Inflammation and oxidative stress during intermittent hypoxia: the impact on chemoreception
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(2) 150. R. Iturriaga and others. sleep breathing disorder, produces partial or complete obstruction of the upper airway during sleep. The resulting airflow interruption causes hypoxia and hypercapnia, negative intrathoraxic pressure, sleep fragmentation and arousal. Among these disturbances, the chronic intermittent hypoxia (CIH) is considered the main factor for the development of systemic diurnal hypertension (Gozal & Kheirandish-Gozal, 2008; Somers et al. 2008). Oxidative stress, inflammation and sympathetic overactivity have been proposed as potential mechanisms involved in OSA-induced hypertension (Somers et al. 2008; Garvey at al. 2009; Dempsey et al. 2010). However, conclusions from studies performed in OSA patients are masked by concomitant comorbidities (Somers et al. 2008). Thus, rodent models exposed to CIH have been developed to mimic the cardiovascular alterations induced by OSA (Fletcher et al. 1992; Peng et al. 2003; Iturriaga et al. 2009). Similar to what is observed in OSA patients (Narkiewicz et al. 1999; Somers et al. 2008), animals exposed to CIH display potentiated sympathetic responses to hypoxia and develop systemic hypertension (Fletcher et al. 1992; Peng et al. 2003; Rey et al. 2004). In addition, CIH-treated animals show enhanced hypoxic ventilatory responses to hypoxia (Rey et al. 2004; Iturriaga et al. 2009; Del Rio et al. 2010). Although Fletcher et al. (1992) found that CB denervation prevented the hypertension in rats exposed to CIH, the idea that the CB may contribute to the progression of the hypertension did not receive much attention. However, carotid sinus nerve recordings performed in animal OSA models have shown that CIH selectively enhances CB chemosensory discharges in normoxia and hypoxia (Peng et al. 2003; Rey et al. 2004; Iturriaga et al. 2009). In addition, Peng et al. (2003) found that CIH produced long-term facilitation of baseline CB discharges following repetitive acute intermittent hypoxia.. Contribution of oxidative stress to the CIH-induced potentiation of the CB chemosensory discharge. Reactive oxygen species and reactive nitrogen species have been proposed as mediators of cardiovascular and cognitive alterations in OSA patients (Somers et al. 2008; Garvey at al. 2009; Dempsey et al. 2010) and animal models of OSA (Del Rio et al. 2010; Peng & Prabhakar, 2003). Studies in rats showed that CIH for 10–21 days produces systemic and local CB oxidative stress (Peng & Prabhakar, 2003; Iturriaga et al. 2009; Del Rio et al. 2010, 2011). Peng & Prabhakar (2003) found that pretreatment for 10 days before CIH with a superoxide dismutase mimetic prevents the rat CB chemosensory potentiation, suggesting that superoxide contributes to enhance CB chemoreception. Also, they found a decrease in the activity of the reactive oxygen species (ROS)-sensitive enzyme. Exp Physiol 100.2 (2015) pp 149–155. aconitase, as well as a reduced activity of the complex I of the mitochondrial electron transport chain, suggesting that the mitochondrion is one of the sources of ROS. More recently, the same group reported evidence that ROS generated by NADPH oxidase (NOX) also contribute to the CB chemosensory potentiation (Peng et al. 2009). We tested whether local CB oxidative stress play a role in the CB chemosensory potentiation and the progression of hypertension in rats exposed to CIH (Del Rio et al. 2010). We measured 3-nitrotyrosine (3-NT) accumulation in the CB as an index of oxidative stress. Superoxide reacts with NO to generate peroxynitrite, a powerful oxidizing agent that nitrates tyrosine residues, forming 3-NT. We found an excessive 3-NT accumulation within CB type I cells and blood vessels in CBs harvested from rats exposed to CIH, which paralleled the enhanced CB chemosensory responses to hypoxia (Del Rio et al. 2010, 2011). In addition, CIH increased plasma lipid peroxidation, enhanced the ventilatory responses to hypoxia and evoked hypertension. Ascorbic acid treatment concomitant with the exposure to CIH reduced the increased plasma lipid peroxidation and the 3-NT accumulation in the CB, reduced the potentiation of the CB chemosensory and ventilatory responses to hypoxia and prevented the hypertension (Del Rio et al. 2010).. Role of pro-inflammatory cytokines in the enhanced CB chemosensory responses induced by CIH. The available evidence suggests that oxidative stress is necessary to potentiate CB hypoxic chemoreception. However, it is a matter of debate whether ROS per se may increase the CB chemosensory discharge (Gonzalez et al. 2007). Thus, it is plausible that molecules downstream of the ROS signalling are responsible for the CB chemosensory potentiation. Indeed, CIH increases the levels of the CB excitatory modulators endothelin-1 (Rey et al. 2006; Pawar et al. 2009; Iturriaga, 2013; Peng et al. 2013) and angiotensin II in the CB (Marcus et al. 2010; Lam et al. 2014) and reduces the levels of the inhibitory modulator NO (Moya et al. 2012). In addition, recent evidence has shown that sustained and intermittent hypoxia may increase the levels of pro-inflammatory cytokines in the CB, with potential implications in OSA (Powell, 2009, Porzionato et al. 2013). Indeed, rat CB type I cells produce interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), with their corresponding receptors. In addition, these cytokines can modulate CB type I cell excitability, neurotransmitter release and chemosensory discharges (Zapata et al. 2011; Porzionato et al. 2013). Shu et al. (2007) found that exogenous application of IL-1β to isolated rat type I cells reduced the O2 -dependent K+ currents, increased the intracellular [Ca2+ ] and increased the C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society.
(3) 151. Carotid body inflammation and intermittent hypoxia. chemosensory discharge in the whole CB. Lam et al. (2012) reported that exposure of rats to intermittent hypoxia for 7 days increased the expression of IL-1β, TNF-α and IL-6 in the CB. Moreover, they found macrophage infiltration, which was reduced by daily treatment with the anti-inflammatory drug dexamethasone or ibuprofen. We found that CIH progressively increases the immunoreactive levels of TNF-α and IL-1β in the rat CB without changing their plasma levels, suggesting a potential role for these cytokines in modulating. A. Sham. CIH. CIH+AA. 200. 200. 100 0. B. 300 200. 200. 100. 100. 0 0 20 40 60 80 100 Time (s). CIH+IBU. 300. fx (Hz). 300. fx (Hz). 300. fx (Hz). the enhanced CB chemosensory activity following CIH (Del Rio et al. 2011). It is known that oxidative stress increases the gene expression and synthesis of pro-inflammatory cytokines, mediated by activation of the transcription factor nuclear factor-κB, activator protein 1 and hypoxia-inducible factor-1α (Prabhakar & Semenza, 2012). In response to oxidative stress, hypoxia-inducible factor-1α evokes translocation of nuclear factor-κB to the nucleus, augmenting the expression of pro-inflammatory genes such as IL-1β, TNF-α, inducible nitric oxide. fx (Hz). Exp Physiol 100.2 (2015) pp 149–155. 0 20 40 60 80 100 Time (s). Sham. 0 20 40 60 80 100 Time (s). CIH. 100 0. 0. CIH+AA. 0 20 40 60 80 100 Time (s). CIH+IBU Normoxia. 0.5 mV 2s. Hypoxia 0.5 mV 2s. Hyperoxia 0.5 mV 2s. C. D Normoxia. Hypoxia 300. 80. fx (Hz). fx (Hz). 120. 40. 200. 100. 0 Sham. CIH. CIH+AA CIH+IBU. 0 Sham. CIH. CIH+AA CIH+IBU. Figure 1. Chronic intermitten hypoxia (CIH)-induced potentiation of carotid body (CB) chemosensory discharge A, effects of ascorbic acid (AA) and ibuprofen (IBU) on the CB chemosensory discharge in rats exposed to CIH for 21 days. Abbreviation: ƒx , CB chemosensory frequency of discharge, expressed in herz. Filled bars indicate hypoxia (10% O2 ). B, representative carotid sinus nerve electroneurograms from rats exposed to CIH and treated with AA or IBU. Note that Dejours test (100% O2 ) shows no differences between all groups. C and D, summary of the effect of CIH on ƒx during normoxia (21% O2 ; C) and hypoxia (10% O2 ; D). ∗∗ P < 0.01 and ∗∗∗ P < 0.001 verus Sham, Neuman–Keuls test after one-way ANOVA. n = 8 rats in each group. This figure is based in part on data previously published in Eur Respir J July 2010 36:143–150; Published ahead of print December 8, 2009, doi:10.1183/09031936.00158109 and Eur Respir J June 2012 39:1492–1500; Published ahead of Print December 19, 2011, doi:10.1183/09031936.0014151, and reproduced with permission of the European Respiratory Society.. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society.
(4) R. Iturriaga and others. synthase and endothelin-1. Accordingly, we found that CBs harvested from rats exposed to CIH for 21 days displayed higher levels of the p65 subunit of nuclear factor-κB, suggesting a plausible role for this factor in the upregulation of pro-inflammatory cytokines during CIH (Del Rio et al. 2012a).. Testing the hypothesis that pro-inflammatory cytokines contribute to the CIH-induced CB chemosensory potentiation. Chronic intermittent hypoxia increases the TNF-α- and IL-1β-immunoreactive levels in the CB, suggesting a potential role for these pro-inflammatory cytokines in modulating the enhanced CB chemosensory activity following CIH (Del Rio et al. 2011). Thus, we investigated whether these cytokines contribute to the CIH-induced CB chemosensory potentiation. We found that ibuprofen, which prevents the CIH-induced increased TNF-α and IL-1β in the CB, failed to impede the potentiation of the CB chemosensory responses to hypoxia, although it effectively prevented the enhanced ventilatory responses to hypoxia and the hypertension (Del Rio et al. 2012b). Figure 1 shows the effects of antioxidant (i.e. ascorbic acid) and anti-inflammatory (i.e. ibuprofen) treatments on the CB chemosensory discharge measured in normoxia and hypoxia from rats exposed to CIH for 21 days. Figure 1A and B illustrates representative recordings of carotid sinus nerve discharges induced by short hypoxic challenges in a sham rat (a rat exposed to air:air cycles instead of a rat exposed to intermittent hypoxia) and in a rat exposed to CIH for 21 days. As is shown in Fig. 1B, CIH increased baseline chemosensory discharges in normoxia and enhanced the chemosensory responses to hypoxia, although no differences were observed between the responses to hyperoxic stimuli. Figure 1C and D summarizes the effects of ascorbic acid and ibuprofen on CB chemosensory discharges measured in normoxia and in response to 10% O2 . Ascorbic acid effectively prevented both the increase in CB chemosensory discharges in normoxia and in response to hypoxia in rats that underwent CIH (Del Rio et al. 2010). In contrast, ibuprofen treatment had no significant effect on the CIH-induced CB discharge potentiation to hypoxia, but prevented the potentiation of CB chemosensory discharges in normoxic conditions (Del Rio et al. 2012b). Figure 2 summarizes the effects of antioxidant and anti-inflammatory treatment on the CB chemosensory responses to several inspired oxygen levels. Two-way ANOVA showed that the overall CB chemosensory curve for P O2 was different in CIH- and CIH-plus-ibuprofen-treated rats (P 0.001) relative to the other groups. A post hoc test showed that CB chemosensory discharge in rats exposed to CIH was. Exp Physiol 100.2 (2015) pp 149–155. higher, not only in the hypoxic range but also in normoxia. Ascorbic acid treatment prevented both hypoxic and normoxic CB chemosensory potentiation, while ibuprofen prevented the potentiation of the normoxic CB chemosensory discharge (P O2 of 140 mmHg) but did not reduce the chemosensory potentiation in the hypoxic range (P O2 < 140 mmHg). Although Lam et al. (2008) reported that the intracellular [Ca2+ ] in CB glomus cells increases with the application of IL-1β and IL-6, and Shu et al. (2007) found that IL-1β and TNF-α may modify the carotid sinus nerve discharge, the fact that pro-inflammatory cytokines produce chemosensory excitation is not well established. Indeed, O’Connor et al. (2012) found that that IL-1β, IL-6 and TNF-α did not elicit changes of vagal paraganglia discharge during normoxia or hypoxia, recorded from the rat superior laryngeal nerve. Chronic intermittent hypoxia-induced cardiorespiratory alterations in normoxia: are the pro-inflammatory cytokines necessary?. Following 21 days of CIH, there is a significant increase in 3-NT formation within the CB (Del Rio et al. 2010). As shown in Fig. 3, ibuprofen did not reduce the increase in 3-NT levels (P > 0.05) compared with rats exposed to CIH that did not receive the anti-inflammatory drug. Given that ibuprofen prevented the increase of TNF-α and IL-1β. 300 CIH CIH+AA CIH+IBU Sham. 200 fx (Hz). 152. 100. 0 0. 100. 200. 300 400 500 PO2 (mmHg). 600. 700. Figure 2. Effects of ascorbic acid (AA) and ibuprofen (IBU) on the CIH-induced CB chemosensory alterations Abbreviation: ƒx , carotid chemosensory frequency of discharge, expressed in herz, recorded at several values of P O2 . ∗ P < 0.05, ∗∗∗ P < 0.001, CIH versus Sham and + P < 0.05, +++ P < 0.001, CIH+IBU versus Sham, Bonferroni test after two-way ANOVA. n = 8 rats in each group. This figure is based in part on data previously published in Eur Respir J July 2010 36:143–150; Published ahead of print December 8, 2009, doi:10.1183/09031936.00158109 and Eur Respir J June 2012 39:1492–1500; Published ahead of Print December 19, 2011, doi:10.1183/09031936.0014151, and reproduced with permission of the European Respiratory Society. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society.
(5) Carotid body inflammation and intermittent hypoxia. Exp Physiol 100.2 (2015) pp 149–155. levels in the CB but failed to impede the formation of 3-NT, it is likely that the enhanced CB chemosensory responses to hypoxia rely on the oxidative stress. Interestingly, our results show a clear dissociation between the effects of pro-inflammatory cytokines on chemosensory discharges during normoxia and hypoxia. Ibuprofen treatment, which did not reduce the CIH-induced oxidative stress in the CB and failed to prevent the increase in hypoxic CB chemosensory discharges induced by CIH, was able to reduce the normoxic chemosensory discharges (Del Rio et al. 2012b). Thus, pro-inflammatory cytokines may contribute to increase the baseline discharge in normoxia, increasing the tonic CB chemosensory drive to the central cardiorespiratory control centres. Accordingly, we found that ibuprofen treatment effectively prevents the development of ventilatory acclimatization as well as the hypertension induced by CIH (Del Rio et al. 2012). Furthermore, we found that ibuprofen markedly reduces the CIH-induced activation of c-fos-positive neurons in the nucleus tractus solitarii (NTS; Del Rio et al. 2012b). It is important to note that the NTS is considered to be the first region where the respiratory gas and blood pressure sensory afferent inputs are primarily integrated (Kumar & Prabhakar, 2012). Thus, it is plausible that the enhanced CB chemoreflex drive in normoxia, as a result of a pro-inflammatory CB state, leads to the cardiorespiratory acclimatization during CIH. However, we cannot rule out a direct effect of pro-inflammatory cytokines on ventilatory and blood pressure control centres located in. A. B. Integrated optical density. Sham. CIH+IBU. CIH. 100 80 60 40 20 0. Sham. CIH. CIH+IBU. Figure 3. Oxidative stress in the CB of rats exposed to CIH is not prevented by ibuprofen treatment A, micrograph showing 3-nitrotyrosine accumulation in the CBs from a sham-treated rat, a rat exposed to CIH and rat exposed to CIH and treated with IBU. B, summary of the effects of ibuprofen on 3-nitrotyrosine formation. ∗∗∗ P < 0.001, CIH versus Sham and +++ P < 0.001, CIH+IBU versus Sham, Neuman–Keuls test after one-way ANOVA. n = 8 rats in each group. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society. 153. the CNS. This interpretation is supported by the fact that ibuprofen reduced both the increased ventilatory hypoxic response and the increased IL-1 and IL-6 levels in the brainstem of rats exposed to chronic hypoxia, suggesting that inflammatory processes in the CNS contribute to the ventilatory acclimatization elicited by sustained hypoxia (Popa et al. 2011). In addition, inflammation in the NTS has been proposed to contribute to the development of neurogenic hypertension. Indeed, Waki et al. (2010) found that pro-inflammatory molecules, such as the junctional adhesion molecule 1, were highly expressed in the NTS of spontaneously hypertensive rats, suggesting that cytokines and chemokines may contribute to hypertension by increasing the neuronal activity in the NTS.. Perspectives. Chronic intermittent hypoxia enhances ventilatory and cardiovascular responses to acute hypoxia, suggesting a major role for the CB in the pathophysiology of OSA. New evidence has shown that CIH elicits oxidative stress in the CB, which contributes to enhance the chemosensory discharges in normoxia and hypoxia, but the exact nature of the molecular targets of the oxidative stress involved in the chemosensory potentiation remains to be elucidated. Based on the available experimental evidence, CIH increases the levels of pro-inflammatory cytokines within the CB, and anti-inflammatory treatment markedly reduces the tonic CB afferent discharge in normoxia but fails to decrease the CB hypoxic response. Thus, it is plausible that the effect of ROS on CB chemoreception is mediated by molecules produced downstream of the ROS signal, which may modulate CB oxygen sensing. acting on blood vessels and/or glomus cells. Increased endothelin-1 and angiotensin II and decreased NO levels in the CB have been proposed as possible mediators of the chemosensory potentiation induced by CIH. Interestingly, all these molecules are downstream targets of the increased ROS production that takes place following CIH. Indeed, it has been shown that ROS are key contributors to the enhanced CB response to hypoxia and to the augmented tonic discharges. However, the end-target molecular entity responsible for the increased neural reactivity to hypoxia in CIH is still debatable. In addition, we provide evidence that CIH increases the levels of pro-inflammatory cytokines in the CB. Nevertheless, no studies have shown the molecular pathways affected by pro-inflammatory molecules in the CB exposed to CIH. Therefore, future studies designed to explain how the CIH-induced oxidative stress and pro-inflammatory cytokines alter ion channel function, intracellular Ca2+ dynamics and transmitter release in the CB glomus cells will provide new insights into the pathophysiology of OSA..
(6) 154. R. Iturriaga and others. References Del Rio R, Moya EA & Iturriaga R (2010). Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link. Eur Respir J 36, 143–150. Del Rio R, Moya EA & Iturriaga R (2011). Differential expression of pro-inflammatory cytokines, endothelin-1 and nitric oxide synthases in the rat carotid body exposed to intermittent hypoxia. Brain Res 1395, 74–85. Del Rio R, Moya EA & Iturriaga R (2012a). Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia. Adv Exp Med Biol 758, 199–205. Del Rio R, Moya EA, Parga MJ, Madrid C & Iturriaga R (2012b). Carotid body inflammation and cardiorespiratory alterations in intermittent hypoxia. Eur Respir J 39, 1492–1500. Dempsey JA, Veasey SC, Morgan BJ & O’Donnell CP (2010). Pathophysiology of sleep apnea. Physiol Rev 90, 47–112. Fletcher EC, Lesske J, Behm R, Miller CC 3rd, Stauss H & Unger T (1992). Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea. J Appl Physiol 72, 1978–1984. Garvey JF, Taylor CT & McNicholas WT (2009). Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. Eur Resp J 33, 1195–1205. Gonzalez C, Agapito MT, Rocher A, Gonzalez-Martin MC, Vega-Agapito V, Gomez-Niño A, Rigual R, Castañeda J & Obeso A (2007). Chemoreception in the context of the general biology of ROS. Respir Physiol Neurobiol 157, 30–44. Gozal D & Kheirandish-Gozal L (2008). Cardiovascular morbidity in obstructive sleep apnea, oxidative stress, inflammation, and much more. Am J Respir Crit Care Med 177, 369–375. Iturriaga R (2013). Intermittent hypoxia: endothelin-1 and hypoxic carotid body chemosensory potentiation. Exp Physiol 98, 1550–1551. Iturriaga R, Moya EA & Del Rio R (2009). Carotid body potentiation induced by intermittent hypoxia: implications for cardiorespiratory changes induced by sleep apnoea. Clin Exp Pharmacol Physiol 36, 1197–1204. Kumar P & Prabhakar NR (2012). Peripheral chemoreceptors: function and plasticity of the carotid body. Compr Physiol 2, 141–219. Lam SY, Liu Y, Ng KM, Lau CF, Liong EC, Tipoe GL & Fung ML (2012). Chronic intermittent hypoxia induces local inflammation of the rat carotid body via functional upregulation of proinflammatory cytokine pathways. Histochem Cell Biol 137, 303–317. Lam SY, Liu Y, Ng KM, Liong EC, Tipoe GL, Leung PS & Fung ML (2014). Upregulation of a local renin–angiotensin system in the rat carotid body during chronic intermittent hypoxia. Exp Physiol 99, 220–231. Lam SY, Tipoe GL, Liong EC & Fung ML (2008). Chronic proinflammatory cytokines in the rat carotid body. Histochem Cell Biol 130, 549–559. Marcus NJ, Li YL, Bird CE, Schultz HD & Morgan BJ (2010). Chronic intermittent hypoxia augments chemoreflex control. Exp Physiol 100.2 (2015) pp 149–155. of sympathetic activity: role of the angiotensin II type 1 receptor. Respir Physiol Neurobiol 171, 36–45. Moya EA, Alcayaga J & Iturriaga R (2012). NO modulation of carotid body chemoreception in health and disease. Respir Physiol Neurobiol 184, 158–164. Narkiewicz K, Van De Borne PJ, Pesek CA, Dyken ME, Montano N & Somers VK (1999). Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99, 1183–1189. O’Connor ET, O’Halloran KD & Jones JF (2012). Pro-inflammatory cytokines do not affect basal or hypoxia-stimulated discharge of rat vagal paraganglia. Exp Physiol 97, 1203–1210. Paton JF, Sobotka PA, Fudim M, Engleman ZJ, Hart EC, McBryde FD, Abdala AP, Marina N, Gourine AV, Lobo M, Patel N, Burchell A, Ratcliffe L & Nightingale A (2013). The carotid body as a therapeutic target for the treatment of sympathetically mediated diseases. Hypertension 61, 5–13. Pawar A, Nanduri J, Yuan G, Khan SA, Wang N, Kumar GK & Prabhakar NR (2009). Reactive oxygen species-dependent endothelin signaling is required for augmented hypoxic sensory response of the neonatal carotid body by intermittent hypoxia. Am J Physiol Regul Integr Comp Physiol 296, R735–R742. Peng YJ, Nanduri J, Raghuraman G, Wang N, Kumar GK & Prabhakar NR (2013). Role of oxidative stress-induced endothelin-converting enzyme activity in the alteration of carotid body function by chronic intermittent hypoxia. Exp Physiol 98, 1620–1630. Peng YJ, Nanduri J, Yuan G, Wang N, Deneris E, Pendyala S, Natarajan V, Kumar GK & Prabhakar NR (2009). NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29, 4903–4910. Peng YJ, Overholt JL, Kline D, Kumar GK & Prabhakar NR (2003). Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas. Proc Natl Acad Sci USA 100, 10073–10078. Peng YJ & Prabhakar NR (2003). Reactive oxygen species in the plasticity of respiratory behavior elicited by chronic intermittent hypoxia. J Appl Physiol 94, 2342–2349. Popa D, Fu Z, Go A & Powell FL (2011). Ibuprofen blocks time-dependent increases in hypoxic ventilation in rats. Respir Physiol Neurobiol 178, 381–386. Powell FL (2009). Adaptation to chronic hypoxia involves immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. Am J Physiol Lung Cell Mol Physiol 296, L156–L157. Porzionato A, Macchi V, De Caro R & Di Giulio C (2013). Inflammatory and immunomodulatory mechanisms in the carotid body. Respir Physiol Neurobiol 187, 31–40. Prabhakar NR & Semenza GL (2012). Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92, 967–1003. Rey S, Del Rio R, Alcayaga J & Iturriaga R (2004). Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia. J Physiol 560, 577–586.. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society.
(7) Exp Physiol 100.2 (2015) pp 149–155. Carotid body inflammation and intermittent hypoxia. Rey S, Del Rio R & Iturriaga R (2006). Contribution of endothelin-1 to the enhanced carotid body chemosensory responses induced by chronic intermittent hypoxia. Brain Res 1086, 152–159. Shu HF, Wang BR, Wang SR, Yao W, Huang HP, Zhou Z, Wang X, Fan J, Wang T & Ju G (2007). IL-1β inhibits IK and increases [Ca2+ ]i in the carotid body glomus cells and increases carotid sinus nerve firings in the rat. Eur J Neurosci 25, 3638–3647. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Russell R, Woo M, & Young T (2008). Sleep apnea and cardiovascular disease an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 52, 686–717.. C 2014 The Authors. Experimental Physiology C 2014 The Physiological Society. 155. Waki H, Gouraud SS, Maeda M & Paton JF (2010). Evidence of specific inflammatory condition in nucleus tractus solitarii of spontaneously hypertensive rats. Exp Physiol 95, 595– 600. Zapata P, Larraı́n C, Reyes P & Fernández R (2011). Immunosensory signalling by carotid body chemoreceptors. Respir Physiol Neurobiol 178, 370–374.. Additional information Competing interests None declared. Funding This work was supported by grants FONDECYT 1100405 and Puente/28 VRI-PUC, Chile..
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