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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

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.

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).

Obstructive sleep apnea syndrome (OSAS) is described as repetitive obstructions of the upper airways during sleep, causing concomitant episodes of systemic hypoxia and associated cardiovascular and metabolic pathologies. The mechanisms generating these pathologies are controversial. Because recurrent hypoxia is the element of inadequate respiration that leads to the pathology, experimental models of OSAS consist in the exposure of the animals to intermittent hypoxia (IH) by cycling O2 percentages in their habitats. A proposed mechanism linking the IH of OSAS to pathologies is the increased production of reactive oxygen species (ROS). However, it has been argued that many patients seem to lack oxidative stress and that, to augment ROS in IH animals, intense hypoxia, seldom encountered in patients, has to be applied. To solve the controversy, we have exposed rats to two intensities of IH (cycles of 10 or 5% O2, 40s, and then 21% O2, 80s; 8h/day, 15 days). We then measured reduced and oxidized glutathione and lipid peroxide levels, aconitase and fumarase activities, and ROS-disposal enzyme activity in liver, brain, and lung. Liver levels of nuclear NF-κB-p65 and plasma C-reactive protein (CRP), as well as lipid levels, were also assessed. Lowest hemoglobin saturations were 91.7 ± 0.8 and 73.5 ± 1.4%. IH caused tissue-specific oxidative stress related to hypoxic intensity. Nuclear NF-κB-p65 and lipid content in the liver and CRP in the plasma all increased with IH intensity, as did both plasma triglycerides and cholesterol. We conclude that IH, even of moderate intensity, causes oxidative stress probably related to the pathologies encountered in OSAS patients.

A circadian rhythm of heart rate and respiratory rate was seen at 1, 8, and 12 months of age in an infant born without ocular tissue, which supports the possibility that the time cues were nonphotic. No melatonin circadian rhythm was detected at any age up to 9 years of age, and this is most likely associated with the anophthalmia and lack of photic input to the suprachiasmatic nucleus. Usually circadian organization is present after the neonatal period and approaches adult levels with development.

Objective: To assess the age at which the circadian rhythm of melatonin begins. Methods: 55 children, divided into groups from the neonatal period to 24 months of life, were studied. Urine samples were taken from 28 newborn babies to measure 6-sulfatoxymelatonin (aMT6s). Salivary samples were collected from infants (27 cases), to measure melatonin (aMT). aMT was measured by RIA and aMT6s by ELISA using commercial kits. Changes in the levels of aMT6s and aMT were evaluated using the Friedman test and Wilcoxon matched pair test. Results: The group aged 27–41 days showed statistically significant differences in daily aMT6s and aMT concentrations. The highest values were always found between 24.00 and 8.00 h. This day/night difference persisted from 2–3 to 13–24 months of age. Conclusion: The data indicate that the circadian melatonin rhythm appears at the end of the neonatal period and persists thereafter.

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.

Adriamycin, an anthracyclinic antibiotic frequently used in quimioterapeutic treatments is highly toxic; it inhibits protein synthesis and provokes prooxidant effects. Melatonin has recently been shown to have high antioxidative properties. We tested if melatonin is able to neutralize the oxidative damage induced by a single dose (20 mg/kg, i.p.) of adriamycin preceded (3 days) and followed (7 days) by a low pharmacological dose (50 microg/kg, i.p.) of melatonin. After the administration of a single dose of adriamycin (20 mg/kg i.p.) to male Wistar rats, the reduced to oxidized glutathione (GSH/GSSG) ratio and the glutathione peroxidase (GPx, E.C. 1.11.1.9.) activity in the brain, intestine, heart, kidney, and lung were significantly reduced. When the treatment of adriamycin was preceded and followed by low pharmacological doses of melatonin, the decrease in the GSH/GSSG ratio was significantly reduced but the reduction in GPx activity was not attenuated. A significant increase in lipid peroxidation products was observed in brain, heart, and kidney tissues after a single administration of adriamycin, which was attenuated by pre- and post-treatment with a low pharmacological dose of melatonin. Our results demonstrate that oxidative damage induced by the antitumor drug, adriamycin, can be reduced by low pharmacological doses of melatonin.

OBJECTIVE To study the circadian rhythm of melatonin in children with enuresis. PATIENTS AND METHODS Twenty-five children, divided into two groups (enuretic patients and controls) were assessed; salivary samples were collected to measure melatonin by radioimmunoassay using commercial kits. Friedman two-way anova and Wilcoxon tests were used to assess the circadian rhythm of melatonin, and anova with between-patient factors and Mann-Whitney tests to compare melatonin values and groups. RESULTS Both groups had statistically significant differences in melatonin concentration during the 24-h period (both P

We have recently described, using perifused pineal glands, that calcium influx participates in the activation of chick pineal gland. This study shows that the loss of perifused chick pineal gland activity is a complex process which seems to involve the release of calcium from intracellular stores, calmodulin and calcium-activated neutral protease (CANP). Pineal glands were perifused with Krebs medium (controls) or with Krebs medium plus the drugs ethylene glycol tetraacetic acid (EGTA; calcium chelator), A23187 (calcium ionophore), EGTA plus A23187 (extra-intra cellular calcium chelation), trifluoperazine and CGS9343B (calmodulin inhibitors), and E-64 (CANP inhibitor) at the time of the natural peak of melatonin release. When EGTA or A23187 were added to the perifusion medium, no effects were observed. On the other hand, when the calcium chelator EGTA plus A23187 (free extra and intracellular calcium levels were dramatically decreased), trifluoperazine, CGS 9343B or E-64 were added to the perifusion medium melatonin synthesis increased significantly and was sustained for 8 h. We propose a prominent role for calcium output from intracellular stores in regulating melatonin production primarily by acting on Ca-calmodulin and calcium-activated neutral protease.

Melatonin is the neurohormone which is synthesized by the pineal gland and secreted rhythmically. The role of calcium in the activation of melatonin production remains unknown. In this study, we demonstrated that calcium input participates in the regulation of chick pineal gland. Pineal glands from Gallus domesticus were perifuse with Krebs medium (controls) or with Krebs medium plus drugs (ethylene glycol tetraacetic acid (EGTA) or calcium ionophore A23187). When EGTA was added to the perifusion medium, free extracellular calcium concentrations were dramatically decreased and melatonin synthesis was decreased. On the other hand, when the calcium ionophore A23187 was added to the perifusion medium, chick pineal glands exhibited a marked increase in secretion of melatonin. No effects were observed when chick pineal glands were treated with drugs during or after the time of the natural peak levels. We propose that calcium input from extracellular medium and output from intracellular calcium reserves are primary mechanisms in the activation of melatonin synthesis in the chick pineal gland.

This paper describes the influence of iron on both nuclear and cytosolic melatonin contents in several tissues of chicks. The neurohormone melatonin was estimated by means of radioimmunoassay. Iron, administered as FeCI3, decreased the nuclear melatonin level in a variety of tissues, including brain, heart, lung, kidney, and erythrocytes (nucleated cells in chicks) but was not seen in either the liver or gut. All variations related with iron were seen in the nuclear fraction, while only in the pineal gland did the melatonin content of the cytosol change as a result of iron treatment. We also observed a day-night rhythm in the nuclear melatonin: high nuclear levels of melatonin at night and low levels during the light period. This is the first report of nuclear localization of melatonin in any avian Cell. L 1996 Wiley-Liss, Inc.

The views presented in this article are the fruit of reflections and discussion with my colleagues at Valladolid and with the members of the Sleep Apnea Hypopnea Syndrome Group of the CIBERES (Spain). We have assembled the article in three sections. In the first one we provide a mechanistic description of obstructive sleep apnea (OSA) and all of its components, including the repetitive episodes of upper airways (UA) obstruction and accompanying hypoxic hypoxia, the respiratory efforts to fight and overcome the obstruction, and the sleep fragmentation due to the hypoxia-triggered arousal reactions, all events occurring during sleep hours with frequencies that might reach up40-50 episodes/sleep hour. When OSA is accompanied by some of the elements of a big cohort of associated pathologies (vascular, metabolic, and neuropsychiatric) it conforms the obstructive sleep apnea syndrome (OSAS). The high frequency of OSAS in adults (35 years old) and the costs in every regard of the treatment makes the syndrome a primary importance socio-sanitary problem. In the second section, we describe the experimental models of OSAS, basically the episodic repetitive hypoxic model described by Fletcher and coworkers in 1992, today named in short intermittent hypoxia (IH). From these lines, we want to call for some kind of consensus among researchers to lessen the dispersion of IH protocols. Finally, in the last section we intend to share our optimism with all ISAC members. The optimism is based on the recognition that carotid body (CB) chemoreceptors are critical elements of one of the main pathophysiologic loops in the genesis of OSAS. Therefore, we believe that all of us, as ISAC members, are well qualified to contribute in multidisciplinary research teams with well defined translational interests.

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.

The views presented in this article are the fruit of reflections and discussion with my colleagues at Valladolid and with the members of the Sleep Apnea Hypopnea Syndrome Group of the CIBERES (Spain). We have assembled the article in three sections. In the first one we provide a mechanistic description of obstructive sleep apnea (OSA) and all of its components, including the repetitive episodes of upper airways (UA) obstruction and accompanying hypoxic hypoxia, the respiratory efforts to fight and overcome the obstruction, and the sleep fragmentation due to the hypoxia-triggered arousal reactions, all events occurring during sleep hours with frequencies that might reach up >40–50 episodes/sleep hour. When OSA is accompanied by some of the elements of a big cohort of associated pathologies (vascular, metabolic, and neuropsychiatric) it conforms the obstructive sleep apnea syndrome (OSAS). The high frequency of OSAS in adults (>35 years old) and the costs in every regard of the treatment makes the syndrome a primary importance socio-sanitary problem. In the second section, we describe the experimental models of OSAS, basically the episodic repetitive hypoxic model described by Fletcher and coworkers in 1992, today named in short intermittent hypoxia (IH). From these lines, we want to call for some kind of consensus among researchers to lessen the dispersion of IH protocols. Finally, in the last section we intend to share our optimism with all ISAC members. The optimism is based on the recognition that carotid body (CB) chemoreceptors are critical elements of one of the main pathophysiologic loops in the genesis of OSAS. Therefore, we believe that all of us, as ISAC members, are well qualified to contribute in multidisciplinary research teams with well defined translational interests., Supported by the MICINN grant (BFU2007-61848) and Accion Integrada PT2009-0172 and ICiii-CIBERES CB06/06/0050.

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).

11 páginas, 6 figuras, 1 tabla., Moderate intake of alcoholic beverages decreases the incidence of cardiovascular pathologies, but it is in dispute if cardioprotective effects are due to ethanol, to polyphenolic compounds present in beverages or to a combination of both. In humans, effects of high, moderate, and low doses of alcoholic beverages are widely studied, but effects of pure alcohol remain unclear. On the other hand, experiments with laboratory animals are centered on high toxicological doses of ethanol but not on low doses. In the present study, we have aimed to mimic in the rat the pattern of alcohol intake in Mediterranean population. Alcohol ingestion is spread along the day and not always related to solid food consumption. We tried to define the beneficial and harmful effects of pure ethanol ingestion without polyphenol’s influence. Experimental rats were given 1% ethanol in their drinking water for 30 days, resulting in a daily ingestion of 0.27 mL of ethanol/rat/d. Ethanol ingestion did not cause deleterious effects on the general status of the animals, but it decreased cholesterol, triglycerides, and catecholamine stores’ rate of utilization in peripheral sympathetic system. Moreover, ethanol lowered pulmonary arterial pressure and did not alter systemic arterial pressure. In the liver, the reduced glutathione/oxidized glutathione ratio was augmented and lipid peroxide, superoxide dismutase, and glutathione peroxidase activities were decreased. However, catalase activity was unaltered. Liver cytochrome P4502E1 distribution and protein level and activity were unchanged by ethanol ingestion. Data indicate a lack of harmful effects and underscore a set of potentially beneficial effects of this dose of ethanol., Funding to this study was provided by Grants BFU2007- 61848 (MEC, Spain), CIBER CB06/06/0050 (FISS-ICiii, Spain) and JCyL GR242.

The arterial carotid body (CB) chemoreceptors are highly vascularized sensory organs located in the proximity of the carotid artery bifurcation and formed by clusters of parenchymal cells. The cell clusters are penetrated by sensory fibers of the carotid sinus nerve (CSN) which form synapses with the parenchymal chemoreceptor cells. Functionally, the CBs are the origin of a regulatory loop devoted to restore O2 availability in situations of hypoxia (Richalet, 1997). To achieve this function chemoreceptor cells detect blood PO2, being activated by hypoxia. Hypoxia increases the rate of the release of neurotransmitters from the cells augmenting the action potential frequency in the CSN; this increased activity stimulates the brainstem regulators of respiration and hyperventilation and increased arterial blood PO2 ensue (Gonzalez et al., 1994).

1. 1. Sarcolemma enriched fractions from rabbit (Oryctolagus cuniculus L.) and frog (Rana ridibunda Seoane) skeletal muscle were obtained. They are in the form of vesicles as shown by electron microscopic examination. 2. 2. These fractions of both sources have a high specific activity in putative membranes markers such as 5'-nucleotidase and (Na+ + K+-ATPase; they were nearly lacking in the mitochondrial marker succinate dehydrogenase. 3. 3. In membrane preparations from rabbit, electrophoretic analysis revealed 7 prominent protein bands (the mol. wts of which range from 30,000 to 200,000 daltons) and 3 bands for glycoproteins. In frog, 8 protein bands (the mol. wt ranging from 35,000 to 175,000) and 4 for glycoproteins were detected. 4. 4. The ratio ‘total lipid: protein’ was near 1 (1.1 in plasma membrane from rabbit, 0.98 in frog). The molar ratio ‘cholesterol : phospholipids’ was found to be 0.43 in rabbit, and 0.57 in frog. 5. 5. Very little carbohydrate was found (0.16 μmole/mg protein in rabbit, and 0.2 μmole/mg protein in frog). Glucose, mannose, galactose and fucose, hexosamines and sialic acid were determined in membranes of both sources.