The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes (P O 2 ∼ 75 Torr) repeated during 8 h for 2-4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg −1 I.P., followed by 8-12 mg I.V.), and ventilatory and cardiovascular responses to NaCN (0.1-100 µg kg −1 I.V.) and several isocapnic levels of oxygen (P O 2 ∼ 20-740 Torr) were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory (V T and V I ) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia (P O 2 < 100 Torr) were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity.

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Intermittent hypoxia, a feature of obstructive sleep apnoea, potentiates ventilatory hypoxic responses, alters heart rate variability and produces hypertension, partially owing to an enhanced carotid body responsiveness to hypoxia. Since oxidative stress is a potential mediator of both chemosensory and cardiorespiratory alterations, we hypothesised that an antioxidant treatment may prevent these alterations.Accordingly, we studied the effects of ascorbic acid (1.25 g?L -1 drinking water) on plasma lipid peroxidation, nitrotyrosine and inducible nitric oxide synthase (iNOS) immunoreactivity in the carotid body, ventilatory and carotid chemosensory responses to acute hypoxia, heart rate variability and arterial blood pressure in male Sprague-Dawley rats exposed to 5% O 2 ; 12 episodes?h -1; 8 h?day -1 or sham condition for 21 days.Intermittent hypoxia increased plasma lipid peroxidation, nitrotyrosine and iNOS expression in the carotid body, enhanced carotid chemosensory and ventilatory hypoxic responses, modified heart rate variability and produced hypertension. Ascorbic acid prevented the increased plasma lipid peroxidation and nitrotyrosine formation within the carotid body, and the enhanced carotid chemosensory and ventilatory responses to hypoxia, as well as heart rate variability alterations and hypertension.The present results support an essential role for oxidative stress in the generation of carotid body chemosensory potentiation and systemic cardiorespiratory alterations induced by intermittent hypoxia.

Chronic intermittent hypoxia (CIH), a main feature of obstructive sleep apnoea (OSA), increases hypoxic ventilatory responses and elicits hypertension, partially attributed to an enhance carotid body (CB) responsiveness to hypoxia. As inflammation has been involved in CIHinduced hypertension and chemosensory potentiation, we tested whether ibuprofen may block CB chemosensory and cardiorespiratory alterations induced by CIH in a rat model of OSA.We studied the effects of ibuprofen (40 mg?kg -1 ?day -1 ) on immunohistochemical interleukin (IL)-1b and tumour necrosis factor (TNF)-a levels in the CB, the number of c-fos-positive neurons in the nucleus tractus solitarii (NTS), CB chemosensory and ventilatory responses to hypoxia, and arterial blood pressure in male rats either exposed for 21 days to 5% O 2 (12 episodes?h ) or kept under sham condition. CIH increased CB TNF-a and IL-1b and c-fos-positive neurons in the NTS, enhanced carotid chemosensory and ventilatory hypoxic responses, and produced hypertension. Ibuprofen prevented CB cytokine overexpression and CIH-induced increases in c-fos-positive neurons in the NTS, the enhanced hypoxic ventilatory responses and hypertension, but failed to impede the CB chemosensory potentiation.Results suggest that pro-inflammatory cytokines may contribute to the CIH-induced cardiorespiratory alterations, acting at several levels of the hypoxic chemoreflex and cardiovascular control pathways. KEYWORDS: Hypertension, hypoxia, inflammation, obstructive sleep apnoea O bstructive sleep apnoea (OSA) syndrome, a rising worldwide health problem, is characterised by chronic intermittent hypoxia (CIH), which is considered the main risk factor for developing hypertension and other cardiovascular diseases [1][2][3]. It has been proposed that oxidative stress, inflammation and sympathetic activation are involved in OSA-induced hypertension [3][4][5][6]. A growing body of evidence suggests that CIH enhances carotid body (CB) chemosensory responses to hypoxia contributing to the OSA-induced hypertension [6][7][8][9]. Indeed, OSA patients and animals exposed to CIH show potentiated ventilatory, sympathetic and cardiovascular responses to acute hypoxia [6][7][8][9][10]. Furthermore, recordings of carotid chemosensory discharges in situ and in vitro have shown that CIH selectively increases basal chemosensory discharges in normoxia and potentiates the chemosensory responses to acute hypoxia in rats and cats [9,[11][12][13].The repetitive episodes of hypoxia-reoxygenation during CIH exposure elicits oxidative stress due to the accumulation of reactive oxygen species (ROS), which are involved in the potentiation of the hypoxic CB chemosensory responses [9,11,13,14] and in the pathological consequences observed in animals exposed to CIH, and in OSA patients [3-5, 8, 9, 13]. Recently, we found that ascorbic acid supplementation, which impedes the systemic and local CB oxidative stress in the rat exposed to CIH for 21 days, prevented enhanced CB chemosensory and ventilatory responses to h...

1. The most usual form of chronic hypoxia in humans is the intermittent hypoxia resulting from obstructive sleep apnoea (OSA). The OSA syndrome is a highly prevalent sleep breathing disorder that is considered an independent risk factor for hypertension and cardiovascular diseases. Endothelial dysfunction, oxidative stress, inflammation and sympathetic activation have been proposed as potential mechanisms involved in the onset of the hypertension. However, evidence for a unique pathogenic mechanism has been difficult to establish in OSA patients because of concomitant comorbidities. Thus, animal models have been developed to study the pathological consequences of exposure to chronic intermittent hypoxia (CIH). 2. Because OSA patients and animals exposed to CIH show augmented ventilatory, sympathetic and cardiovascular responses to acute hypoxia, it has been proposed that enhanced carotid body responsiveness to hypoxia is involved in the autonomic changes induced by OSA and in the development of the hypertension. Recently, this proposal has received further support from recordings of carotid body chemosensory neural discharges in situ and in vitro showing that exposure of animals to CIH increases basal carotid body chemosensory discharges and enhances the chemosensory response to hypoxia. 3. In the present brief review, we discuss the evidence supporting an important role for the carotid body in the progression of cardiorespiratory changes induced by OSA and the contribution of oxidative stress, endothelin-1 and pro-inflammatory molecules in the potentiation of the carotid body chemosensory function induced by CIH.

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The obstructive sleep apnea (OSA), a worldwide sleep breathing disorder that affect 9% of women and 24% of adult men, 1 is an independent risk factor for systemic hypertension and stroke and is associated with atrial arrhythmogenesis. [2][3][4][5][6] Chronic intermittent hypoxia (CIH), which is the principal feature of OSA, is considered the main factor for the hypertension.2-4,7 CIH produces autonomic dysfunction characterized by sympathetic hyperactivity, alterations of heart rate (HR) variability (HRV), and reduction of cardiac baroreflex efficiency. [8][9][10][11][12][13][14] Although the link between OSA and hypertension is well established, the mechanisms responsible for the autonomic imbalance and the hypertension are not entirely known. CIH produces oxidative stress, inflammation, and endothelial dysfunction that contribute to the hypertension. [2][3][4]7 However, a growing body of evidences suggests that the carotid body (CB), the main oxygen chemoreceptor organ, 15 plays a crucial role in the development of autonomic alterations and hypertension after CIH. Indeed, patients with OSA and animals exposed to CIH show enhanced cardiorespiratory and sympathetic responses to hypoxia, suggesting that CIH potentiates the CB-mediated chemoreflex drive. 7,13,[16][17][18][19] found that bilateral CB denervation before the CIH exposure prevents the development of the hypertension in rats. Despite this important result, the idea that the CB chemoreceptor contributes to the progression of cardiovascular pathologies associated with OSA was not seriously considered until the last decade. Indeed, in the last years, the proposal that the CB is involved in the progression of the CIH-induced hypertension received further attention . 3,4,7,18,21,22 Neural recordings of CB chemosensory activity have shown that CIH selectively Abstract-Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) chemosensory responses to hypoxia and produces autonomic dysfunction, cardiac arrhythmias, and hypertension. We tested whether autonomic alterations, arrhythmogenesis, and the progression of hypertension induced by CIH depend on the enhanced CB chemosensory drive, by ablation of the CB chemoreceptors. Male Sprague-Dawley rats were exposed to control (Sham) conditions for 7 days and then to CIH (5% O 2 , 12/h 8 h/d) for a total of 28 days. At 21 days of CIH exposure, rats underwent bilateral CB ablation and then exposed to CIH for 7 additional days. Arterial blood pressure and ventilatory chemoreflex response to hypoxia were measured in conscious rats. In addition, cardiac autonomic imbalance, cardiac baroreflex gain, and arrhythmia score were assessed during the length of the experiments.In separate experimental series, we measured extracellular matrix remodeling content in cardiac atrial tissue and systemic oxidative stress. CIH induced hypertension, enhanced ventilatory response to hypoxia, induced autonomic imbalance toward sympathetic preponderance, reduced baroreflex gain, and inc...

The carotid body (CB) is the main peripheral chemoreceptor for arterial respiratory gases O2 and CO2, and pH, eliciting reflex ventilatory, cardiovascular and humoral responses to maintain homeostasis. This review examines the fundamental biology underlying CB chemoreceptor function, its contribution to integrated physiologic responses, and its role in maintaining health and potentiating disease. Emphasis will be placed on: i) Transduction mechanisms in chemoreceptor (type I) cells, highlighting the role played by the hypoxic inhibition of O2-dependent K+ channels and mitochondrial oxidative metabolism, and their modification by intracellular molecules and other ionic channels; ii) Synaptic mechanisms linking type I cells and petrosal nerve terminals, focusing on the role played by the main proposed transmitters and modulatory gases, and the participation of glial cells in regulation of the chemosensory process; iii) Integrated reflex responses to CB activation, emphasizing that the responses differ dramatically depending on the nature of the physiological, pathological or environmental challenges, and the interactions of the chemoreceptor reflex with other reflexes in optimizing oxygen delivery to the tissues; and iv) The contribution of enhanced CB chemosensory discharge to autonomic and cardiorespiratory pathophysiology in obstructive sleep apnea, congestive heart failure, resistant hypertension and metabolic diseases, and how modulation of enhanced CB reactivity in disease conditions may attenuate pathophysiology.