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Obstructive sleep apnoea (OSA) affects an estimated 3–7% of the adult population, the frequency doubling at ages >60–65 years. As it evolves, OSA becomes frequently associated with cardiovascular, metabolic and neuropsychiatric pathologies defining OSA syndrome (OSAS). Exposing experimental animals to chronic intermittent hypoxia (CIH) can be used as a model of the recurrent hypoxic and O2 desaturation patterns observed in OSA patients. CIH is an important OSA event triggering associated pathologies; CIH induces carotid body (CB)-driven exaggerated sympathetic tone and overproduction of reactive oxygen species, related to the pathogenic mechanisms of associated pathologies observed in OSAS. Aiming to discover why OSAS is clinically less conspicuous in aged patients, the present study compares CIH effects in young (3–4 months) and aged (22–24 months) rats. To define potential distinctive patterns of these pathogenic mechanisms, mean arterial blood pressure as the final CIH outcome was measured. In young rats, CIH augmented CB sensory responses to hypoxia, decreased hypoxic ventilation and augmented sympathetic activity (plasma catecholamine levels and renal artery content and synthesis rate). An increased brainstem integration of CB sensory input as a trigger of sympathetic activity is suggested. CIH also caused an oxidative status decreasing aconitase/fumarase ratio and superoxide dismutase activity. In aged animals, CIH minimally affected CB responses, ventilation and sympathetic-related parameters leaving redox status unaltered. In young animals, CIH caused hypertension and in aged animals, whose baseline blood pressure was augmented, CIH did not augment it further. Plausible mechanisms of the differences and potential significance of these findings for the diagnosis and therapy of OSAS are discussed.

Adult mammalians possess three cell systems that are activated by acute bodily hypoxia: pulmonary artery smooth muscle cells (PASMC), carotid body chemoreceptor cells (CBCC) and erythropoietin (EPO)-producing cells. In rats, chronic perinatal hyperoxia causes permanent carotid body (CB) atrophy and functional alterations of surviving CBCC. There are no studies on PASMC or EPO-producing cells. Our aim is to define possible long-lasting functional changes in PASMC or EPO-producing cells (measured as EPO plasma levels) and, further, to analyse CBCC functional alterations. We used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55–60% O2 for the last 5–6 days of pregnancy and 4 weeks after birth). Perinatal hyperoxia causes an almost complete loss of hypoxic pulmonary vasoconstriction (HPV), which was correlated with lung oxidative status in early postnatal life and prevented by antioxidant supplementation in the diet. O2-sensitivity of K+ currents in the PASMC of hyperoxic animals is normal, indicating that their inhibition is not sufficient to trigger HPV. Perinatal hyperoxia also abrogated responses elicited by hypoxia on catecholamine and cAMP metabolism in the CB. An increase in EPO plasma levels elicited by hypoxia was identical in hyperoxic and control animals, implying a normal functioning of EPO-producing cells. The loss of HPV observed in adult rats and caused by perinatal hyperoxia, comparable to oxygen therapy in premature infants, might represent a previously unrecognized complication of such a medical intervention capable of aggravating medical conditions such as regional pneumonias, atelectases or general anaesthesia in adult life. Key points Adult animals that have been perinatally exposed to oxygen-rich atmospheres (hyperoxia), recalling those used for oxygen therapy in infants, exhibit a loss of hypoxic pulmonary vasoconstriction, whereas vasoconstriction elicited by depolarizing agents is maintained. Loss of pulmonary hypoxic vasoconstriction is not linked to alterations in oxygen-sensitive K+ currents in pulmonary artery smooth muscle cells. Loss of hypoxic vasoconstriction is associated with early postnatal oxidative damage and corrected by an antioxidant diet. Perinatal hyperoxia damages carotid body chemoreceptor cell function and the antioxidant diet does not reverse it. The hypoxia-elicited increase in erythropoietin plasma levels is not affected by perinatal hyperoxia. The potential clinical significance of the findings in clinical situations such as pneumonia, chronic obstructive pulmonary disease or general anaesthesia is considered. Introduction Mammals possess three interrelated systems that work in concert to maintain an adequate supply of O2 to their organs, thus preventing or alleviating the adverse effects of hypoxia. Pulmonary artery smooth muscle cells (PASMC) sense alveolar hypoxia and respond with a Ca2+-dependent contractile response. In situations of uneven ventilation of the lungs, contraction of PASMC almost instantaneously diverts blood to well ventilated lung regions to optimize ventilation/perfusion matching and blood oxygenation (Marshall et al. 1994a,b; Sylvester et al. 2012). Carotid body (CB) chemoreceptor cells (CBCC) detect hypoxic hypoxia and respond with a Ca2+-dependent release of neurotransmitters triggering respiratory reflexes that increase alveolar ventilation, alveolar and haemoglobin saturation (Gonzalez et al. 1994; Kumar, 2009). Erythropoietin (EPO)-producing cells (primarily interstitial fibroblasts in the kidney) sense local tissue hypoxia and, in a time scale of a few hours, respond with increased rates of EPO gene transcription and translation and increased secretion of EPO hormone; EPO augments the O2-carrying capacity of blood by stimulating erythrocyte production in the bone marrow (Jelkmann, 1992). The three O2-sensing cell systems exhibit low hypoxic thresholds (i.e. they start responding when is relatively high: alveolar or arterial of 65–70 mmHg; O2 content >90%) and their coordinated function allows healthy humans to assure an adequate O2 content in arterial blood at barometric pressures as low as 400 mmHg or an ambient of 84 mmHg (Ward et al. 1995; Gonzalez et al. 2002). Thus, as a whole, these three cell types represent the general system that adult mammals employ to compensate for or adapt to systemic hypoxia (Gonzalez et al. 2010). The aortic and neuroepithelial bodies and, in the full-term fetus and newborn, the adrenal medulla also contribute to those adjustments. Perinatal exposure of rats to a hyperoxic atmosphere (60% O2, 4 weeks) produces permanent hypotrophy of the CB and a marked diminution of the response of the organ to hypoxia when assessed as the carotid sinus nerve action potential frequency (the afferent arm of the CB chemoreflex; Ling et al. 1997; Erickson et al. 1998; Fuller et al. 2002; Bisgard et al. 2003; Prieto Lloret et al. 2004; Wenninger et al. 2006; Bavis et al. 2013). However, when the CB chemoreflex is explored via phrenic nerve activity or ventilation (i.e. the efferent arm of the chemoreflex), the dysfunction produced by perinatal hyperoxia is appreciated differently. In the original study of Ling et al. (1996), it was reported that 1 month of perinatal hyperoxic treatment caused a marked decrease in hypoxic ventilation when the animals were studied up to the age of 5 months (i.e. 4 months after hyperoxic treatment); it was concluded that animals may suffer impaired chemoresponsiveness throughout their lives. By contrast, in our previous study (Prieto-Lloret et al. 2004), as well as those of Dauger et al. (2003) and Wenninger et al. (2006), no alterations in control, hypoxic and hypercapnic ventilation were noted when animals were explored at ≥ 4 months of age. In another study, Ling et al. (1998) extended their observations until the animals reached 14 months of age and they found a marked decrease in the hypoxic response that recovered with time, so that, at 14 months of age, the responses to hypoxia were normalized. Subsequently, Fuller et al. (2002) re-examined the issue and found that animals aged up to 14–15 months exhibited functional impairment in the hypoxic responses and concluded that perinatal hyperoxia causes life-long impairment of carotid chemoreceptor function; a recent review is provided by Bavis et al. (2013). Prieto-Lloret et al. (2004) and, more recently, Kim et al. (2013) located the hyperoxic damage in surviving CBCC in a step prior to cell depolarization and Ca2+ entry into the hypoxic transduction cascade (Gonzalez et al. 1992). By contrast to the situation for CB, there are no studies exploring the effects of perinatal hyperoxia on the other two systems of oxygen-sensitive cells. Clinically, it is important to determine whether exposure to perinatal hyperoxia damages PASMC and hypoxic pulmonary vasoconstriction (HPV) because, although oxygen therapy in hypoxemic, usually premature, newborn infants is aimed at restoring a normal blood O2 content and avoiding hyperoxaemia, lung tissues are unavoidably exposed to hyperoxia. Thus, if hyperoxia deteriorates the HPV, it would imply the loss of an important homeostatic mechanism. This loss could be fatal in lung pathologies such as non-generalized pneumonias or atelectases or mild chronic obstructive pulmonary diseases, as well as in situations of general anaesthesia, particularly in thoracic surgery, where systemic arterial is supported by HPV (Glasser et al. 1983, Eisenkraft, 1990; Marshall et al. 1994a,b; Nagendran et al. 2006; Karzai and Schwarzkopf, 2009; Sylvester et al. 2012). Additionally, hyperoxaemia is a frequent undesirable accident in infant oxygen therapy (Tracy et al. 2004; Hartnett and Penn, 2012; Bavis et al. 2013), which not only would augment the exposure of PASMC to high , but also would expose EPO-producing cells to abnormally high . In this context, the present study aimed to further analyse the functional alterations in the CB and to define possible alterations in the other two O2-sensing cell types. Accordingly, we used 3- to 4-month-old rats born and reared in a normal atmosphere or exposed to perinatal hyperoxia (55–60% O2 for the last 6 days of pregnancy and the initial 4 weeks after birth). Additionally, although it has been reported that perinatal hyperoxia does not cause oxidative stress as assessed via plasma carbonylated proteins (Bavis et al. 2008), it should be expected to result in an increase in reactive oxygen species (Turrens et al. 2003; Halliwell and Gutteridge 2007). We measured the levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) in the liver, brain and lung, and found that the glutathione redox potential was diminished in the liver and lung in hyperoxic animals of 7 days of age. This prompted additional experiments in which mothers and litters received an antioxidant diet during hyperoxic exposure. We found that perinatal hyperoxic exposure alters the metabolism of catecholamine (CA) in the CB but causes no alteration in the ventilatory response to hypoxia or hypercapnia. Hyperoxic animals showed a normal EPO plasma levels in response to 10 h of hypoxic exposure. By contrast, we found that hyperoxic exposure caused an almost complete loss of HPV. An antioxidant diet corrected the deviations of the redox status and prevented the loss of the HPV but did not reverse the alterations in the CB. The potential mechanisms and clinical significance of the findings are discussed.