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1.  Chronic intermittent hypoxia increases rat sternohyoid muscle NADPH oxidase expression with attendant modest oxidative stress 
Chronic intermittent hypoxia (CIH) causes upper airway muscle dysfunction. We hypothesized that the superoxide generating NADPH oxidase (NOX) is upregulated in CIH-exposed muscle causing oxidative stress. Adult male Wistar rats were exposed to intermittent hypoxia (5% O2 at the nadir for 90 s followed by 210 s of normoxia), for 8 h per day for 14 days. The effect of CIH exposure on the expression of NOX subunits, total myosin and 4-hydroxynonenal (4-HNE) protein adducts in sternohyoid muscle was determined by western blotting and densitometry. Sternohyoid protein free thiol and carbonyl group contents were determined by 1D electrophoresis using specific fluorophore probes. Aconitase and glutathione reductase activities were measured as indices of oxidative stress. HIF-1α content and key oxidative and glycolytic enzyme activities were determined. Contractile properties of sternohyoid muscle were determined ex vivo in the absence and presence of apocynin (putative NOX inhibitor). We observed an increase in NOX 2 and p47 phox expression in CIH-exposed sternohyoid muscle with decreased aconitase and glutathione reductase activities. There was no evidence, however, of increased lipid peroxidation or protein oxidation in CIH-exposed muscle. CIH exposure did not affect sternohyoid HIF-1α content or aldolase, lactate dehydrogenase, or glyceraldehyde-3-phosphate dehydrogenase activities. Citrate synthase activity was also unaffected by CIH exposure. Apocynin significantly increased sternohyoid force and power. We conclude that CIH exposure upregulates NOX expression in rat sternohyoid muscle with concomitant modest oxidative stress but it does not result in a HIF-1α-dependent increase in glycolytic enzyme activity. Constitutive NOX activity decreases sternohyoid force and power. Our results implicate NOX-dependent reactive oxygen species in CIH-induced upper airway muscle dysfunction which likely relates to redox modulation of key regulatory proteins in excitation-contraction coupling.
doi:10.3389/fphys.2015.00015
PMCID: PMC4311627
apocynin; intermittent hypoxia; NADPH oxidase; oxidative stress; respiratory muscle; sternohyoid; sleep apnea; upper airway
2.  CHRONIC INTERMITTENT HYPOXIA AFFECTS INTEGRATION OF SENSORY INPUT BY NEURONS IN THE NUCLEUS TRACTUS SOLITARII 
The autonomic nervous and respiratory systems, as well as their coupling, adapt over a wide range of conditions. Chronic intermittent hypoxia (CIH) is a model for recurrent apneas and induces alterations in breathing and increases in sympathetic nerve activity which may ultimately result in hypertension if left untreated. These alterations are believed to be due to increases in the carotid body chemoreflex pathway. Here we present evidence that the nucleus tractus solitarii (nTS), the central brainstem termination site of chemoreceptor afferents, expresses a form of synaptic plasticity that increases overall nTS activity following intermittent hypoxia. Following CIH, an increase in presynaptic spontaneous neurotransmitter release occurs under baseline conditions. Furthermore, during and following afferent stimulation there is an augmentation of spontaneous transmitter release that occurs out of synchrony with sensory stimulation. On the other hand, afferent evoked synchronous transmitter release is attenuated. Overall, this shift from synchronous to asynchronous transmitter release enhances nTS cellular discharge. The role of the neurotransmitter dopamine in CIH-induced plasticity is also discussed. Dopamine attenuates synaptic transmission in nTS cells by blockade of N-type calcium channels, and this mechanism occurs tonically following normoxia and CIH. This dopaminergic pathway, however, is not altered in CIH. Taken together, alterations in nTS synaptic activity may play a role in the changes of chemoreflex function and cardiorespiratory activity in the CIH apnea model.
doi:10.1016/j.resp.2010.04.015
PMCID: PMC2953573  PMID: 20416405
chemoreflex; cardiovascular; baroreflex; respiration; synaptic transmission; action potential
3.  Glucoregulatory Consequences and Cardiorespiratory Parameters in Rats Exposed to Chronic–Intermittent Hypoxia: Effects of the Duration of Exposure and Losartan 
Background: Obstructive sleep apnea (OSA) is associated with glucose intolerance. Both chronic sleep disruption and recurrent blood oxygen desaturations (chronic–intermittent hypoxia, CIH) may cause, or exacerbate, metabolic derangements. Methods: To assess the impact of CIH alone, without accompanying upper airway obstructions, on the counter-regulatory response to glucose load and cardiorespiratory parameters, we exposed adult male Sprague-Dawley rats to CIH or sham room air exchanges for 10 h/day for 7, 21, or 35 days and then, 1 day after conclusion of CIH exposure, conducted intravenous glucose-tolerance tests (ivgtt) under urethane anesthesia. Additional rats underwent 35 days of CIH followed by 35 days of regular housing, or had 35 day-long CIH exposure combined with daily administration of the type 1 angiotensin II receptor antagonist, losartan (15 mg/kg, p.o.), and then were also subjected to ivgtt. Results: Compared with the corresponding control groups, CIH rats had progressively reduced glucose-stimulated insulin release and impaired glucose clearance, only mildly elevated heart rate and/or arterial blood pressure and slightly reduced respiratory rate. The differences in insulin release between the CIH and sham-treated rats disappeared in the rats normally housed for 35 days after 35 days of CIH/sham exposure. The losartan-treated rats had improved insulin sensitivity, with no evidence of suppressed insulin release in the CIH group. Conclusion: In adult rats, the glucose-stimulated insulin release is gradually suppressed with the duration of exposure to CIH, but the effect is reversible. Elimination of the detrimental effect of CIH on insulin release by losartan suggests that CIH disrupts glucoregulation through angiotensin/catecholaminergic pathways. Accordingly, treatment with continuous positive airway pressure may ameliorate pre-diabetic conditions in OSA patients, in part, by reducing sympathoexcitatory effects of recurrent nocturnal hypoxia.
doi:10.3389/fneur.2012.00051
PMCID: PMC3321439  PMID: 22509173
angiotensin II; blood pressure; diabetes; intravenous glucose-tolerance test; insulin; norepinephrine; obstructive sleep apnea; sympathetic system
4.  NADPH oxidase is required for the Sensory Plasticity of the Carotid body by Chronic Intermittent Hypoxia 
Respiratory moto-neuron response to hypoxia is reflex in nature and carotid body sensory receptor constitutes the afferent limb of this reflex. Recent studies showed that repetitive exposures to hypoxia evokes long term facilitation of sensory nerve discharge (sLTF) of the carotid body in rodents exposed to chronic intermittent hypoxia (CIH). Although studies with anti-oxidants suggested the involvement of reactive oxygen species (ROS)-mediated signaling in eliciting sLTF, the source of and the mechanisms associated with ROS generation have not yet been investigated. We tested the hypothesis that ROS generated by NADPH oxidase (NOX) mediate CIH-evoked sLTF. Experiments were performed on ex vivo carotid bodies from rats and mice exposed either to 10 days of CIH or normoxia. Acute repetitive hypoxia evoked a ~12 fold increase in NOX activity in CIH but not in control carotid bodies, and this effect was associated with up-regulation of NOX2 mRNA and protein, which was primarily localized to glomus cells of the carotid body. sLTF was prevented by NOX inhibitors and was absent in mice deficient in NOX2. NOX activation by CIH required 5-HT release and activation of 5-HT2 receptors coupled to PKC signaling. Studies with ROS scavengers revealed that H2O2 generated from O2·− contributes to sLTF. Priming with H2O2 elicited sLTF of carotid bodies from normoxic control rats and mice, similar to that seen in CIH treated animals. These observations reveal a novel role for NOX-induced ROS signaling in mediating sensory plasticity of the carotid body.
doi:10.1523/JNEUROSCI.4768-08.2009
PMCID: PMC2692682  PMID: 19369559
NADPH oxidase; intermittent hypoxia; sensory plasticity; recurrent apneas; sympathetic excitation; chemosensory
5.  Carotid body potentiation during chronic intermittent hypoxia: implication for hypertension 
Autonomic dysfunction is involved in the development of hypertension in humans with obstructive sleep apnea, and animals exposed to chronic intermittent hypoxia (CIH). It has been proposed that a crucial step in the development of the hypertension is the potentiation of the carotid body (CB) chemosensory responses to hypoxia, but the temporal progression of the CB chemosensory, autonomic and hypertensive changes induced by CIH are not known. We tested the hypothesis that CB potentiation precedes the autonomic imbalance and the hypertension in rats exposed to CIH. Thus, we studied the changes in CB chemosensory and ventilatory responsiveness to hypoxia, the spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and arterial blood pressure in pentobarbital anesthetized rats exposed to CIH for 7, 14, and 21 days. After 7 days of CIH, CB chemosensory and ventilatory responses to hypoxia were enhanced, while BRS was significantly reduced by 2-fold in CIH-rats compared to sham-rats. These alterations persisted until 21 days of CIH. After 14 days, CIH shifted the HRV power spectra suggesting a predominance of sympathetic over parasympathetic tone. In contrast, hypertension was found after 21 days of CIH. Concomitant changes between the gain of spectral HRV, BRS, and ventilatory hypoxic chemoreflex showed that the CIH-induced BRS attenuation preceded the HRV changes. CIH induced a simultaneous decrease of the BRS gain along with an increase of the hypoxic ventilatory gain. Present results show that CIH-induced persistent hypertension was preceded by early changes in CB chemosensory control of cardiorespiratory and autonomic function.
doi:10.3389/fphys.2014.00434
PMCID: PMC4228839  PMID: 25429271
carotid body; intermittent hypoxia; autonomic imbalance; hypertension
6.  The Role of NADPH Oxidase in Chronic Intermittent Hypoxia-Induced Pulmonary Hypertension in Mice 
Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2−·) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase–derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor β and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase–derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.
doi:10.1165/rcmb.2008-0145OC
PMCID: PMC2677439  PMID: 18952568
hypoxia; pulmonary hypertension; nitric oxide; NADPH oxidase
7.  The efficacy of antihypertensive drugs in chronic intermittent hypoxia conditions 
Sleep apnea/hypopnea disorders include centrally originated diseases and obstructive sleep apnea (OSA). This last condition is renowned as a frequent secondary cause of hypertension (HT). The mechanisms involved in the pathogenesis of HT can be summarized in relation to two main pathways: sympathetic nervous system stimulation mediated mainly by activation of carotid body (CB) chemoreflexes and/or asphyxia, and, by no means the least important, the systemic effects of chronic intermittent hypoxia (CIH). The use of animal models has revealed that CIH is the critical stimulus underlying sympathetic activity and hypertension, and that this effect requires the presence of functional arterial chemoreceptors, which are hyperactive in CIH. These models of CIH mimic the HT observed in humans and allow the study of CIH independently without the mechanical obstruction component. The effect of continuous positive airway pressure (CPAP), the gold standard treatment for OSA patients, to reduce blood pressure seems to be modest and concomitant antihypertensive therapy is still required. We focus this review on the efficacy of pharmacological interventions to revert HT associated with CIH conditions in both animal models and humans. First, we explore the experimental animal models, developed to mimic HT related to CIH, which have been used to investigate the effect of antihypertensive drugs (AHDs). Second, we review what is known about drug efficacy to reverse HT induced by CIH in animals. Moreover, findings in humans with OSA are cited to demonstrate the lack of strong evidence for the establishment of a first-line antihypertensive regimen for these patients. Indeed, specific therapeutic guidelines for the pharmacological treatment of HT in these patients are still lacking. Finally, we discuss the future perspectives concerning the non-pharmacological and pharmacological management of this particular type of HT.
doi:10.3389/fphys.2014.00361
PMCID: PMC4170135  PMID: 25295010
antihypertensive drugs; blood pressure; chronic intermittent hypoxia; hypertension; obstructive sleep apnea
8.  Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia 
Previous studies suggest that carotid body responses to long-term changes in environmental oxygen differ between neonates and adults. In the present study we tested the hypothesis that the effects of chronic intermittent hypoxia (CIH) on the carotid body differ between neonates and adult rats. Experiments were performed on neonatal (1–10 days) and adult (6–8 wk) males exposed either to CIH (9 episodes/h; 8 h/day) or to normoxia. Sensory activity was recorded from ex vivo carotid bodies. CIH augmented the hypoxic sensory response (HSR) in both groups. The magnitude of CIH-evoked hypoxic sensitization was significantly greater in neonates than in adults. Seventy-two episodes of CIH were sufficient to evoke hypoxic sensitization in neonates, whereas as many as 720 CIH episodes were required in adults, suggesting that neonatal carotid bodies are more sensitive to CIH than adult carotid bodies. CIH-induced hypoxic sensitization was reversed in adult rats after reexposure to 10 days of normoxia, whereas the effects of neonatal CIH persisted into adult life (2 mo). Acute intermittent hypoxia (IH) evoked sensory long-term facilitation of the carotid body activity (sensory LTF, i.e., increased baseline neural activity following acute IH) in CIH-exposed adults but not in neonates. The effects of CIH were associated with hyperplasia of glomus cells in neonatal but not in adult carotid bodies. These observations demonstrate that responses to CIH differ between neonates and adults with regard to the magnitude of sensitization of HSR, susceptibility to CIH, induction of sensory LTF, reversibility of the responses, and morphological remodeling of the chemoreceptor tissue.
doi:10.1152/japplphysiol.00644.2007
PMCID: PMC3893879  PMID: 18187605
sensory long-term facilitation; hyperplasia; glomus cells
9.  Erectile Dysfunction in a Murine Model of Sleep Apnea 
Rationale: Erectile dysfunction (ED) is frequent in obstructive sleep apnea syndrome (OSAS). Chronic intermittent hypoxia (CIH), one of the hallmarks of OSAS, could mediate ED.
Objectives: To determine whether intermittent hypoxia during sleep affects erectile dysfunction in mice.
Methods: Three groups of C57BL/6 mice were exposed to CIH for 5 or 24 weeks. Sexual function was evaluated by in vivo telemetry of corpus spongiosum pressure. Spontaneous erections, sexual activity during mating, and noncontact tests were assessed after 5 weeks of CIH and after treatment with tadalafil. Plasma testosterone was measured after 8 and 24 weeks of CIH, and the expression of nitric oxide synthase (NOS) isoforms was examined in penile tissue.
Measurements and Main Results: Noncontact, spontaneous, and contact sexual activity in the mice was suppressed after CIH. Spontaneous erection counts decreased after the first week of CIH by 55% (P < 0.001) and remained unchanged thereafter. Recovery of erectile activity during normoxia for 6 weeks was incomplete. Compared with control mice, latencies for mounts and intromissions increased by 60- and 40-fold, respectively (P < 0.001), and the sexual activity index decreased sixfold. Tadalafil treatment significantly attenuated these effects. Immunoblot analyses of NOS proteins in the erectile tissue showed decreased expression of endothelial NOS after CIH (P < 0.01), with no changes in plasma testosterone levels after 8 and 24 weeks of CIH.
Conclusions: CIH during sleep is associated with decreased libido in mice. The decreased expression of endothelial NOS protein in erectile tissue and the favorable response to tadalafil suggest that altered nitric oxide mechanisms underlie CIH-mediated ED. No changes in testosterone emerge after intermittent hypoxia.
doi:10.1164/rccm.200801-190OC
PMCID: PMC2542437  PMID: 18535258
nitric oxide synthase; erectile dysfunction; sleep apnea; intermittent hypoxia
10.  Role of Oxidative Stress Induced Endothelin Converting Enzyme Activity in the Alteration of Carotid Body Function by Chronic Intermittent Hypoxia 
Experimental physiology  2013;98(11):10.1113/expphysiol.2013.073700.
Chronic intermittent hypoxia (CIH) leads to remodeling of the carotid body function manifested by augmented sensory response to hypoxia and induction of sensory long-term facilitation (LTF). It was proposed that endothelin-1 (ET-1) contributes to CIH-induced hypoxic hypersensitivity of the carotid body. The objectives of the present study were: a) to delineate the mechanisms by which CIH up regulates ET-1 expression in the carotid body, and b) to assess whether ET-1 also contributes to sensory LTF. Experiments were performed on adult, male rats exposed to alternating cycles of 5% O2 (15s) and room air (5min), 9 episodes/hr and 8hr/day for 10 days. CIH increased ET-1 levels in glomus cells without significantly altering preproendothelin-1 mRNA levels. The activity of endothelin-converting enzyme (ECE) increased with concomitant elevation of ET-1 levels in CIH exposed carotid bodies, and MnTMPyP, a membrane permeable antioxidant prevented these effects. Hypoxia facilitated ET-1 release from CIH-treated carotid body, a requisite for activation of ET receptors; however, hypoxia had no effect on ET-1 release from control carotid bodies. In CIH exposed carotid bodies, mRNAs encoding ETA receptor were up regulated and an ETA receptor specific antagonist abolished CIH-induced hypersensitivity of the hypoxic response, whereas it had no effect on the sensory LTF. These results suggest that ECE-dependent increased production of ET-1 coupled with hypoxia-evoked ET-1 release and the ensuing ETA receptor activation mediate the CIH-induced carotid body hypersensitivity to hypoxia, but the ETA signaling pathway is not associated with sensory LTF elicited by CIH.
doi:10.1113/expphysiol.2013.073700
PMCID: PMC3808500  PMID: 23913764
Recurrent apnea; endothelin-converting enzyme; endothelin-1 release; ETA receptors
11.  Endothelin 1–Dependent Neurovascular Dysfunction in Chronic Intermittent Hypoxia 
Hypertension  2012;60(1):106-113.
Obstructive sleep apnea, a condition resulting in chronic intermittent hypoxia (CIH), is an independent risk factor for stroke and dementia, but the mechanisms of the effect are unknown. We tested the hypothesis that CIH increases cerebrovascular risk by altering critical mechanisms regulating cerebral blood flow thereby lowering cerebrovascular reserves. Male C57Bl6/J mice were subjected to CIH (10% O2 for 90 seconds/room air for 90 seconds; during sleep hours) or sham treatment for 35 days. Somatosensory cortex blood flow was assessed by laser Doppler flowmetry in anesthetized mice equipped with a cranial window. CIH increased mean arterial pressure (from 74±2 to 83±3 mm Hg; P<0.05) and attenuated the blood flow increase produced by neural activity (whisker stimulation; −39±2%; P<0.05) or neocortical application of endothelium-dependent vasodilators (acetylcholine response: −41±3%; P<0.05). The cerebrovascular dysfunction was associated with oxidative stress in cerebral resistance arterioles and was abrogated by free radical scavenging or NADPH oxidase inhibition. Furthermore, cerebrovascular dysfunction and free radical increase were not observed in mice lacking the NOX2 subunit of NADPH oxidase. CIH markedly increased endothelin 1 in cerebral blood vessels, whereas cerebrovascular dysfunction and oxidative stress were abrogated by neocortical application of the endothelin type A receptor antagonist BQ123. These data demonstrate for the first time that CIH alters key regulatory mechanisms of the cerebral circulation through endothelin 1 and NADPH oxidase– derived radicals. The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain’s susceptibility to cerebral ischemia.
doi:10.1161/HYPERTENSIONAHA.112.193672
PMCID: PMC3529143  PMID: 22689747
obstructive sleep apnea; reactive oxygen species; neurovascular coupling; endothelium-dependent vasodilation
12.  Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus 
Chronic intermittent hypoxia (CIH) is a concomitant of sleep apnea that produces a slowly developing chemosensory-dependent blood pressure elevation ascribed in part to NMDA receptor-dependent plasticity and reduced nitric oxide (NO) signaling in the carotid body. The hypothalamic paraventricular nucleus (PVN) is responsive to hypoxic stress and also contains neurons that express NMDA receptors and neuronal nitric oxide synthase (nNOS). We tested the hypothesis that extended (35 day) CIH results in a decrease in the surface/synaptic availability of the essential NMDA NR1 subunit in nNOS-containing neurons and NMDA-induced NO production in the PVN of mice. As compared with controls, the 35 day CIH-exposed mice showed a significant increase in blood pressure and an increased density of NR1 immunogold particles located in the cytoplasm of nNOS-containing dendrites. Neither of these between-group differences was seen after 14 days, even though there was already a reduction in the NR1 plasmalemmal density at this time point. Patch-clamp recording of PVN neurons in slices showed a significant reduction in NMDA currents after either 14 or 35 day exposure to CIH as compared with sham controls. In contrast, NO production, as measured by the NO-sensitive fluorescent dye DAF-FM, was suppressed only in the 35 day CIH group. We conclude that CIH produces a reduction in the surface/synaptic targeting of NR1 in nNOS neurons and decreases NMDA receptor-mediated currents in the PVN prior to the emergence of hypertension, the development of which may be enabled by suppression of NO signaling in this brain region.
doi:10.1523/JNEUROSCI.3367-10.2010
PMCID: PMC2951676  PMID: 20826673
hypertension; sleep apnea; sympathetic nerve activity; NR1; immunocytochemistry; electron microscopy
13.  Resetting of the sympathetic baroreflex is associated with the onset of hypertension during chronic intermittent hypoxia 
Chronic intermittent hypoxia (CIH) is a model of the arterial hypoxemia that accompanies sleep apnea and increases resting arterial pressure (AP). We examined the effects of 7 days exposure to CIH on arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats. Sprague-Dawley rats (15 +/− 2 weeks old) were exposed to CIH (9% oxygen for 3min every 10 min, 8 h per day) for 7 days (n = 16) while control rats (n = 18) were maintained in normoxia. Baroreflex regulation of RSNA and HR were estimated in Inactin anesthetized and artificially ventilated rats during infusions of phenylephrine and nitroprusside to manipulate AP. After exposure to CIH, resting mean AP was higher in CIH than in control group (115 +/− 7 vs. 105 +/− 7, P<0.001). Resting HR did not differ between the two groups. Exposure to CIH shifted the AP-RSNA relationship rightward (approximately 10 mmHg, P<0.01). CIH did not alter maximum gain of the baroreflex control of RSNA (−2.6 +/− 0.6 vs. −2.5 +/− 0.6 arbitrary units (au)/mmHg) and HR (−1.8 +/− 0.6 vs. −1.8 +/− 0.7 bpm/mmHg, CIH vs. control). In addition, cardiac spontaneous baroreflex sensitivity in conscious rats (n = 8) also did not change during exposure to CIH. These results indicate that resetting of the sympathetic baroreflex control, rather than an impairment of its sensitivity, is associated with an onset of hypertension induced by CIH.
doi:10.1016/j.autneu.2012.10.015
PMCID: PMC3529839  PMID: 23167993
sleep apnea; hypertension; sympathetic nerve activity; baroreflex
14.  Molecular Mechanisms of Chronic Intermittent Hypoxia and Hypertension 
Obstructive sleep apnea (OSA) is characterized by episodes of repeated airway obstruction resulting in cessation (apnea) or reduction (hypopnea) in airflow during sleep. These events lead to intermittent hypoxia and hypercapnia, sleep fragmentation, and changes in intrathoracic pressure, and are associated with a marked surge in sympathetic activity and an abrupt increase in blood pressure. Blood pressure remains elevated during wakefulness despite the absence of obstructive events resulting in a high prevalence of hypertension in patients with OSA. There is substantial evidence that suggests that chronic intermittent hypoxia (CIH) leads to sustained sympathoexcitation during the day and changes in vasculature resulting in hypertension in patients with OSA. Mechanisms of sympathoexcitation include augmentation of peripheral chemoreflex sensitivity and a direct effect on central sites of sympathetic regulation. Interestingly, the vascular changes that occur with CIH have been ascribed to the same molecules that have been implicated in the augmented sympathetic tone in CIH. This review will discuss the hypothesized molecular mechanisms involved in the development of hypertension with CIH, will build a conceptual model for the development of hypertension following CIH, and will propose a systems biology approach in further elucidating the relationship between CIH and the development of hypertension.
PMCID: PMC3634614  PMID: 23140119
obstructive sleep apnea; hypertension; chronic intermittent hypoxia; sympathoexcitation; systems biology
15.  An essential role for ΔFosB in the median preoptic nucleus in the sustained hypertensive effects of chronic intermittent hypoxia 
Hypertension  2012;60(1):179-187.
One of the main clinical features of obstructive sleep apnea (OSA) is sustained hypertension and elevated sympathetic activity during waking hours. Chronic intermittent hypoxia (CIH), animal model of the hypoxemia associated with OSA, produces a similar sustained increase in blood pressure. This study determined the role of ΔFosB in the median preoptic nucleus (MnPO) in the sustained increase in mean arterial pressure (MAP) associated with CIH. Rats were injected in the MnPO with viral vectors that expressed green fluorescent protein (GFP) alone or GFP plus a dominant negative construct that inhibits the transcriptional effects of ΔFosB. In GFP injected rats and uninjected controls, 7 day exposure to CIH increased MAP by 7–10 mmHg during both intermittent hypoxia exposure and normoxia. Dominant negative inhibition of MnPO ΔFosB did not affect changes in MAP during intermittent hypoxia exposure but significantly reduced the sustained component of the blood pressure response to CIH during the normoxic dark phase. Inhibition of MnPO ΔFosB reduced the FosB/ΔFosB staining in the paraventricular nucleus and rostral ventrolateral medulla but not the nucleus of the solitary tract. PCR-array analysis identified five AP-1 regulated genes expressed in the MnPO that were increased by CIH exposure: ace1, ace2, nos1, nos3, prdx2, and map3k3. Dominant negative inhibition of ΔFosB in the MnPO blocked increased expression of each of these genes in rats exposed to CIH except for Prdx2. ΔFosB may mediate transcriptional activity in MnPO necessary for sustained CIH hypertension suggesting that neural adaptations may contribute to diurnal hypertension in OSA.
doi:10.1161/HYPERTENSIONAHA.112.193789
PMCID: PMC3415378  PMID: 22689746
hypertension; sleep apnea; angiotensin; hypothalamus; sympathetic nervous system
16.  EFFECT OF AT1 RECEPTOR BLOCKADE ON INTERMITTENT HYPOXIA-INDUCED ENDOTHELIAL DYSFUNCTION 
Chronic intermittent hypoxia (CIH) raises arterial pressure, impairs vasodilator responsiveness, and increases circulating angiotensin II (Ang II); however, the role of Ang II in CIH-induced vascular dysfunction is unknown. Rats were exposed to CIH or room air (NORM), and a subset of these animals was treated with losartan (Los) during the exposure period. After 28 days, vasodilatory responses to acetylcholine or nitroprusside were measured in isolated gracilis arteries. Superoxide levels and Ang II receptor protein expression were measured in saphenous arteries. After 28 days, arterial pressure was increased and acetylcholine-induced vasodilation was blunted in CIH vs. NORM, and this was prevented by Los. Responses to nitroprusside and superoxide levels did not differ between CIH and NORM. Expression of AT2R was decreased and the AT1R:AT2R ratio was increased in CIH vs. NORM, but this was unaffected by Los. These results indicate that the blood pressure elevation and endothelial dysfunction associated with CIH is dependent, at least in part, on RAS signaling.
doi:10.1016/j.resp.2012.05.025
PMCID: PMC3409315  PMID: 22728949
Intermittent hypoxia; Endothelial function; Angiotensin II
17.  Melatonin Attenuates Intermittent Hypoxia-Induced Lipid Peroxidation and Local Inflammation in Rat Adrenal Medulla 
Chronic intermittent hypoxia (CIH) induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague–Dawley rats were exposed to air (normoxic control) or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg) or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD)-1 and SOD-2) were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6) and mediators (inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)) were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome.
doi:10.3390/ijms151018437
PMCID: PMC4227224  PMID: 25314303
chronic intermittent hypoxia; cardiovascular; cellular injury; anti-oxidant
18.  Nitric Oxide and Superoxide Anion Balance in Rats Exposed to Chronic and Long Term Intermittent Hypoxia 
BioMed Research International  2014;2014:610474.
Work at high altitude in shifts exposes humans to a new form of chronic intermittent hypoxia, with still unknown health consequences. We have established a rat model resembling this situation, which develops a milder form of right ventricular hypertrophy and pulmonary artery remodelling compared to continuous chronic exposure. We aimed to compare the alterations in pulmonary artery nitric oxide (NO) availability induced by these forms of hypoxia and the mechanisms implicated. Rats were exposed for 46 days to normoxia or hypobaric hypoxia, either continuous (CH) or intermittent (2 day shifts, CIH2x2), and assessed: NO and superoxide anion availability (fluorescent indicators and confocal microscopy); expression of phosphorylated endothelial NO synthase (eNOS), NADPH-oxidase (p22phox), and 3-nitrotyrosine (western blotting); and NADPH-oxidase location (immunohistochemistry). Compared to normoxia, (1) NO availability was reduced and superoxide anion was increased in both hypoxic groups, with a larger effect in CH, (2) eNOS expression was only reduced in CH, (3) NADPH-oxidase was similarly increased in both hypoxic groups, and (4) 3-nitrotyrosine was increased to a larger extent in CH. In conclusion, intermittent hypoxia reduces NO availability through superoxide anion destruction, without reducing its synthesis, while continuous hypoxia affects both, producing larger nitrosative damage which could be related to the more severe cardiovascular alterations.
doi:10.1155/2014/610474
PMCID: PMC3955675  PMID: 24719876
19.  Adiponectin protects rat heart from left ventricular remodeling induced by chronic intermittent hypoxia via inhibition of TGF-β/smad2/3 pathway 
Journal of Thoracic Disease  2014;6(9):1278-1284.
Objective
Obstructive sleep apnea syndrome (OSAS) is associated with many cardiovascular disorders. Chronic intermittent hypoxia (CIH) is the primary player in OSAS of the many associated factors. This study was in order to investigate the effects of the Adiponectin (Ad) on left ventricular remodeling induced by CIH.
Methods
Forty-five rats were randomly divided into three groups: normal control (NC) group, CIH group and CIH plus Ad supplemented (CIH + Ad) group. After 35 days’ CIH exposure, masson analysis was used to detect the left ventricular fibrosis and western blot was used to measure the protein expression of collagen I, collagen III and TGF-β/smad2/3 pathway. Gene analysis by RT-PCR was used to study the MMP2 and TIMP2.
Results
After CIH exposure, the fibrosis of left ventricular in CIH group was significantly remarkable than that in both NC and CIH + Ad groups (P<0.05), although statistical difference existed between NC and CIH + Ad groups (P<0.05). In addition, the protein expression of collagen I as well as collagen III and the ratio of mRNA levels of MMP2/TIMP2 were the highest in CIH group but the lowest in NC group, with CIH + Ad group in between. There was a significant difference among three groups (all P<0.05). The TGF-β/smad2/3 pathway was activated obviously in CIH group, but less noticeably in CIH + Ad group (P<0.05) with a significant difference in the two groups.
Conclusions
The present study showed that Ad could ameliorate the left ventricular remodeling induced by CIH via inhibition of the expression of TGF-β/smad2/3 pathway.
doi:10.3978/j.issn.2072-1439.2014.07.44
PMCID: PMC4178112  PMID: 25276370
Chronic intermittent hypoxia (CIH); left ventricular remodeling; adiponectin
20.  Chronic Intermittent Hypoxia Alters Density of Aminergic Terminals and Receptors in the Hypoglossal Motor Nucleus 
Rationale: Patients with obstructive sleep apnea (OSA) adapt to the anatomical vulnerability of their upper airway by generating increased activity in upper airway–dilating muscles during wakefulness. Norepinephrine (NE) and serotonin (5-HT) mediate, through α1-adrenergic and 5-HT2A receptors, a wake-related excitatory drive to upper airway motoneurons. In patients with OSA, this drive is necessary to maintain their upper airway open. We tested whether chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, affects aminergic innervation of XII motoneurons that innervate tongue-protruding muscles in a manner that could alter their airway-dilatory action.
Objectives: To determine the impact of CIH on neurochemical markers of NE and 5-HT innervation of the XII nucleus.
Methods: NE and 5-HT terminal varicosities and α1-adrenergic and 5-HT2A receptors were immunohistochemically visualized and quantified in the XII nucleus in adult rats exposed to CIH or room air exchanges for 10 h/d for 34 to 40 days.
Measurements and Main Results: CIH-exposed rats had approximately 40% higher density of NE terminals and approximately 20% higher density of 5-HT terminals in the ventromedial quadrant of the XII nucleus, the region that controls tongue protruder muscles, than sham-treated rats. XII motoneurons expressing α1-adrenoceptors were also approximately 10% more numerous in CIH rats, whereas 5-HT2A receptor density tended to be lower in CIH rats.
Conclusions: CIH-elicited increase of NE and 5-HT terminal density and increased expression of α1-adrenoceptors in the XII nucleus may lead to augmentation of endogenous aminergic excitatory drives to XII motoneurons, thereby contributing to the increased upper airway motor tone in patients with OSA.
doi:10.1164/rccm.200912-1884OC
PMCID: PMC3001268  PMID: 20622040
chronic-intermittent hypoxia; hypoglossal motoneurons; obstructive sleep apnea; norepinephrine; serotonin
21.  Adiponectin Alleviates Genioglossal Mitochondrial Dysfunction in Rats Exposed to Intermittent Hypoxia 
PLoS ONE  2014;9(10):e109284.
Background
Genioglossal dysfunction is involved in the pathophysiology of obstructive sleep apnea hypoxia syndrome (OSAHS) characterized by nocturnal chronic intermittent hypoxia (CIH). The pathophysiology of genioglossal dysfunction and possible targeted pharmacotherapy for alleviation of genioglossal injury in CIH require further investigation.
Methodology/Principal Findings
Rats in the control group were exposed to normal air, while rats in the CIH group and CIH+adiponectin (AD) group were exposed to the same CIH condition (CIH 8 hr/day for 5 successive weeks). Furthermore, rats in CIH+AD group were administrated intravenous AD supplementation at the dosage of 10 µg, twice a week for 5 consecutive weeks. We found that CIH-induced genioglossus (GG) injury was correlated with mitochondrial dysfunction, reduction in the numbers of mitochondrias, impaired mitochondrial ultrastructure, and a reduction in type I fibers. Compared with the CIH group, impaired mitochondrial structure and function was significantly improved and a percentage of type I fiber was elevated in the CIH+AD group. Moreover, compared with the control group, the rats’ GG in the CIH group showed a significant decrease in phosphorylation of LKB1, AMPK, and PGC1-α, whereas there was significant rescue of such reduction in phosphorylation within the CIH+AD group.
Conclusions
CIH exposure reduces mitochondrial biogenesis and impairs mitochondrial function in GG, while AD supplementation increases mitochondrial contents and alleviates CIH-induced mitochondrial dysfunction possibly through the AMPK pathway.
doi:10.1371/journal.pone.0109284
PMCID: PMC4203718  PMID: 25329318
22.  Cyclic Intermittent Hypoxia Enhances Renal Sympathetic Response To ICV ET-1 In Conscious Rats 
To test the hypothesis that central changes in sympathoregulation might contribute to sympathoexcitation after cyclic intermittent hypoxia (CIH) we exposed male Sprague-Dawley rats to CIH or to room air sham (Sham) for 8 hours/d for 3 weeks. After completion of the exposure we assessed heart rate, mean arterial pressure and renal sympathetic nerve activity in conscious animals before and after intracerebroventricular (i.c.v.) administration of endothelin-1 (ET-1, 3 pmol). CIH-exposed animals had a significantly greater sympathetic response to ET-1 than did Sham-exposed animals (CIH 137.8 ± 15.6% of baseline; Sham 112.2 ± 10.0 % of baseline; CIH vs. Sham, P = 0.0373). This enhanced sympathetic response to i.c.v. ET-1 was associated with greater expression of endothelin receptor A (ETA) protein in the subfornical organs of CIH-exposed relative to Sham-exposed rats. We conclude that 3-week CIH exposure enhances central ET-1 receptor expression and the sympathetic response to i.c.v. ET-1 suggesting central endothelin may contribute to the sympathetic and hemodynamic response to cyclic intermittent hypoxia.
doi:10.1016/j.resp.2010.03.008
PMCID: PMC2884044  PMID: 20227529
Intermittent hypoxia; sympathetic nervous system; endothelin; subfornical organ; intracerebroventricular injection
23.  Chronic intermittent hypoxia reduces neurokinin-1 (NK1) receptor density in small dendrites of non-catecholaminergic neurons in mouse nucleus tractus solitarius 
Experimental neurology  2010;223(2):634-644.
Chronic intermittent hypoxia (CIH) is a frequent concomitant of sleep apnea, which can increase sympathetic nerve activity through mechanisms involving chemoreceptor inputs to the commissural nucleus of the solitary tract (cNTS). These chemosensory inputs co-store glutamate and substance P (SP), an endogenous ligand for neurokinin-1 (NK1) receptors. Acute hypoxia results in internalization of NK1 receptors, suggesting that CIH also may affect the subcellular distribution of NK1 receptors in subpopulations of cNTS neurons, some of which may express tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis (TH). To test this hypothesis, we examined dual immunolabeling for the NK1 receptor and TH in the cNTS of male mice subjected to 10 days or 35 days of CIH or intermittent air. Electron microscopy revealed that NK1 receptors and TH were almost exclusively localized within separate somatodendritic profiles in cNTS of control mice. In dendrites, immunogold particles identifying NK1 receptors were prevalent in the cytoplasm and on the plasmalemmal surface. Compared with controls, CIH produced a significant region-specific decrease in the cytoplasmic (10 and 35 days, P< 0.05, unpaired Student t-test) and extrasynaptic plasmalemmal (35 days, P< 0.01, unpaired Student t-test) density of NK1 immunogold particles exclusively in small (<0.1 µm) dendrites without TH immunoreactivity. These results suggest that CIH produces a duration-dependent reduction in the availability of NK1 receptors preferentially in small dendrites of non-catecholaminergic neurons in the cNTS. The implications of our findings are discussed with respect to their potential involvement in the slowly developing hypertension seen in sleep apnea patients.
doi:10.1016/j.expneurol.2010.02.013
PMCID: PMC2864350  PMID: 20206166
peptide receptors; sleep apnea; hypertension; respiratory reflexes; substance P
24.  Chronic intermittent hypoxia sensitizes acute hypothalamic-pituitary-adrenal stress reactivity and Fos induction in the rat locus coeruleus in response to subsequent immobilization stress 
Neuroscience  2008;154(4):1639-1647.
Obstructive sleep apnea (OSA) is associated with several pathophysiological conditions, including hypertension, obesity, insulin resistance, hypothalamic-pituitary-adrenal (HPA) dysregulation, and other endocrine and metabolic disturbances comprising the “metabolic syndrome”. Repeated episodes of hypoxia in OSA may represent a chronic intermittent stress, leading to HPA dysregulation. Alterations in HPA reactivity could then contribute to or exacerbate other pathophysiological processes. We showed previously that another metabolic stressor, chronic intermittent cold stress, enhanced noradrenergic facilitation of acute HPA stress reactivity. In this study, we investigated whether chronic intermittent hypoxia (CIH), a rat model for the arterial hypoxemia that accompanies OSA, similarly sensitizes the HPA response to novel acute stress. Rats were exposed to CIH (alternating cycles of normoxia [3 min at 21% O2] and hypoxia [3 min at 10% O2], repeated continuously for 8 hr/day during the light portion of the cycle for 7 days). On the day after the final CIH exposure, there were no differences in baseline plasma ACTH, but the peak ACTH response to 30 min acute immobilization stress was greater in CIH-stressed rats than in controls. Induction of Fos expression by acute immobilization stress was comparable following CIH in several HPA-modulatory brain regions, including the paraventricular nucleus, bed nucleus of the stria terminalis, and amygdala. Fos induction was attenuated in lateral hypothalamus, an HPA-inhibitory region. By contrast, acute Fos induction was enhanced in noradrenergic neurons in the locus coeruleus following CIH exposure. Thus, similar to chronic cold stress, CIH sensitized acute HPA- and noradrenergic stress reactivity. Plasticity in the acute stress response is important for long-term adaptation, but may also contribute to pathophysiological conditions associated with states of chronic or repeated stress, such as OSA. Determining the neural mechanisms underlying these adaptations may help us better understand the etiology of such disorders, and inform the development of more effective treatments.
doi:10.1016/j.neuroscience.2008.04.068
PMCID: PMC2522385  PMID: 18554809
adrenocorticotropic hormone; metabolic syndrome; norepinephrine; obstructive sleep apnea; paraventricular nucleus; stress
25.  Resveratrol attenuates intermittent hypoxia-induced insulin resistance in rats: Involvement of Sirtuin 1 and the phosphatidylinositol-4,5-bisphosphate 3-kinase/AKT pathway 
Molecular Medicine Reports  2014;11(1):151-158.
Obstructive sleep apnea can induce chronic intermittent hypoxia (CIH) during sleep and is associated with obesity and diabetes. Resveratrol (RSV), a polyphenolic phytoalexin, can regulate glucose metabolism, thereby reducing insulin resistance. The present study aimed to assess whether RSV attenuates CIH-induced insulin resistance in rats and the underlying mechanisms. A total of 40 rats were randomly assigned into five groups: i) Control; ii) subjected to CIH only; iii) subjected to CIH and treated with 3 mg/kg/day of RSV; iv) subjected to CIH and treated with 30 mg/kg/day of RSV; v) subjected to CIH and treated with 60 mg/kg/day of RSV. All animals were sacrificed following 28 days of treatment. Subsequently, the blood and livers were harvested and blood insulin and glucose levels were measured. Levels of sirtuin (Sirt) 1, insulin receptor (InsR) and glucose transporter 2 (Glut2) in the liver were measured. RSV treatment was demonstrated to suppress weight gain and improve hepatic morphology. RSV treatment also significantly reduced the homeostasis model assessment estimate of insulin resistance of the rats exposed to CIH. This effect occurred in a dose-dependent manner. RSV significantly upregulated liver Sirt1 levels and inhibited InsR and Glut2 expression in the liver. Additionally, RSV activated the phosphorylation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and AKT. The present study demonstrates that RSV prevents CIH-induced insulin resistance in rats. Upregulation of Sirt1 and activation of PI3K/AKT signaling may be involved in this process.
doi:10.3892/mmr.2014.2762
PMCID: PMC4237082  PMID: 25352008
resveratrol; intermittent hypoxia; insulin resistance; sirtuin 1; obstructive sleep apnea

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