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(1) Background: The aim of this study was to explore the role of perceived stress and the health locus of control in Crohn’s disease and their influence upon the development of flare-ups of this disease. (2) Methods: Stress and the external locus of control were evaluated in a sample of 64 Crohn’s patients (flare-up phase versus latency phase). The perceived stress scale (PSS-14) and the multidimensional health locus of control scale were the measurement instruments used. (3) Results: The results indicate that the patients have high stress levels during a flare-up (26.13; 27.44; 28.79; 29.67); high stress levels (28.07; 29.67; 27.44; 28.07) if they have a high external locus of control; and that the external locus of control and stress levels have a significant influence upon the existence of flare-ups in those patients with low external locus of control levels (χ2 = 11.127; df = 1: p < 0.001). (4) Conclusions: Actions aimed at reducing stress and external locus of control levels are necessary in Crohn’s disease.

Persistent COVID, long COVID, long-effects, long-term effects or chronic COVID are all names of a new syndrome caused by a set of multi-organ symptoms that appear after having been infected with SARS-CoV-2 [1]. These symptoms occur 4 or even 12 weeks after the acute phase of COVID-19 disease and persist over time. These are not sequela or what is commonly referred to as post-COVID, which is due to severe acute SARS-CoV-2 disease and causes hospital admission and even intensive care. In long COVID, symptoms occur regardless of the severity of the disease in the acute phase. Furthermore, there is no cure period per se, as the symptoms do not disappear, but rather often occur in outbreaks. However, having long COVID is not incompatible with suffering from sequela related to having gone through the acute phase severely

Producción Científica, The early stages of the COVID-19 pandemic presented the characteristics of a traumatic event that could trigger post-traumatic stress disorder. Emergency Medical Services workers are already a high-risk group due to their professional development. The research project aimed to analyse the impact of the COVID-19 pandemic on EMS professionals in terms of their mental health. For this purpose, we present a descriptive crosssectional study with survey methodology. A total of 317 EMS workers (doctors, nurses, and emergency medical technicians) were recruited voluntarily. Psychological distress, post-traumatic stress disorder, and insomnia were assessed. The instruments were the General Health Questionnaire-12 (GHQ-12), the Davidson Trauma Scale (DTS-8), and the Athens Insomnia Scale (AIS-8). We found that 36% of respondents had psychological distress, 30.9% potentially had PTSD, and 60.9% experienced insomnia. Years of work experience were found to be positively correlated, albeit with low effect, with the PTSD score (r = 0.133). Finally, it can be stated that the COVID-19 pandemic has been a traumatic event for EMS workers. The number of professionals presenting psychological distress, possible PTSD, or insomnia increased dramatically during the early phases of the pandemic. This study highlights the need for mental health disorder prevention programmes for EMS workers in the face of a pandemic.

[Background]: The problems involved in obtaining authorization in favor of organ donation have led us to evaluate the level of knowledge and attitudes of a group of Spanish adolescents (14-16 years) regarding organ donation, transplantation, and brain death. The evaluation was carried out before and after a health education intervention by nursing personnel., [Methods]: Experimental, prospective and quantitative study. The educational intervention was carried out at Las Salinas high school (Laguna de Duero, Spain). We collected 86 preworkshop questionnaires and 88 post-workshop questionnaires., [Results]: The composition of the groups did not differ significantly in sex (P = .653), age (P = .266), or in the desire to be a donor (P = .099). We found significant postworkshop improvements in knowledge about brain death (P < .001) and which organs can be donated (P < .001), as well as in the total score (18.29 ± 2.45 before vs 21.47 ± 2.70 after) (P < .001). We discovered a vast lack of knowledge about the organs that cannot be transplanted, which included the penis (38.4%), uterus (31.4%), prostate (41.9%), or bladder (37.2%); these beliefs decreased significantly after the intervention (P < .01). The increase in knowledge of the organs that can be donated, including eye (P = .024), lung (P = .025), stomach (P < .001), intestine (P = .001), and skin (P < .001), was also significant., [Conclusions]: The good results reflected the importance of conducting educational programs taught by health personnel on donation and organ transplantation in adolescents.

© 2021 by the authors., Several studies demonstrated a link between obstructive sleep apnea (OSA) and the development of insulin resistance. However, the main event triggering insulin resistance in OSA remains to be clarified. Herein, we investigated the effect of mild and severe chronic intermittent hypoxia (CIH) on whole-body metabolic deregulation and visceral adipose tissue dysfunction. Moreover, we studied the contribution of obesity to CIH-induced dysmetabolic states. Experiments were performed in male Wistar rats submitted to a control and high-fat (HF) diet. Two CIH protocols were tested: A mild CIH paradigm (5/6 hypoxic (5% O2) cycles/h, 10.5 h/day) during 35 days and a severe CIH paradigm (30 hypoxic (5% O2) cycles, 8 h/day) during 15 days. Fasting glycemia, insulinemia, insulin sensitivity, weight, and fat mass were assessed. Adipose tissue hypoxia, inflammation, angiogenesis, oxidative stress, and metabolism were investigated. Mild and severe CIH increased insulin levels and induced whole-body insulin resistance in control animals, effects not associated with weight gain. In control animals, CIH did not modify adipocytes perimeter as well as adipose tissue hypoxia, angiogenesis, inflammation or oxidative stress. In HF animals, severe CIH attenuated the increase in adipocytes perimeter, adipose tissue hypoxia, angiogenesis, and dysmetabolism. In conclusion, adipose tissue dysfunction is not the main trigger for initial dysmetabolism in CIH. CIH in an early stage might have a protective role against the deleterious effects of HF diet on adipose tissue metabolism., The present study was supported by grant reference BFU2015-70616-R (MINECO/FEDER; DGICYT), and VA106G18 (JCyL), Spain and by the Portuguese Foundation for Science and Technology with contracts for Fátima O. Martins (CEECIND/04266/2017) and Joana F. Sacramento (CEEC IND/02428/2018) and a PhD Grant for Bernardete F. Melo (PD/BD/128336/2017).

Producción Científica, (1) Background: The confinement of the population in response to the COVID-19 pandemic was related to an increased risk of suffering from anxiety and/or depression in previous studies with other populations. (2) Methods: descriptive study using surveys (Goldberg Anxiety and Depression Scale) with 808 participants over 18 years of age between 14 and 20 of May 2020 during the confinement due to the SARS-CoV-2 virus in Spain. (3) Results: 63% of the participants were at risk of suffering from anxiety and 64.9% were at risk of depression. Variables reaching statistical significance were: age (t anxiety = −0.139 and t depression = −0.153), gender (t anxiety = −4.152 and t depression = −4.178), marital status (anxiety F = 2.893 and depression F = 3.011), symptoms compatible with COVID-19 (t anxiety = −4.177 and t depression = −3.791), previous need for psychological help (t anxiety = −5.385 and t depression = −7.136) and need for such help at the time of the study (t anxiety = −9.144 and depression = −10.995). In addition, we generated two regression models that estimate the risk of anxiety and depression. (4) Conclusions: more than half of the participants were at risk of suffering from anxiety and/or depression, confirming the negative effect of confinement on the population

During ageing the carotid body (CB) exhibits a decline in its functionality. Here we investigated the effect of ageing on functional CB characteristics as well as the contribution of adenosine and ATP to CB chemosensory activity. Experiments were performed in 3‐month‐old and 20‐ to 24‐month‐old male Wistar rats. Ageing decreased: the number of tyrosine hydroxylase immune‐positive cells, but not type II cells or nestin‐positive cells in the CB; the expression of P2X2 and A2A receptors in the petrosal ganglion; and the basal and hypoxic release of adenosine and ATP from the CB. Ageing increased ecto‐nucleotidase (CD73) immune‐positive cells and the expression of synaptosome associated protein 25 (SNAP25) and equilibrative nucleoside transporter 1 (ENT1) in the CB. Additionally, ageing did not modify basal carotid sinus nerve (CSN) activity or the activity in response to hypercapnia, but decreased CSN activity in hypoxia. The contribution of adenosine and ATP to stimuli‐evoked CSN chemosensory activity in aged animals followed the same pattern of 3‐month‐old animals. Bilateral common carotid occlusions during 5, 10 and 15 s increased ventilation proportionally to the duration of ischaemia, an effect decreased by ageing. ATP contributed around 50% to ischaemic‐ventilatory responses in young and aged rats; the contribution of adenosine was dependent on the intensity of ischaemia, being maximal in ischaemias of 5 s (50%) and much smaller in 15 s ischaemias. Our results demonstrate that both ATP and adenosine contribute to CB chemosensory activity in ageing. Though CB responses to hypoxia, but not to hypercapnia, decrease with age, the relative contribution of both ATP and adenosine for CB activity is maintained., This study was supported by the Portuguese Foundation for Science and Technology grant PTDC/SAU‐ORG/111 417/2009 to S.V.C. and by Grants BFU2015‐70616R from MINECO‐FEDER, Spain.

Clinical studies have demonstrated a link between obstructive sleep apnea (OSA) and insulin resistance (IR), however it is not clear which is the main event that determines IR development. We hypothesize that hyperinsulinemia is a main driver of IR in chronic intermittent hypoxia (CIH), that mimics OSA, independently of obesity, adipose tissue hypoxia and severity of CIH. Male Wistar Rats were submitted to 2 CIH protocols: 1) a mild CIH paradigm obtained by 5/6 hypoxic (5%O2) cycles/h, 10.5 h/day during 35 days; and 2) a severe CIH paradigm obtained by 40 s, 5%O2/80 s, air, equivalent to an apnoea–hypopnoea index of 30, 8h/day for 14 days. CIH animals were compared with controls. Fasting glycemia, insulinemia, C-peptide and insulin sensitivity through KITTand HOMA index were measured. Insulin clearance was calculated. Weight and fat mass were assessed. Adipose tissue dysfunction and inflammation were assessed by evaluation of several proteins involved in insulin signaling pathways and hypoxia and inflammation pathways. Mild CIH increased insulin secretion by 214% (CTLmildCIH =1.01±0.21ug/L) while severe CIH increased by 103% (CTLsevereCIH= 1.1±0.04ug/L) with no alterations in fasting glycemia in both CIH protocols. HOMA index increased by 112% in mild CIH and by 108% in severe CIH animals. None of CIH protocols alter weight gain and fat mass deposition. Mild and severe CIH increased IR in adipose tissue, with no changes in HIF1 and 2α expression. We can conclude that both mild and severe CIH protocols induce insulin resistance, which is associated with an increase insulin secretion by the pancreas being independent of obesity and fat mass.

Introduction and Aim: Female gender is a risk factor in pulmonary arterial hypertension (PAH) development. Despite the protective role of estrogens in young female individuals, the fact that they have higher risk of developing PAH leads to the “estrogens paradox”. Our aim was to study if there are sex and age differences in the pulmonary vascular responses in a PAH rat model. Methods: We exposed young and old male and female rats to chronic hypoxia of 11%O2 for 2 weeks (CH) to study the estrogen’s role in PAH development, measuring hemodynamic and cardiac parameters. Results: After CH exposure, young female rats showed a higher increase of pulmonary arterial pressure (PAP) and right ventricular hypertrophy (Fulton index >30%) than their male counterparts. The effect of CH on PAP was larger in young animals than in old ones, although changes in the Fulton index were similar. Conversely, CH generated endothelial damage in young male but not in young female rats p Conclusion: These data suggest a PAH sexual dimorphism in rat, where young females develop PAH faster than young males, although their PA are less prone to endothelial damage in CH. In aged animals, effects of CH are blunted, and differences between males and females are absent. We postulate that the link between sex and pulmonary circulation is probably due to differences in the vascular contractility properties.

En esta tesis doctoral se han estudiado los mecanismos fisiopatológicos de la apnea obstructiva del sueño y la obesidad utilizando para ello modelos animales de rata de hipoxia intermitente crónica (HIC) durante 14 días y dieta rica en grasa durante 12 semanas. Nuestros resultados indican que la HIC y la dieta rica en grasa causan patologías cardiovasculares y metabólicas asociadas a una disregulación del estrés oxidativo y de la actividad simpática. En los animales obesos todos los parámetros estudiados están más alterados que en los animales expuestos a HIC y cuando se combinan ambas situaciones la mayoría de las alteraciones observadas tienden a agravarse. También hemos estudiado la función de la leptina, la hormona de la saciedad, sobre el cuerpo carotídeo (CC) en ratas controles. La leptina aumenta la ventilación en situaciones de normoxia e hipoxia pero no parece que esta activación esté mediado por el CC., Departamento de Bioquímica, Biología Molecular y Fisiología

The sleep apnea-hypopnea syndrome (SAHS) involves periods of intermittent hypoxia, experimentally reproduced by exposing animal models to oscillatory PO2 patterns. In both situations, chronic intermittent hypoxia (CIH) exposure produces carotid body (CB) hyperactivation generating an increased input to the brainstem which originates sympathetic hyperactivity, followed by hypertension that is abolished by CB denervation. CB has dopamine (DA) receptors in chemoreceptor cells acting as DA-2 autoreceptors. The aim was to check if blocking DA-2 receptors could decrease the CB hypersensitivity produced by CIH, minimizing CIH-related effects. Domperidone (DOM), a selective peripheral DA-2 receptor antagonist that does not cross the blood-brain barrier, was used to examine its effect on CIH (30 days) exposed rats. Arterial pressure, CB secretory activity and whole-body plethysmography were measured. DOM, acute or chronically administered during the last 15 days of CIH, reversed the hypertension produced by CIH, an analogous effect to that obtained with CB denervation. DOM marginally decreased blood pressure in control animals and did not affect hypoxic ventilatory response in control or CIH animals. No adverse effects were observed. DOM, used as gastrokinetic and antiemetic drug, could be a therapeutic opportunity for hypertension in SAHS patients&rsquo, resistant to standard treatments.

Guinea pigs (GP), originally from the Andes, have absence of hypoxia-driven carotid body (CB) reflex. Neonatal mammals have an immature CB chemo reflex and respond to hypoxia with metabolic changes arising from direct effects of hypoxia on adrenal medulla (AM). Our working hypothesis is that adult GP would mimic neonatal mammals. Plasma epinephrine (E) has an AM origin, while norepinephrine (NE) is mainly originated in sympathetic endings, implying that specific GP changes in plasma E/NE ratio, and in blood glucose and lactate levels during hypoxia would be observed. Experiments were performed on young adult GP and rats. Hypoxic ventilation (10% O

Resumen del trabajo presentado al European Respiratory Society (ERS) International Congress, celebrado en Paris (Francia) del 15 al 19 de septiembre de 2018., [Rationale & Aim]: Experimental evidences indicate a correlation among chronic intermittent hypoxia (CIH), increased carotid body (CB) activity, enhanced sympatho-respiratory coupling and arterial hypertension. The recurrent hypoxia/reoxygenation episodes in CIH models produce CB sensitization increasing secretory response and chemoreceptor input to the brainstem, exaggerating the sympathetic reflex. CIH effect in the guinea pig CB, with a hypofunctional CB and lack of ventilatory responses to hypoxia, has not been studied., [Methods]: Guinea pigs were exposed to CIH (21%O2-80s / 5%O2-40s 8h/day; 30 days) and CB secretory response, pletismographic parameters, systemic arterial pressure and sympathetic activity were measured and compared to control animals., [Results]: Ventilatory data showed that only intense hypoxia induced significant increase of minute ventilation in both groups of animals. CB response to hypoxia (catecholamine (CA) secretion or Ca2+i changes) were not observed in C or CIH animals. Plasma CA, heart rate and mean arterial blood pressure were significantly increased in CIH guinea pigs., [Conclusion]: CIH induced hypoxic activation of the sympathetic system non-dependent of CB chemoreceptors, promoting cardiovascular adjustments. Guinea pigs can be a model to study the CB-dependent and nondependent effects induced by CIH., Spanish Ministry of Economy and Competitiveness, MINECO/FEDER, UE (BFU2015-70616-R) and CIBERES, ISCiii (CB06/06/0050).

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.

Resumen del trabajo presentado al European Respiratory Society (ERS) International Congress, celebrado en Paris (Francia) del 15 al 19 de septiembre de 2018., [Rationale & Aim]: Chronic sustained hypoxia (CSH) initiates physiological adaptations to maintain oxygen levels but also has deleterious effects as pulmonary hypertension (PH). Chronic intermittent hypoxia (CIH), as found in obstructive sleep apnea, is associated with the development of systemic hypertension and cardiovascular pathologies. Our aim was to compare systemic and pulmonary hypertension and endothelial dysfunction development in rats exposed to CSH vs. CIH., [Methods]: We exposed male rats to sustained hypoxic atmosphere (10%O2; pO2≈70 mmHg, 14 days) or intermittent hypoxia (5%O2 40s, 21%O2 80s, 8h/day, 21 days). We measured pulmonary artery (PA) pressure by right heart catheterization, Fulton index, vasomotor responses in PA using small vessels myography and L- arginine-NO metabolism., [Results]: Systemic and pulmonary hypertension, besides left ventricular hypertrophy, occurs in response to CIH exposure in rats, preserving pulmonary artery endothelial integrity, but decreasing NO production and eNOS protein expression. Conversely, CSH exposure triggers CB mediated respiratory chemoreflex, PH and right ventricular hypertrophy, besides blunted pulmonary vascular relaxation to carbachol and reduced plasma L-arginine: asymmetric dimethyl arginine (ADMA) ratio., [Conclusion]: CSH and CIH point to different targets and different mechanisms to produce endothelial dysfunction and systemic and pulmonary hypertension in the rat., Spanish Ministry of Economy and Competitiveness, MINECO/FEDER, UE (BFU2015-70616-R); CIBER Enfermedades Respiratorias, ISCiii (CIBERES, CB06/06/0050).

Resumen del trabajo presentado al European Respiratory Society (ERS) International Congress, celebrado en Paris (Francia) del 15 al 19 de septiembre de 2018.

Guinea pigs (GP), originally from the Andes, have absence of hypoxia-driven carotid body (CB) reflex. Neonatal mammals have an immature CB chemo reflex and respond to hypoxia with metabolic changes arising from direct effects of hypoxia on adrenal medulla (AM). Our working hypothesis is that adult GP would mimic neonatal mammals. Plasma epinephrine (E) has an AM origin, while norepinephrine (NE) is mainly originated in sympathetic endings, implying that specific GP changes in plasma E/NE ratio, and in blood glucose and lactate levels during hypoxia would be observed. Experiments were performed on young adult GP and rats. Hypoxic ventilation (10% O2) increased E and NE plasma levels similarly in both species but PaO2 was lower in GP than in rats. Plasma E/NE ratio in GP was higher (≈1.0) than in rats (≈0.5). The hypoxia-evoked increases in blood glucose and lactate were smaller in GP than in the rat. The AM of both species contain comparable E content, but NE was four times lower in GP than in rats. GP superior cervical ganglion also had lower NE content than rats and an unusual high level of dopamine, a negative modulator of sympathetic transmission. Isolated AM from GP released half of E and one tenth of NE than the rat AM, and hypoxia did not alter the time course of CA outflow. These data indicate the absence of direct effects of hypoxia on AM in the GP, and a lower noradrenergic tone in this species. Pathways for hypoxic sympatho-adrenal system activation in GP are discussed., This work was supported by Grants BFU2015-63706R (MINECO, FEDER-UE) and CIBER CB06/06/0050 from ISCiii (Spain).

Leptin plays a role in the control of breathing, acting mainly on central nervous system; however, leptin receptors have been recently shown to be expressed in the carotid body (CB), and this finding suggests a physiological role for leptin in the regulation of CB function. Leptin increases minute ventilation in both basal and hypoxic conditions in rats. It increases the frequency of carotid sinus nerve discharge in basal conditions, as well as the release of adenosine from the CB. However, in a metabolic syndrome animal model, the effects of leptin in ventilatory control, carotid sinus nerve activity and adenosine release by the CB are blunted. Although leptin may be involved in triggering CB overactivation in initial stages of obesity and dysmetabolism, resistance to leptin signalling and blunting of responses develops in metabolic syndrome animal models.Leptin plays a role in the control of breathing, acting mainly on central nervous system structures. Leptin receptors are expressed in the carotid body (CB) and this finding has been associated with a putative physiological role of leptin in the regulation of CB function. Since, the CBs are implicated in energy metabolism, here we tested the effects of different concentrations of leptin administration on ventilatory parameters and on carotid sinus nerve (CSN) activity in control and high-fat (HF) diet fed rats, in order to clarify the role of leptin in ventilation control in metabolic disease states. We also investigated the expression of leptin receptors and the neurotransmitters involved in leptin signalling in the CBs. We found that in non-disease conditions, leptin increases minute ventilation in both basal and hypoxic conditions. However, in the HF model, the effect of leptin in ventilatory control is blunted. We also observed that HF rats display an increased frequency of CSN discharge in basal conditions that is not altered by leptin, in contrast to what is observed in control animals. Leptin did not modify intracellular Ca

[Aims/hypothesis]: We recently described that carotid body (CB) over-activation is involved in the aetiology of insulin resistance and arterial hypertension in animal models of the metabolic syndrome. Additionally, we have demonstrated that CB activity is increased in animal models of insulin resistance, and that carotid sinus nerve (CSN) resection prevents the development of insulin resistance and arterial hypertension induced by high-energy diets. Here, we tested whether the functional abolition of CB by CSN transection would reverse pre-established insulin resistance, dyslipidaemia, obesity, autonomic dysfunction and hypertension in animal models of the metabolic syndrome. The effect of CSN resection on insulin signalling pathways and tissue-specific glucose uptake was evaluated in skeletal muscle, adipose tissue and liver. [Methods]: Experiments were performed in male Wistar rats submitted to two high-energy diets: a high-fat diet, representing a model of insulin resistance, hypertension and obesity, and a high-sucrose diet, representing a lean model of insulin resistance and hypertension. Half of each group was submitted to chronic bilateral resection of the CSN. Age-matched control rats were also used. [Results]: CSN resection normalised systemic sympathetic nervous system activity and reversed weight gain induced by high-energy diets. It also normalised plasma glucose and insulin levels, insulin sensitivity lipid profile, arterial pressure and endothelial function by improving glucose uptake by the liver and perienteric adipose tissue. [Conclusions/interpretation]: We concluded that functional abolition of CB activity restores insulin sensitivity and glucose homeostasis by positively affecting insulin signalling pathways in visceral adipose tissue and liver., This study was supported by the Portuguese Foundation for Science and Technology (FCT), grants EXPL/NEU-SCC/2183 and Pest-C/SAU/UI3282/2011, grant BFU2015-70616-R (MINECO/FEDER, UE) (Spain) and grant CIBER CB06/06/0050 from the Institute of Health Carlos III (Spain). JFS and MJR are supported by PhD Grants from FCT, PD/BD/105890/2014 and SFR/BD/88983/2012, respectively.

Background: Recent studies have reported, albeit with discrepancies, an association between severity of OSA and cancer incidence/mortality. Discrepancies are likely due to the large number of OSA-linked comorbidities and uncontrolled variables among patients.In mice, short term IH mimicking OSA augments tumour growth and metastasis of implanted tumours, but whether or not IH enhances spontaneous tumorigenesis has not been studied. Aim: To test the hypothesis that long term IH increases spontaneous tumorigenesis in mice. Methods: The study was designed with IH as the only variable. To mimic the situation in humans in terms of genetic diversity, outbreed mice (Swiss CD1) were used. IH was long-lasting (8/h day; 3 months; ∼8-10 yr at human scale) and was applied from age 15 to 18 months, equivalent to a human age (50-60 yr) with high tumorigenesis and OSA rates. Two intensities of IH were used: 80 s air/40 s 12% O 2 (N=49) or 7.5% O 2 (N=53). Control mice (N=55) remained in room air. On sacrifice, blood and tissues were collected to determine tumoral markers. Necropsy allowed macroscopic identification of tumoral masses which were stored (4% formaldehyde) for histology. Results: Tumoral masses were found in 36.4% of control mice (8 liver, 7 lung, 5 skin), in 38.8% of 12% O 2 IH mice (11 liver, 7 lung, 1 skin) and in 63.5% (χ 2 = 7.85; p= 0.005 vs. control) of the 7.5% O 2 IH mice (11 liver, 15 lung, 7 skin). Conclusion: IH mimicking OSA augments multi-organ spontaneous tumorigenesis in a O 2 desaturation-related manner. Data would help to interpret cancer incidence in OSA patients. Support: Spanish Association Against Cancer (AECC) and CIBERES, ISCiii, Spain.

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.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.

The cascade of transduction of hypoxia and hypercapnia, the natural stimuli to chemoreceptor cells, is incompletely understood. A particular gap in that knowledge is the role played by second messengers, or in a most ample term, of modulators. A recently described modulator of chemoreceptor cell responses is the gaseous transmitter hydrogen sulfide, which has been proposed as a specific activator of the hypoxic responses in the carotid body, both at the level of the chemoreceptor cell response or at the level of the global output of the organ. Since sulfide behaves in this regard as cAMP, we explored the possibility that sulfide effects were mediated by the more classical messenger. Data indicate that exogenous and endogenous sulfide inhibits adenyl cyclase finding additionally that inhibition of adenylyl cyclase does not modify chemoreceptor cell responses elicited by sulfide. We have also observed that transient receptor potential cation channels A1 (TRPA1) are not regulated by sulfide in chemoreceptor cells., This work was supported by Grants BFU2012-37459 from the Ministry of Economy and Competitiveness (Spain) of and Grant CIBER CB06/06/0050 from the Institute of Health Carlos III (Spain) to C. G.

Leptin is a hormone produced mostly in adipose tissue and playing a key role in the control of feeding and energy expenditure aiming to maintain a balance between food intake and metabolic activity. In recent years, it has been described that leptin might also contributes to control ventilation as the administration of the hormone reverses the hypoxia and hypercapnia commonly encountered in ob/ob mice which show absence of the functional hormone. In addition, it has been shown that the carotid body (CB) of the rat expresses leptin as well as the functional leptin-B receptor. Therefore, the possibility exists that the ventilatory effects of leptin are mediated by the CB chemoreceptors. In the experiments described below we confirm the stimulatory effect of leptin on ventilation, finding additionally that the CB does not mediate the instant to instant control of ventilation.

Obstructive sleep apnea (OSA) consists of sleep-related repetitive obstructions of upper airways that generate episodes of recurrent or intermittent hypoxia (IH). OSA commonly generates cardiovascular and metabolic pathologies defining the obstructive sleep apnea syndrome (OSAS). Literature usually links OSA-associated pathologies to IH episodes that would cause an oxidative status and a carotid body-mediated sympathetic hyperactivity. Because cardiovascular and metabolic pathologies in obese patients and those with OSAS are analogous, we used models (24-wk-old Wistar rats) of IH (applied from weeks 22 to 24) and diet-induced obesity (O; animals fed a high-fat diet from weeks 12 to 24) to define the effect of each individual maneuver and their combination on the oxidative status and sympathetic tone of animals, and to quantify cardiovascular and metabolic parameters and their deviation from normality. We found that IH and O cause an oxidative status (increased lipid peroxides and diminished activities of superoxide dismutases), an inflammatory status (augmented C-reactive protein and nuclear factor kappa-B activation), and sympathetic hyperactivity (augmented plasma and renal artery catecholamine levels and synthesis rate); combined treatments worsened those alterations. IH and O augmented liver lipid content and plasma cholesterol, triglycerides, leptin, glycemia, insulin levels, and HOMA index, and caused hypertension; most of these parameters were aggravated when IH and O were combined. IH diminished ventilatory response to hypoxia, and hypercapnia and O created a restrictive ventilatory pattern; a combination of treatments led to restrictive hypoventilation. Data demonstrate that IH and O cause comparable metabolic and cardiovascular pathologies via misregulation of the redox status and sympathetic hyperactivity., Support for this study was provided by Spanish Ministry of Economy and Competitiveness Grant BFU2012-37459 and Spanish Ministry of Health Institute Carlos III Grant CIBER CB06/06/0050 to C.G.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)., When de Castro entered the carotid body (CB) field, the organ was considered to be a small autonomic ganglion, a gland, a glomus or glomerulus, or a paraganglion. In his 1928 paper, de Castro concluded: "In sum, the Glomus caroticum is innervated by centripetal fibers, whose trophic centers are located in the sensory ganglia of the glossopharyngeal, and not by centrifugal [efferent] or secretomotor fibers as is the case for glands; these are precisely the facts which lead to suppose that the Glomus caroticum is a sensory organ." A few pages down, de Castro wrote: "The Glomus represents an organ with multiple receptors furnished with specialized receptor cells like those of other sensory organs [taste buds?]...As a plausible hypothesis we propose that the Glomus caroticum represents a sensory organ, at present the only one in its kind, dedicated to capture certain qualitative variations in the composition of blood, a function that, possibly by a reflex mechanism would have an effect on the functional activity of other organs... Therefore, the sensory fiber would not be directly stimulated by blood, but via the intermediation of the epithelial cells of the organ, which, as their structure suggests, possess a secretory function which would participate in the stimulation of the centripetal fibers." In our article we will recreate the experiments that allowed Fernando de Castro to reach this first conclusion. Also, we will scrutinize the natural endowments and the scientific knowledge that drove de Castro to make the triple hypotheses: the CB as chemoreceptor (variations in blood composition), as a secondary sensory receptor which functioning involves a chemical synapse, and as a center, origin of systemic reflexes. After a brief account of the systemic reflex effects resulting from the CB stimulation, we will complete our article with a general view of the cellular-molecular mechanisms currently thought to be involved in the functioning of this arterial chemoreceptor. © 2014 Gonzalez, Conde, Gallego-Martín, Olea, Gonzalez-Obeso, Ramirez, Yubero, Agapito, Gomez-Niño, Obeso, Rigual and Rocher., This work was supported by the Spanish Ministry of Economy and Competitiveness (Grant number BFU2012-37459 to Constancio Gonzalez), by Spanish Ministry of Health-Institute Carlos III (Grant CIBER CB06/06/0050 to Constancio Gonzalez) and by PTDC/SAU-ORG/111417/2009 (Portugal to Silvia V. Conde).

Serotonin or 5-HT is a biogenic amine present in the carotid body (CB) of several species as evidenced in many immunocytochemical studies and in a few biochemical measurements. Early literature on 5-HT actions in the CB in all studied species has lead to the conclusion that it does not participate in the setting of conducted action potentials in the sensory nerve of the CB. However, during the last 10 years very important roles in the cellular physiology of the CB have been proposed for this biogenic amine. These roles include a primary role in setting the excitability of chemoreceptor cells via an autocrine or paracrine action, and thereby, the conducted activity in the carotid sinus nerve, and a critical role in the genesis of long term sensory facilitation observed in CBs of animals exposed to intermittent hypoxia. These facts, along with important discrepancies in the endogenous levels of 5-HT in the CB prompted present study conducted in rat CBs. We measured CB endogenous 5-HT content by HPLC with electrochemical detection and found levels of 5-HT in the range of 15-22 pmole/mg tissue in control and chronically hypoxic animals either sustained or intermittent, with no significant differences among them. 5-HT and the 5-HT2A antagonist ketanserin dose-dependently activated chemoreceptor cells as assessed by their capacity to release catecholamines from freshly isolated CB. In preliminary experiments we have observed that intense hypoxia and high extracellular K(+) promote a small release of 5-HT from CB which is not dependent on the presence of extracellular Ca(2+). Further studies are needed to firmly establish the dynamics of 5-HT in the CB of the rat.

Ventilatory effects of chronic cigarette smoke (CS) alone or associated to chronic hypoxia (CH), as frequently occurs in chronic obstructive pulmonary disease (COPD), remain unknown. We have addressed this problem using whole-body plethysmography in guinea-pigs, common models to study harmful effects of CS on the respiratory system. Breathing frequencies (Bf) in control (2-5 months old) guinea pigs is 90-100 breaths/min, their tidal volume (TV) increased with age but lagged behind body weight gain and, as consequence, their minute volume (MV)/Kg decreased with age. MV did not change by acutely breathing 10% O(2) but doubled while breathing 5% CO(2) in air. Exposure to chronic sustained hypoxia (15 days, 12% O(2), CH) did not elicit ventilatory acclimatization nor adaptation. These findings confirm the unresponsiveness of the guinea pig CB to hypoxia. Exposure to CS (3 months) increased Bf and MV but association with CH blunted CS effects. We conclude that CS and CH association accelerates CS-induced respiratory system damage leading to a hypoventilation that can worsen the ongoing COPD process.

Neural plasticity is defined as a persistent change in the morphology and/or function based on prior experiences. Plasticity is well evident when the triggering experience occurs early in life, but in the case of respiratory control plasticity, it also can be triggered in adult life. We have combined a 10 days postnatal hypoxic (PH) (0-10 days of age;11% O(2)) and a 15 days intermittent hypoxia (IH) exposures in the adulthood (90-105 days of age; 5% O(2), 40 s/20% O(2), 80 s; 8 h/day) to test if early PH interacts with IH of the adulthood to generate detrimental plastic changes. After recording of ventilatory parameters, the brains were studied immunocytochemically for localization of the organization pattern of non-phosphorylated subunit of neurofilament H (NFH) and tyrosine hydroxylase (TH) expression in the nucleus tractus solitarius (Sol) and caudal (CVL) and rostral ventrolateral reticular (RVL) nuclei, areas related to central cardio-respiratory regulation. In comparison to control, PH male rats (but not females) at 1 month of age hyperventilated at rest, in response to moderate hypoxia (12% O(2)) and 5% CO(2), the effect being due to increased tidal volume. At 3.5 months sex differences in ventilation disappeared and it was indistinguishable between control and PH. IH tended to decrease ventilation in both control (C) and PH animals. PH augmented PENH values in air and in hypoxic conditions when compared with C group. IH in both groups, tended to decrease the PENH value, being statistically different in PH+IH. Results also show an increment of disorganization of NFH-positive labeled structures at the level of Sol and CVL/RVL nuclei in PH, IH and HP+HI groups. PH rats showed differences in the number of TH-positive neurons at the level of CVL/RVL nuclei, which was increased in the PH and PH+IH groups with respect to C one. In conclusion, PH alters the central morpho-physiological organization and the catecholaminergic components of cardio-respiratory nuclei, whose effects were enhanced after a period of IH in the adulthood.

Serotonin or 5-HT is a biogenic amine present in the carotid body (CB) of several species as evidenced in many immunocytochemical studies and in a few biochemical measurements. Early literature on 5-HT actions in the CB in all studied species has lead to the conclusion that it does not participate in the setting of conducted action potentials in the sensory nerve of the CB. However, during the last 10 years very important roles in the cellular physiology of the CB have been proposed for this biogenic amine. These roles include a primary role in setting the excitability of chemoreceptor cells via an autocrine or paracrine action, and thereby, the conducted activity in the carotid sinus nerve, and a critical role in the genesis of long term sensory facilitation observed in CBs of animals exposed to intermittent hypoxia. These facts, along with important discrepancies in the endogenous levels of 5-HT in the CB prompted present study conducted in rat CBs. We measured CB endogenous 5-HT content by HPLC with electrochemical detection and found levels of 5-HT in the range of 15–22 pmole/mg tissue in control and chronically hypoxic animals either sustained or intermittent, with no significant differences among them. 5-HT and the 5-HT2A antagonist ketanserin dose-dependently activated chemoreceptor cells as assessed by their capacity to release catecholamines from freshly isolated CB. In preliminary experiments we have observed that intense hypoxia and high extracellular K+ promote a small release of 5-HT from CB which is not dependent on the presence of extracellular Ca2+. Further studies are needed to firmly establish the dynamics of 5-HT in the CB of the rat., Supported by Grants BFU2007-61848 (DGICYT), CIBER CB06/06/0050 (ISCiii), and Accion Integrada (Micinn, Spain) PT2009-0172.

Neural plasticity is defined as a persistent change in the morphology and/or function based on prior experiences. Plasticity is well evident when the triggering experience occurs early in life, but in the case of respiratory control plasticity, it also can be triggered in adult life. We have combined a 10 days postnatal hypoxic (PH) (0–10 days of age;11% O2) and a 15 days intermittent hypoxia (IH) exposures in the adulthood (90–105 days of age; 5% O2, 40 s/20% O2, 80 s; 8 h/day) to test if early PH interacts with IH of the adulthood to generate detrimental plastic changes. After recording of ventilatory parameters, the brains were studied immunocytochemically for localization of the organization pattern of non-phosphorylated subunit of neurofilament H (NFH) and tyrosine hydroxylase (TH) expression in the nucleus tractus solitarius (Sol) and caudal (CVL) and rostral ventrolateral reticular (RVL) nuclei, areas related to central cardio-respiratory regulation. In comparison to control, PH male rats (but not females) at 1 month of age hyperventilated at rest, in response to moderate hypoxia (12% O2) and 5% CO2, the effect being due to increased tidal volume. At 3.5 months sex differences in ventilation disappeared and it was indistinguishable between control and PH. IH tended to decrease ventilation in both control (C) and PH animals. PH augmented PENH values in air and in hypoxic conditions when compared with C group. IH in both groups, tended to decrease the PENH value, being statistically different in PH+IH. Results also show an increment of disorganization of NFH-positive labeled structures at the level of Sol and CVL/RVL nuclei in PH, IH and HP+HI groups. PH rats showed differences in the number of TH-positive neurons at the level of CVL/RVL nuclei, which was increased in the PH and PH+IH groups with respect to C one. In conclusion, PH alters the central morpho-physiological organization and the catecholaminergic components of cardio-respiratory nuclei, whose effects were enhanced after a period of IH in the adulthood., Supported by Grants BFU2007-61848 (DGICYT), CIBER CB06/06/0050 (ISCiii), and P08-CVI-03934 and P09-CVI-4617 (Junta de Andalucía).

Ventilatory effects of chronic cigarette smoke (CS) alone or associated to chronic hypoxia (CH), as frequently occurs in chronic obstructive pulmonary disease (COPD), remain unknown. We have addressed this problem using whole-body plethysmography in guinea-pigs, common models to study harmful effects of CS on the respiratory system. Breathing frequencies (Bf) in control (2–5 months old) guinea pigs is 90–100 breaths/min, their tidal volume (TV) increased with age but lagged behind body weight gain and, as consequence, their minute volume (MV)/Kg decreased with age. MV did not change by acutely breathing 10% O2 but doubled while breathing 5% CO2 in air. Exposure to chronic sustained hypoxia (15 days, 12% O2, CH) did not elicit ventilatory acclimatization nor adaptation. These findings confirm the unresponsiveness of the guinea pig CB to hypoxia. Exposure to CS (3 months) increased Bf and MV but association with CH blunted CS effects. We conclude that CS and CH association accelerates CS-induced respiratory system damage leading to a hypoventilation that can worsen the ongoing COPD process., The work was supported by the “Ministerio de Ciencia e Innovación of Spain”(grant number BFU2007-61848) and by the “Instituto Carlos III”(grant number CIBER CB06/06/0050).

Obstructive sleep apnea is a frequent medical condition consisting in repetitive sleep-related episodes of upper airways obstruction and concurrent events of arterial blood hypoxia. There is a frequent association of cardiovascular diseases and other pathologies to this condition conforming the obstructive sleep apnea syndrome (OSAS). Laboratory models of OSAS consist in animals exposed to repetitive episodes of intermittent hypoxia (IH) which also develop cardiovascular pathologies, mostly hypertension. The overall OSAS pathophysiology appears to be linked to the repetitive hypoxia, which would cause a sensitization of carotid body (CB) chemoreflex and chemoreflex-driven hyperreactivity of the sympathetic nervous system. However, this proposal is uncertain because hyperventilation, reflecting the CB sensitization, and increased plasma CA levels, reflecting sympathetic hyperreactivity, are not constant findings in patients with OSAS and IH animals. Aiming to solve these uncertainties we have studied the entire CB chemoreflex arch in a rat model of IH, including activity of chemoreceptor cells and CB generated afferent activity to brainstem. The efferent activity was measured as ventilation in normoxia, hypoxia, and hypercapnia. Norepinephrine turnover in renal artery sympathetic endings was also assessed. Findings indicate a sensitization of the CB function to hypoxia evidenced by exaggerated chemoreceptor cell and CB afferent activity. Yet, IH rats exhibited marked hypoventilation in all studied conditions and increased turnover of norepinephrine in sympathetic endings. We conclude that IH produces a bias in the integration of the input arising from the CB with a diminished drive of ventilation and an exaggerated activation of brainstem sympathetic neurons. © 2010 Wiley-Liss, Inc..