies establish that nitric oxide is inhibitory in the carotid body and that NOS expression may be regulated in specific disease states, there are no prior studies suggesting that CIH exposure decreases NOS expression in the carotid body. In fact, Di Giulio et al. (2003) demonstrated increased carotid body NOS expression after 12 days of continuous hypoxia (10% O2 ) in rats. In contrast, however, Kusakabe et al. (1998) showed that rats exposed to more prolonged hypoxia (10% O2 with 3–4% CO2 for 3 months) had reduced numbers of NOS immunoreactive fibers in their carotid bodies. Few studies have examined the effect of CIH on NOS expression in the carotid body, but Marcus et al. (2010) recently demonstrated significant reductions in nNOS protein in carotid bodies of CIH-exposed relative to Sham-exposed rats, and our own unpublished data suggest that not only is NOS message and protein reduced after CIH exposure (Fig. 1) but the functional responses to the NO-donor S-nitroso-Nacetyl-d,l-penicillamine (SNAP) (Fig. 2) and to the neuronal nitric
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J.W. Weiss et al. / Respiratory Physiology & Neurobiology 184 (2012) 192–196
Fig. 1. (A) Representative RT-PCR result of neuronal NOS mRNA in carotid bodies from rats exposed to room air Sham or cyclic intermittent hypoxia (CIH) for 8 h/day for 5 weeks. PCR product was not detected if reverse transcriptase was omitted from the reaction in tubes (Actin (−)). (B) Relative nNOS mRNA amount in carotid bodies of Sham and CIH rats. Data are mean of percent of sham ± SD. (C) Representative Western blot result of neuronal NOS protein in Sham and CIH carotid bodies. (D) Relative nNOS protein amount in carotid bodies of Sham and CIH rats. Data are mean ± SD. All data were from three individual experiments running in triplicates, n = 5 in each group (*P < 0.005).
Discharge of CSN (% of baseline)
oxide synthase inhibitor (l-omega-nitro arginine (l-NNA), data not presented) support decreased functional NO generation in the carotid bodies of CIH-exposed rats. Carotid chemosensory afferent activity is not the only determinant of sympathetic activity. Outflow from post-ganglionic renal sympathetic nerves is modulated by input from pre-ganglionic neurons in the spinal cord which, in turn, receive input from sympathetic pre-motor neurons in a number of locations in the central nervous system including the rostral ventral lateral medulla (RVLM), the medullary raphe, the A5 area of the pons, and the paraventricular nucleus (PVN) of the hypothalamus (Dampney et al., 700 600
Sham CIH
500
**
400
** ##
300 200 100 0 Control
SNAP
Fig. 2. Carotid sinus nerve activity (CSN, whole nerve recording) in response to treatment with endothelin-1 before (Control) and after treatment with the NOdonor S-nitroso-N-acetyl-d,l-penicillamine (SNAP). Open bars represent recordings from rats exposed to room air sham (Sham, n = 5) while closed bars represent rats exposed to cyclic intermittent hypoxia (CIH, n = 5). All exposures were for 8 h/day for 5 weeks. CSN increases in response to endothelin in both Sham and CIH exposed rats but the increase is greater in CIH exposed animals. The nitric oxide donor SNAP significantly reduces CSN response in both Sham and in CIH exposed rats but the decrease is significantly greater in CIH animals (**P < 0.05; ##P < 0.01).
2003). In addition, these pre-motor neurons receive input from a wide variety of CNS locations including neurons within the circumventricular organs (CVO) in the lamina terminalis (Dampney et al., 2003, 2005). Evidence suggests that all these regions may be involved in states of pathological sympathoexcitation, with greatest attention recently on the role of the PVN, RVLM and subfornical organ (SFO) in several animal models of sustained hypertension – SHR and Dahl-sensitive rats (DiBona, 2004) – and in the heightened sympathetic activity that is associated with congestive heart failure (CHF) (Felder et al., 2003). While modulation of sympathetic activity within the PVN is complex, a number of studies suggest that sustained sympathoexcitation can occur as a consequence of down regulation of neuronal nitric oxide synthase (nNOS) in neurons in the PVN because such neurons are sympathoinhibitory (Campese et al., 2002, 2004; Zhang et al., 1997). Patel and colleagues have established that reduced NOS expression in PVN is one contributor to heightened sympathetic activity after induction of CHF in rats (Patel, 2000). We have previously reported that 5-week CIH exposure decreases expression of nNOS message in neurons of the PVN (Huang et al., 2007). Recently, Coleman et al. (2010) reported that the essential NMDA receptor constituent, NR1, has reduced surface/synaptic availability in nNOS containing neurons in the PVN of mice exposed for 35 days to CIH. Immunogold staining revealed increased density of NR1 particles in cytoplasm, suggesting the defect was in transporting the NR1 components to the cell membrane. NO production, as measured by NO-sensitive fluorescent dye, was reduced after CIH. This altered NR1 trafficking was associated with increased arterial pressure in the CIH exposed animals. Interestingly, the changes in NR1 trafficking and NO production were not present after 14 days of exposure, but were evident after 35 days. This does not correspond to the time course of development of hypertension after CIH exposure (Kanagy et al., 2001) suggesting altered NO production may sustain altered sympathetic activity but may not initiate the increase in sympathetic outflow.
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Nevertheless, we speculate that decreased NO bioavailability in the PVN, in part due to decreased NOS expression, contributes to increased sympathetic outflow after CIH exposure.
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exposure, leads to NOS uncoupling and consequent reduced nitric oxide bioavailability in these tissues. 5. Conclusion
4. NO and vascular tone in OSA Thus, there is evidence suggesting decreased NO bioavailability in carotid body and PVN contributes to sympathoexcitation after CIH exposure. There are equally compelling data suggesting decreased NO bioavailability contributes to impaired vasodilation in OSA patients exposed to nocturnal desaturations and in CIH exposed rats. Carlson et al. (1995) were the first to report impaired endothelium-dependent vasodilation in OSA patients compared to age, sex and weight matched non-apneic controls. Forearm blood flow after intra-arterial acetylcholine (ACh) was reduced in patients compared to controls and patients had higher minimal vascular resistance after SNP. Kato studied OSA patients at the time of diagnosis, before any therapy, and also found a reduced response to ACh relative to weight matched control individuals but responses to SNP and verapamil were similar between the groups (Kato et al., 2000). More recently, Lattimore et al. (2006) measured endothelium dependent (ACh) and endothelium independent (SNP) responses in OSA patients before and after 3 months of CPAP treatment. They also assessed forearm vascular response to intra-arterial administration of the NOS inhibitor l-NMMA. After CPAP the response to ACh increased and there was a greater reduction in flow after l-NMMA, but the response to SNP was unchanged, findings consistent with improved nitric oxide mediated endothelium dependent vasodilation. Tahawi, working in Fletcher’s laboratory, used CIHexposed rats to examine in vivo responses of cremasteric arterioles to norepinephrine (NE), endothelin-1 (ET-1), Ach and the NOS inhibitor l-NAME (Tahawi et al., 2001). CIH exposed rats had attenuated ACh induced vasodilation relative to sham-exposed animals. The degree of vasoconstriction to l-NAME was also reduced in CIH animals compared with sham rats. Responses to NE and ET-1 were not different between the groups. The effect of CIH exposure on arterial eNOS expression has not been well studied but Jelic et al. (2008) harvested venous endothelial cells from OSA patients and control subjects. They performed immunofluorescence staining for eNOS protein, phosphorylated eNOS, and markers of oxidative stress (nitrotyrosine). Expression of eNOS and phosphorylated eNOS were significantly reduced in patients relative to controls while nitrotyrosine was increased. Effective CPAP treatment resulted in substantial increases in eNOS and phosphorylated eNOS and reductions in nitrotyrosine. These studies and our own preliminary data below are the basis for our hypotheses that CIH exposure reduces NO bioavailability, both in areas of sympathoregulation and in endothelium. This reduced bioavailability contributes to sustained sympathoexcitation and reduced arterial vasodilation, which, in turn, produce arterial hypertension. One cause of reduced bioavailability, down regulation of constitutive nitric oxide synthase expression (Kavdia and Popel, 2004), is supported by our preliminary studies. Another mechanism that might cause reduced bioavailability, uncoupling of NOS activity where the enzyme produces superoxide (O2 − ) instead of NO• , and/or the scavenging of NO• by increased production of reactive oxygen species (ROS), has not been examined in humans or animals exposed to CIH. Nevertheless, there is evidence to suggest that such NOS “uncoupling” may also contribute to decreased NO bioavailability after CIH exposure. Studies by Jelic et al. (2008) among others indicate increased ROS generation in human arterial endothelial cells after CIH exposure in sleep apnea. Peng et al. (2003) have provided evidence of increased ROS signaling in carotid bodies of mice after CIH exposure. We speculate that such increased ROS generation, produced in neural and endothelial tissue after CIH
In summary, substantial evidence links OSA, through nocturnal CIH, to arterial hypertension through sympathoexcitation and altered vascular reactivity. Published work suggests that a common mechanism for both sympathoexcitation and altered vascular function after CIH exposure is decreased availability of nitric oxide, in both neural tissue and in endothelium. Further studies are needed to determine whether altered NO bioavailability can account for the heightened sympathetic activity and reduced vascular dilation that characterize CIH exposure and obstructive sleep apnea. References Abdala, A.P., McBryde, F.D., Marina, N., Hendy, E.B., Engelman, Z.J., Fudim, M., Sobotka, P.A., Gourine, A.V., Paton, J.F.R. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. Journal of Physiology, in press. Bao, G., Metrevelli, N., Li, R., Taylor, A., Fletcher, E.C., 1997. Blood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system. Journal of Applied Physiology 83, 95–101. Brooks, D., Horner, R.L., Kimoff, R.J., Kozar, L.F., Render-Texeira, C.L., Phillipson, E.A., 1997a. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. American Journal of Respiratory and Critical Care Medicine 155, 1609–1617. Brooks, D., Horner, R.L., Kozar, L.F., Render-Texeira, C.L., Phillipson, E.A., 1997b. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. Journal of Clinical Investigation 99, 109. Campese, V.M., Ye, S., Zhong, H., 2002. Downregulation of neuronal nitric oxide synthase and interleukin-1 mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 39, 519–524. Campese, V.M., Ye, S., Zhong, H., Yanamadala, V., Ye, Z., Chiu, J., 2004. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. American Journal of Physiology – Heart and Circulatory Physiology 287, H695–H703. Carlson, J., Rangemark, C., Hedner, J., 1995. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. Journal of Hypertension 14, 577–584. Carlson, J.T., Hedner, J., Elam, M., Ejnell, H., Sellgren, J., Wallin, B.G., 1993. Augmented resting sympathetic nerve activity in awake patients with obstructive sleep apnea. Chest 103, 1763–1768. Coleman, C.G., Wang, G., Park, L., Anrather, J., Delagrammatikas, G.J., Chan, J., Zhou, J., Iadecola, C., Pickel, V.M., 2010. Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. Journal of Neuroscience 30, 12103–12112. Dampney, R.A.L., Horiuchi, J., Killinger, S., Sherrif, M.J., Tan, P.S.P., McDowall, L.M., 2005. Long-term regulation of arterial pressure by hypothalamic nuclei: some critical questions. Clinical and Experimental Pharmacology and Physiology 32, 419–425. Dampney, R.A.L., Horiuchi, J., Tagawa, T., Fontes, M.A.P., Potts, P.D., Polson, J.W., 2003. Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone. Acta Physiologica 177, 209–218. Di Giulio, C., Huang, W.X., Mokashi, A., Roy, A., Cacchio, M., Macri, M.A., Lahiri, S., 2003. Sustained hypoxia promotes hyperactive response of carotid body in the cat. Respiratory Physiology and Neurobiology 134, 69–74. DiBona, G.F., 2004. The sympathetic nervous system and hypertension: recent developments. Hypertension 43, 147–150. Felder, R.B., Francis, J., Zhang, Z.-H., Wei, S.-G., Weiss, R.M., Johnson, A.K., 2003. Heart failure and the brain: new perspectives. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 284, R259–R276. Fletcher, E.C., Lesske, J., Qian, W., Miller, C.C.I., Unger, T., 1992. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19, 555–561. Gujic, M., Laude, D., Houssiere, A., Beloka, S., Argacha, J.F., Adamopoulos, D., Xhaet, O., Elghozi, J.L., van de Borne, P., 2007. Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human. Journal of Physiology 585, 165–174. Hedner, J., Wilcox, I., Laks, L., Grunstein, R.R., Sullivan, C.E., 1992. A specific and potent pressor effect of hypoxia in patients with sleep apnea. American Review of Respiratory Disease 146, 1240–1245. Hla, K.M., Young, T.B., Bidwell, T., Palta, M., Skatrud, J.B., Dempsey, J., 1994. Sleep apnea and hypertension: a population-based study. Annals of Internal Medicine 120, 382–388. Huang, J., Tamisier, R., Ji, E., Tong, J., Weiss, W.J., 2007. Chronic intermittent hypoxia modulates nNOS mRNA and protein expression in the rat hypothalamus. Respiratory Physiology and Neurobiology 158, 30–38.
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Imadojemu, V.A., Gleeson, K., Quraishi, S.A., Kunselman, A.R., Sinoway, L.I., Leuenberger, U.A., 2002. Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. American Journal of Respiratory and Critical Care Medicine 165, 950–953. Jelic, S., Padeletti, M., Kawut, S.M., Higgins, C., Canfield, S.M., Onat, D., Colombo, P.C., Basner, R.C., Factor, P., LeJemtel, T.H., 2008. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 117, 2270–2278. Kanagy, N.L., Walker, B.R., Nelin, L.D., 2001. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 37 (Part 2), 511–515. Kato, M., Roberts-Thomson, P., Phillips, B.G., Haynes, W.G., Winnicki, M., Accurso, V., Somers, V.K., 2000. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102, 2607–2610. Kavdia, M., Popel, A.S., 2004. Contribution of nNOS- and eNOS-derived NO to microvascular smooth muscle NO exposure. Journal of Applied Physiology 97, 293–301. Kusakabe, T., Matsuda, H., Harada, Y., Hayashida, Y., Gono, Y., Kawakami, T., Takenaka, T., 1998. Changes in the distribution of nitric oxide synthase immunoreactive nerve fibers in the chronically hypoxic rat carotid body. Brain Research 795, 292–296. Lattimore, J.L., Wilcox, I., Skilton, M., Langenfeld, M., Celermajer, D.S., 2006. Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 61, 491–495. Marcus, N.J., Li, Y.L., Bird, C.E., Schultz, H.D., Morgan, B.J., 2010. Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: role of the angiotensin II type 1 receptor. Respiratory Physiology and Neurobiology 171, 36–45. Nieto, F.J., Young, T.B., Lind, B.K., Shahar, E., Samet, J.M., Redline, S., D’Agostino, R.B., Newman, A.B., Lebowitz, M.D., Pickering, T.G., 2000. Association of sleepdisordered breathing sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283, 1829–1836. Osborn, J.L., Plato, C.F., Gordon, E., He, X.R., 1997. Long-term increases in renal sympathetic nerve activity and hypertension. Clinical and Experimental Pharmacology and Physiology 24, 72–76. Patel, K.P., 2000. Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. Heart Failure Reviews 5, 73–86. Peng, Y., Kline, D.D., Dick, T.E., Prabhakar, N.R., 2001. Chronic intermittent hypoxia enhances carotid body chemoreceptor response to low oxygen. In: Poon, Kazemi, H. (Eds.), Frontiers in Modeling and Control of Breathing. Kluwer Academic/Plenum Publishers, New York, pp. 33–37.
Peng, Y.-J., Overholt, J.L., Kline, D., Kumar, G.K., Prabhakar, N.R., 2003. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proceedings of the National Academy of Sciences 100, 10073–10078. Prabhakar, N.R., Kumar, G.K., Chang, H.C., Agani, F.H., Haxhiu, M.A., 1993. Nitric oxide in the sensory function of the carotid body. Brain Research 625, 16–22. Remsberg, S., Launois, S.H., Weiss, J.W., 1999. Patients with obstructive sleep apnea have an abnormal peripheral vascular response to hypoxia. Journal of Applied Physiology 87, 1148–1153. Schoorlemmer, G.H.M., Rossi, M.V., Tufik, S., Cravo, S.L., 2011. A new method to produce obstructive sleep apnoea in conscious unrestrained rats. Experimental Physiology 96, 1010–1018. Summers, B.A., Overholt, J.L., Prabhakar, N.R., 1999. Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism. Journal of Neurophysiology 81, 1449–1457. Sun, S.Y., Wang, W., Zucker, I.H., Schultz, H.D., 1999a. Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. Journal of Applied Physiology 86, 1273–1282. Sun, S.Y., Wang, W., Zucker, I.H., Schultz, H.D., 1999b. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. Journal of Applied Physiology 86, 1264–1272. Tahawi, Z., Orolinova, N., Joshua, I.G., Bader, M., Fletcher, E.C., 2001. Selected contribution: altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. Journal of Applied Physiology 90, 2007–2013. Tun, Y., Hida, W., Okabe, S., Kikuchi, Y., Kurosawa, H., Tabata, M., Shirato, K., 2000. Effects of nasal continuous positive airway pressure on awake ventilatory responses to hypoxia and hypercapnia in patients with obstructive sleep apnea. Tohoku Journal of Experimental Medicine 190, 157–168. Wang, Z.-Z., Bredt, D.S., Fidone, S., Stensaas, L., 1993. Neurons synthesizing nitric oxide innervate the mammalian carotid body. Journal of Comparative Neurology 336, 419–432. Waradeker, N.V., Sinoway, L.I., Zwillich, C.W., Leuenberger, U.A., 1996. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. American Journal of Respiratory and Critical Care Medicine 153, 1333–1338. Young, T., Palta, M., Dempsey, J., Skatrud, J.B., Weber, S., Badr, S., 1993. The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine 328, 1230–1235. Zhang, K., Mayhan, W.G., Patel, K.P., 1997. Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 273, R864–R872.
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Review
Nitric oxide and obstructive sleep apnea夽 J. Woodrow Weiss a,∗ , Yuzhen Liu a , Xianghong Li a , En-sheng Ji b a b
Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States Department of Physiology, Shijiazhuang 050091, Hebei, PR China
a r t i c l e
i n f o
Article history: Accepted 13 August 2012 Keywords: Obstructive sleep apnea Nitric oxide Hypertension
a b s t r a c t Obstructive sleep apnea is a common disease, affecting 16% of the working age population. Although sleep apnea has a well-established connection to daytime sleepiness presumably mediated through repetitive sleep disruption, some other consequences are less well understood. Clinical, epidemiological, and physiological investigations have demonstrated a connection between sleep apnea and daytime hypertension. The elevation of arterial pressure is evident during waking, when patients are not hypoxic, and is mediated by sustained sympathoexcitation and by altered peripheral vascular reactivity. This review summarizes data suggesting that both the sympathoexcitation and the altered vascular reactivity are, at least in part, a consequence of reduced expression of nitric oxide synthase, in neural tissue and in endothelium. Reduced nitric oxide generation in central and peripheral sites of sympathoregulation and in endothelium together may, in part, explain the elevations in waking pressures observed in sleep apnea patients. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Patients with sleep apnea experience repetitive upper airway obstructions during sleep, as each obstruction is terminated by arousal and is accompanied by oxygen desaturation. The Wisconsin Sleep Cohort Study attempted to define the occurrence of obstructive sleep apnea (OSA) in working-age, community dwelling individuals by screening subjects with symptom questionnaires and sleep studies. These investigators measured sleep apnea prevalence, defined as volunteers with positive sleep studies and symptoms of daytime sleepiness, as 4% of working age males, with prevalence in females approximately half as great. If subjects with positive sleep studies who denied symptoms were included, the male prevalence swelled to 24% and female prevalence to 9% for an overall prevalence of 16% (Young et al., 1993). Because of this high prevalence, considerable recent attention has been focused on the consequences of this disease. Repetitive sleep disruption and sleep fragmentation have obvious influences on daytime performance and cognitive function, but there are other systemic consequences that are pertinent to this review. In particular, as detailed below, patients with obstructive sleep apnea
夽 This paper is part of a special issue entitled “Gasotransmitters and Respiration: Consequences in Health and Disease”, guest-edited by Prem Kumar and Chris Peers. ∗ Corresponding author at: 330 Brookline Avenue, Boston, MA 02215, United States. Tel.: +1 617 667 4895; fax: +1 617 667 1604. E-mail addresses: [email protected], [email protected] (J.W. Weiss). 1569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2012.08.011
demonstrate alterations in nitric oxide production in critical areas of sympathoregulation (carotid body and central nervous system) that lead to increased peripheral chemosensitivity and augmented central sympathetic processing. Combined with dysregulation of nitric oxide (NO) production in systemic arteries, the sustained sympathoexcitation displayed by OSA patients produces increases in arterial pressure that persist even during waking. 2. Hypertension as a consequence of OSA Of the different possible cardiovascular consequences experienced by sleep apnea patients, the best documented is systemic arterial hypertension – hypertension that is evident during waking, not just during sleep. Convincing data from both the Wisconsin Sleep Cohort Study (Hla et al., 1994) and the Sleep Heart Health Study (Nieto et al., 2000), a second community-based epidemiologic investigation, have established a link between OSA and systemic elevations in arterial pressure. While these epidemiological studies have linked OSA and hypertension they have not revealed the mechanisms that link nocturnal upper airway obstruction to elevated arterial pressure, but two animal models provided important evidence that links nocturnal hypoxia, rather than sleep disruption or thoracic pressure changes, to altered hemodynamics. The first model represented an attempt to mimic the nocturnal fluctuations in oxygen saturation experienced by sleep apnea patients. In this model, rats were exposed to cyclic intermittent hypocapnic hypoxia (CIH) for 8 h each day induced by alterations in inspired oxygen concentration (Fletcher et al., 1992) – an exposure that results in significant increases in arterial pressure. The second
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model more closely mimicked the thoracic pressure changes and the episodic asphyxia of obstructive sleep apnea. In this model, which used a chronic dog preparation, a computer was used to activate a solenoid valve that occluded a tracheotomy tube whenever the animal slept (Brooks et al., 1997b). The occlusion was released when the animal awakened, mimicking human sleep apnea. Providing strong support for a causal relationship of sleep apnea to hypertension, animals subjected to this protocol for 2 months developed sustained daytime elevations of arterial pressure that resolved when the airway occlusions were halted (Brooks et al., 1997a). Reinforcing the link of nocturnal cyclic intermittent hypoxia to daytime arterial pressure increases, Brooks and colleagues used this model to establish that airway obstructions, but not nocturnal acoustic arousals, lead to the development of hypertension in the animals (Brooks et al., 1997a). Although not yet used to assess hemodynamic consequences of airway obstruction, new models of sleep apnea using induced obstructions in rodents hold promise for future investigations of the mechanisms of OSA hypertension (Schoorlemmer et al., 2011). While it is now accepted that CIH links OSA to hypertension, there is still debate about the mechanisms that provide that link. Two primary mechanisms have been proposed by which the nocturnal cyclic hypoxia of OSA might contribute to increased arterial pressure. The first mechanism that might link OSA and CIH to diurnal hypertension is the development of sustained sympathoexcitation. Although long-term control of arterial pressure has been thought to be regulated through hormonal and renal regulation of intravascular volume, recent animal studies suggest that sympathoexcitation contributes to sustained hypertension in several models including the Spontaneously Hypertensive Rat (SHR) and models of renal insufficiency induced hypertension (Osborn et al., 1997). Significantly, in the model of CIH induced hypertension in rats, the renal sympathetic nervous system is necessary for the change in blood pressure, as section of the renal nerves prior to the exposure to CIH prevents the rise in arterial pressure (Bao et al., 1997). Carlson and colleagues were the first to use peroneal microneurography to assess sympathetic activity in OSA patients (Carlson et al., 1993). These investigators reported marked elevations of muscle sympathetic nerve activity (MSNA) in OSA patients while awake compared to non-apneic controls, a finding now confirmed by others (Waradeker et al., 1996). Further supporting the connection between sleep apnea and sympathetic hyperactivity is the evidence that effective sleep apnea treatment with nasal continuous positive airway pressure (CPAP) results in a decrease in resting sympathetic tone, again assessed with peroneal microneurography (Waradeker et al., 1996). The second mechanism that might link OSA and CIH to diurnal hypertension is through the development of impaired vasodilation. A number of years ago Tahawi et al. (2001) suggested altered vascular function in rats exposed to CIH for 5 weeks. Hedner et al. (1992) showed that OSA patients have an abnormal pressor response when exposed acutely to hypoxia during waking, compared to non-apneic control subjects who maintained or decreased arterial pressure during an identical exposure. Remsberg et al. (1999) used forearm plethysmograpy to demonstrate that OSA patients vasoconstrict during the same hypoxic exposure used by Hedner while non-apneic volunteers routinely vasodilate. Subsequent studies by Kato et al. (2000) and Carlson et al. (1995) established that OSA patients have reduced flow-mediated vasodilation relative to nonapneic control subjects and Imadojemu et al. (2002) has shown that effective CPAP treatment improves flow-mediated dilation in OSA patients. Thus, cyclic intermittent hypoxia in rats and in OSA patients is associated with both sustained sympathoexcitation and impaired vasodilation. To understand the connection of OSA to arterial hypertension we therefore need to understand how exposure
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to CIH causes these apparently unconnected pathophysiological conditions. Although sustained sympathoexcitation and impaired vasodilation might seem unlikely to share a common pathogenesis, we believe evidence suggests that both sympathoexcitation and abnormal vascular reactivity are linked to CIH exposure by decreased nitric oxide bioavailability, in neural tissues and in endothelium.
3. NO and sympathetic outflow in OSA Efferent sympathetic outflow is influenced by peripheral reflex activity (Gujic et al., 2007) and also by central sympathetic processing. Our own and published data suggest that CIH exposure alters both peripheral chemosensitivity and central sympathoregulation. Peng et al. (2001) have reported an increase in carotid sinus nerve activity during both normoxia and during re-challenge to hypoxia in rats previously exposed for 14 days of cyclic hypoxia (20 s every 5 min, 8 h/day). Supporting the hypothesis that untreated OSA may increase chemosensitivity in a recent manuscript which reported that OSA patients treated with nasal continuous positive airway pressure (nasal CPAP) for 3 months demonstrate a decrease in the ventilatory response to progressive hypoxia relative to their untreated baseline (Tun et al., 2000). Interestingly, recent studies suggest increased carotid chemosensitivity may characterize not only OSA hypertension, but other forms of sympathetically mediated hypertension as well (Abdala et al., in press). Although the cause of increased chemosensitivity after CIH exposure is unknown, one possible explanation is altered bioavailability of NO in the carotid body. A number of investigators have explored the role of nitric oxide in altering carotid chemosensitivity. After Wang et al. (1993) demonstrated a plexus of NOS-containing neurons in the carotid body associated with type 1 (glomus) cells with cell bodies located in the petrosal ganglion, Prabhakar et al. (1993) showed that NOS inhibition with N(omega)nitro-l-arginine (l-NNA) increased carotid sinus nerve activity in a dose-dependent manner. Summers et al. (1999) provided evidence that one way in which NO acts on glomus cells is by inhibiting Ltype calcium channels through a mechanism that is at least in part independent of cGMP. In a series of studies, Sun and Schultz applied these findings to a specific disease state, showing that NOS activity is reduced in the carotid bodies of rabbits with pacing-induced congestive heart failure and that NOS inhibition increased baseline carotid sinus nerve activity and chemosensitivity to hypoxia in sham, but not CHF carotid bodies (Sun et al., 1999a,b). This same laboratory later demonstrated that gene transfer of nNOS to carotid bodies of CHF rabbits substantially blunted both the augmented chemosensitivity and the sustained sympathoexcitation that occur in CHF. Although these studies establish that nitric oxide is inhibitory in the carotid body and that NOS expression may be regulated in specific disease states, there are no prior studies suggesting that CIH exposure decreases NOS expression in the carotid body. In fact, Di Giulio et al. (2003) demonstrated increased carotid body NOS expression after 12 days of continuous hypoxia (10% O2 ) in rats. In contrast, however, Kusakabe et al. (1998) showed that rats exposed to more prolonged hypoxia (10% O2 with 3–4% CO2 for 3 months) had reduced numbers of NOS immunoreactive fibers in their carotid bodies. Few studies have examined the effect of CIH on NOS expression in the carotid body, but Marcus et al. (2010) recently demonstrated significant reductions in nNOS protein in carotid bodies of CIH-exposed relative to Sham-exposed rats, and our own unpublished data suggest that not only is NOS message and protein reduced after CIH exposure (Fig. 1) but the functional responses to the NO-donor S-nitroso-Nacetyl-d,l-penicillamine (SNAP) (Fig. 2) and to the neuronal nitric
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Fig. 1. (A) Representative RT-PCR result of neuronal NOS mRNA in carotid bodies from rats exposed to room air Sham or cyclic intermittent hypoxia (CIH) for 8 h/day for 5 weeks. PCR product was not detected if reverse transcriptase was omitted from the reaction in tubes (Actin (−)). (B) Relative nNOS mRNA amount in carotid bodies of Sham and CIH rats. Data are mean of percent of sham ± SD. (C) Representative Western blot result of neuronal NOS protein in Sham and CIH carotid bodies. (D) Relative nNOS protein amount in carotid bodies of Sham and CIH rats. Data are mean ± SD. All data were from three individual experiments running in triplicates, n = 5 in each group (*P < 0.005).
Discharge of CSN (% of baseline)
oxide synthase inhibitor (l-omega-nitro arginine (l-NNA), data not presented) support decreased functional NO generation in the carotid bodies of CIH-exposed rats. Carotid chemosensory afferent activity is not the only determinant of sympathetic activity. Outflow from post-ganglionic renal sympathetic nerves is modulated by input from pre-ganglionic neurons in the spinal cord which, in turn, receive input from sympathetic pre-motor neurons in a number of locations in the central nervous system including the rostral ventral lateral medulla (RVLM), the medullary raphe, the A5 area of the pons, and the paraventricular nucleus (PVN) of the hypothalamus (Dampney et al., 700 600
Sham CIH
500
**
400
** ##
300 200 100 0 Control
SNAP
Fig. 2. Carotid sinus nerve activity (CSN, whole nerve recording) in response to treatment with endothelin-1 before (Control) and after treatment with the NOdonor S-nitroso-N-acetyl-d,l-penicillamine (SNAP). Open bars represent recordings from rats exposed to room air sham (Sham, n = 5) while closed bars represent rats exposed to cyclic intermittent hypoxia (CIH, n = 5). All exposures were for 8 h/day for 5 weeks. CSN increases in response to endothelin in both Sham and CIH exposed rats but the increase is greater in CIH exposed animals. The nitric oxide donor SNAP significantly reduces CSN response in both Sham and in CIH exposed rats but the decrease is significantly greater in CIH animals (**P < 0.05; ##P < 0.01).
2003). In addition, these pre-motor neurons receive input from a wide variety of CNS locations including neurons within the circumventricular organs (CVO) in the lamina terminalis (Dampney et al., 2003, 2005). Evidence suggests that all these regions may be involved in states of pathological sympathoexcitation, with greatest attention recently on the role of the PVN, RVLM and subfornical organ (SFO) in several animal models of sustained hypertension – SHR and Dahl-sensitive rats (DiBona, 2004) – and in the heightened sympathetic activity that is associated with congestive heart failure (CHF) (Felder et al., 2003). While modulation of sympathetic activity within the PVN is complex, a number of studies suggest that sustained sympathoexcitation can occur as a consequence of down regulation of neuronal nitric oxide synthase (nNOS) in neurons in the PVN because such neurons are sympathoinhibitory (Campese et al., 2002, 2004; Zhang et al., 1997). Patel and colleagues have established that reduced NOS expression in PVN is one contributor to heightened sympathetic activity after induction of CHF in rats (Patel, 2000). We have previously reported that 5-week CIH exposure decreases expression of nNOS message in neurons of the PVN (Huang et al., 2007). Recently, Coleman et al. (2010) reported that the essential NMDA receptor constituent, NR1, has reduced surface/synaptic availability in nNOS containing neurons in the PVN of mice exposed for 35 days to CIH. Immunogold staining revealed increased density of NR1 particles in cytoplasm, suggesting the defect was in transporting the NR1 components to the cell membrane. NO production, as measured by NO-sensitive fluorescent dye, was reduced after CIH. This altered NR1 trafficking was associated with increased arterial pressure in the CIH exposed animals. Interestingly, the changes in NR1 trafficking and NO production were not present after 14 days of exposure, but were evident after 35 days. This does not correspond to the time course of development of hypertension after CIH exposure (Kanagy et al., 2001) suggesting altered NO production may sustain altered sympathetic activity but may not initiate the increase in sympathetic outflow.
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Nevertheless, we speculate that decreased NO bioavailability in the PVN, in part due to decreased NOS expression, contributes to increased sympathetic outflow after CIH exposure.
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exposure, leads to NOS uncoupling and consequent reduced nitric oxide bioavailability in these tissues. 5. Conclusion
4. NO and vascular tone in OSA Thus, there is evidence suggesting decreased NO bioavailability in carotid body and PVN contributes to sympathoexcitation after CIH exposure. There are equally compelling data suggesting decreased NO bioavailability contributes to impaired vasodilation in OSA patients exposed to nocturnal desaturations and in CIH exposed rats. Carlson et al. (1995) were the first to report impaired endothelium-dependent vasodilation in OSA patients compared to age, sex and weight matched non-apneic controls. Forearm blood flow after intra-arterial acetylcholine (ACh) was reduced in patients compared to controls and patients had higher minimal vascular resistance after SNP. Kato studied OSA patients at the time of diagnosis, before any therapy, and also found a reduced response to ACh relative to weight matched control individuals but responses to SNP and verapamil were similar between the groups (Kato et al., 2000). More recently, Lattimore et al. (2006) measured endothelium dependent (ACh) and endothelium independent (SNP) responses in OSA patients before and after 3 months of CPAP treatment. They also assessed forearm vascular response to intra-arterial administration of the NOS inhibitor l-NMMA. After CPAP the response to ACh increased and there was a greater reduction in flow after l-NMMA, but the response to SNP was unchanged, findings consistent with improved nitric oxide mediated endothelium dependent vasodilation. Tahawi, working in Fletcher’s laboratory, used CIHexposed rats to examine in vivo responses of cremasteric arterioles to norepinephrine (NE), endothelin-1 (ET-1), Ach and the NOS inhibitor l-NAME (Tahawi et al., 2001). CIH exposed rats had attenuated ACh induced vasodilation relative to sham-exposed animals. The degree of vasoconstriction to l-NAME was also reduced in CIH animals compared with sham rats. Responses to NE and ET-1 were not different between the groups. The effect of CIH exposure on arterial eNOS expression has not been well studied but Jelic et al. (2008) harvested venous endothelial cells from OSA patients and control subjects. They performed immunofluorescence staining for eNOS protein, phosphorylated eNOS, and markers of oxidative stress (nitrotyrosine). Expression of eNOS and phosphorylated eNOS were significantly reduced in patients relative to controls while nitrotyrosine was increased. Effective CPAP treatment resulted in substantial increases in eNOS and phosphorylated eNOS and reductions in nitrotyrosine. These studies and our own preliminary data below are the basis for our hypotheses that CIH exposure reduces NO bioavailability, both in areas of sympathoregulation and in endothelium. This reduced bioavailability contributes to sustained sympathoexcitation and reduced arterial vasodilation, which, in turn, produce arterial hypertension. One cause of reduced bioavailability, down regulation of constitutive nitric oxide synthase expression (Kavdia and Popel, 2004), is supported by our preliminary studies. Another mechanism that might cause reduced bioavailability, uncoupling of NOS activity where the enzyme produces superoxide (O2 − ) instead of NO• , and/or the scavenging of NO• by increased production of reactive oxygen species (ROS), has not been examined in humans or animals exposed to CIH. Nevertheless, there is evidence to suggest that such NOS “uncoupling” may also contribute to decreased NO bioavailability after CIH exposure. Studies by Jelic et al. (2008) among others indicate increased ROS generation in human arterial endothelial cells after CIH exposure in sleep apnea. Peng et al. (2003) have provided evidence of increased ROS signaling in carotid bodies of mice after CIH exposure. We speculate that such increased ROS generation, produced in neural and endothelial tissue after CIH
In summary, substantial evidence links OSA, through nocturnal CIH, to arterial hypertension through sympathoexcitation and altered vascular reactivity. Published work suggests that a common mechanism for both sympathoexcitation and altered vascular function after CIH exposure is decreased availability of nitric oxide, in both neural tissue and in endothelium. Further studies are needed to determine whether altered NO bioavailability can account for the heightened sympathetic activity and reduced vascular dilation that characterize CIH exposure and obstructive sleep apnea. References Abdala, A.P., McBryde, F.D., Marina, N., Hendy, E.B., Engelman, Z.J., Fudim, M., Sobotka, P.A., Gourine, A.V., Paton, J.F.R. Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat. Journal of Physiology, in press. Bao, G., Metrevelli, N., Li, R., Taylor, A., Fletcher, E.C., 1997. Blood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system. Journal of Applied Physiology 83, 95–101. Brooks, D., Horner, R.L., Kimoff, R.J., Kozar, L.F., Render-Texeira, C.L., Phillipson, E.A., 1997a. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. American Journal of Respiratory and Critical Care Medicine 155, 1609–1617. Brooks, D., Horner, R.L., Kozar, L.F., Render-Texeira, C.L., Phillipson, E.A., 1997b. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model. Journal of Clinical Investigation 99, 109. Campese, V.M., Ye, S., Zhong, H., 2002. Downregulation of neuronal nitric oxide synthase and interleukin-1 mediates angiotensin II-dependent stimulation of sympathetic nerve activity. Hypertension 39, 519–524. Campese, V.M., Ye, S., Zhong, H., Yanamadala, V., Ye, Z., Chiu, J., 2004. Reactive oxygen species stimulate central and peripheral sympathetic nervous system activity. American Journal of Physiology – Heart and Circulatory Physiology 287, H695–H703. Carlson, J., Rangemark, C., Hedner, J., 1995. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnoea. Journal of Hypertension 14, 577–584. Carlson, J.T., Hedner, J., Elam, M., Ejnell, H., Sellgren, J., Wallin, B.G., 1993. Augmented resting sympathetic nerve activity in awake patients with obstructive sleep apnea. Chest 103, 1763–1768. Coleman, C.G., Wang, G., Park, L., Anrather, J., Delagrammatikas, G.J., Chan, J., Zhou, J., Iadecola, C., Pickel, V.M., 2010. Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. Journal of Neuroscience 30, 12103–12112. Dampney, R.A.L., Horiuchi, J., Killinger, S., Sherrif, M.J., Tan, P.S.P., McDowall, L.M., 2005. Long-term regulation of arterial pressure by hypothalamic nuclei: some critical questions. Clinical and Experimental Pharmacology and Physiology 32, 419–425. Dampney, R.A.L., Horiuchi, J., Tagawa, T., Fontes, M.A.P., Potts, P.D., Polson, J.W., 2003. Medullary and supramedullary mechanisms regulating sympathetic vasomotor tone. Acta Physiologica 177, 209–218. Di Giulio, C., Huang, W.X., Mokashi, A., Roy, A., Cacchio, M., Macri, M.A., Lahiri, S., 2003. Sustained hypoxia promotes hyperactive response of carotid body in the cat. Respiratory Physiology and Neurobiology 134, 69–74. DiBona, G.F., 2004. The sympathetic nervous system and hypertension: recent developments. Hypertension 43, 147–150. Felder, R.B., Francis, J., Zhang, Z.-H., Wei, S.-G., Weiss, R.M., Johnson, A.K., 2003. Heart failure and the brain: new perspectives. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 284, R259–R276. Fletcher, E.C., Lesske, J., Qian, W., Miller, C.C.I., Unger, T., 1992. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 19, 555–561. Gujic, M., Laude, D., Houssiere, A., Beloka, S., Argacha, J.F., Adamopoulos, D., Xhaet, O., Elghozi, J.L., van de Borne, P., 2007. Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human. Journal of Physiology 585, 165–174. Hedner, J., Wilcox, I., Laks, L., Grunstein, R.R., Sullivan, C.E., 1992. A specific and potent pressor effect of hypoxia in patients with sleep apnea. American Review of Respiratory Disease 146, 1240–1245. Hla, K.M., Young, T.B., Bidwell, T., Palta, M., Skatrud, J.B., Dempsey, J., 1994. Sleep apnea and hypertension: a population-based study. Annals of Internal Medicine 120, 382–388. Huang, J., Tamisier, R., Ji, E., Tong, J., Weiss, W.J., 2007. Chronic intermittent hypoxia modulates nNOS mRNA and protein expression in the rat hypothalamus. Respiratory Physiology and Neurobiology 158, 30–38.
196
J.W. Weiss et al. / Respiratory Physiology & Neurobiology 184 (2012) 192–196
Imadojemu, V.A., Gleeson, K., Quraishi, S.A., Kunselman, A.R., Sinoway, L.I., Leuenberger, U.A., 2002. Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy. American Journal of Respiratory and Critical Care Medicine 165, 950–953. Jelic, S., Padeletti, M., Kawut, S.M., Higgins, C., Canfield, S.M., Onat, D., Colombo, P.C., Basner, R.C., Factor, P., LeJemtel, T.H., 2008. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 117, 2270–2278. Kanagy, N.L., Walker, B.R., Nelin, L.D., 2001. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension 37 (Part 2), 511–515. Kato, M., Roberts-Thomson, P., Phillips, B.G., Haynes, W.G., Winnicki, M., Accurso, V., Somers, V.K., 2000. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 102, 2607–2610. Kavdia, M., Popel, A.S., 2004. Contribution of nNOS- and eNOS-derived NO to microvascular smooth muscle NO exposure. Journal of Applied Physiology 97, 293–301. Kusakabe, T., Matsuda, H., Harada, Y., Hayashida, Y., Gono, Y., Kawakami, T., Takenaka, T., 1998. Changes in the distribution of nitric oxide synthase immunoreactive nerve fibers in the chronically hypoxic rat carotid body. Brain Research 795, 292–296. Lattimore, J.L., Wilcox, I., Skilton, M., Langenfeld, M., Celermajer, D.S., 2006. Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation. Thorax 61, 491–495. Marcus, N.J., Li, Y.L., Bird, C.E., Schultz, H.D., Morgan, B.J., 2010. Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: role of the angiotensin II type 1 receptor. Respiratory Physiology and Neurobiology 171, 36–45. Nieto, F.J., Young, T.B., Lind, B.K., Shahar, E., Samet, J.M., Redline, S., D’Agostino, R.B., Newman, A.B., Lebowitz, M.D., Pickering, T.G., 2000. Association of sleepdisordered breathing sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283, 1829–1836. Osborn, J.L., Plato, C.F., Gordon, E., He, X.R., 1997. Long-term increases in renal sympathetic nerve activity and hypertension. Clinical and Experimental Pharmacology and Physiology 24, 72–76. Patel, K.P., 2000. Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. Heart Failure Reviews 5, 73–86. Peng, Y., Kline, D.D., Dick, T.E., Prabhakar, N.R., 2001. Chronic intermittent hypoxia enhances carotid body chemoreceptor response to low oxygen. In: Poon, Kazemi, H. (Eds.), Frontiers in Modeling and Control of Breathing. Kluwer Academic/Plenum Publishers, New York, pp. 33–37.
Peng, Y.-J., Overholt, J.L., Kline, D., Kumar, G.K., Prabhakar, N.R., 2003. Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proceedings of the National Academy of Sciences 100, 10073–10078. Prabhakar, N.R., Kumar, G.K., Chang, H.C., Agani, F.H., Haxhiu, M.A., 1993. Nitric oxide in the sensory function of the carotid body. Brain Research 625, 16–22. Remsberg, S., Launois, S.H., Weiss, J.W., 1999. Patients with obstructive sleep apnea have an abnormal peripheral vascular response to hypoxia. Journal of Applied Physiology 87, 1148–1153. Schoorlemmer, G.H.M., Rossi, M.V., Tufik, S., Cravo, S.L., 2011. A new method to produce obstructive sleep apnoea in conscious unrestrained rats. Experimental Physiology 96, 1010–1018. Summers, B.A., Overholt, J.L., Prabhakar, N.R., 1999. Nitric oxide inhibits L-type Ca2+ current in glomus cells of the rabbit carotid body via a cGMP-independent mechanism. Journal of Neurophysiology 81, 1449–1457. Sun, S.Y., Wang, W., Zucker, I.H., Schultz, H.D., 1999a. Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. Journal of Applied Physiology 86, 1273–1282. Sun, S.Y., Wang, W., Zucker, I.H., Schultz, H.D., 1999b. Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. Journal of Applied Physiology 86, 1264–1272. Tahawi, Z., Orolinova, N., Joshua, I.G., Bader, M., Fletcher, E.C., 2001. Selected contribution: altered vascular reactivity in arterioles of chronic intermittent hypoxic rats. Journal of Applied Physiology 90, 2007–2013. Tun, Y., Hida, W., Okabe, S., Kikuchi, Y., Kurosawa, H., Tabata, M., Shirato, K., 2000. Effects of nasal continuous positive airway pressure on awake ventilatory responses to hypoxia and hypercapnia in patients with obstructive sleep apnea. Tohoku Journal of Experimental Medicine 190, 157–168. Wang, Z.-Z., Bredt, D.S., Fidone, S., Stensaas, L., 1993. Neurons synthesizing nitric oxide innervate the mammalian carotid body. Journal of Comparative Neurology 336, 419–432. Waradeker, N.V., Sinoway, L.I., Zwillich, C.W., Leuenberger, U.A., 1996. Influence of treatment on muscle sympathetic nerve activity in sleep apnea. American Journal of Respiratory and Critical Care Medicine 153, 1333–1338. Young, T., Palta, M., Dempsey, J., Skatrud, J.B., Weber, S., Badr, S., 1993. The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine 328, 1230–1235. Zhang, K., Mayhan, W.G., Patel, K.P., 1997. Nitric oxide within the paraventricular nucleus mediates changes in renal sympathetic nerve activity. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology 273, R864–R872.