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La suplementación con algas marinas, tanto macroalgas como microalgas, busca una nutrición óptima y completa. Las microalgas destacan por su alto contenido en nutrientes esenciales, antioxidantes y propiedades antiinflamatorias. Su biodisponibilidad única y capacidad para reducir inflamación y estrés oxidativo las hace valiosas para deportistas que buscan mejorar su rendimiento y recuperación., Grado en Enfermería

La cronobiología estudia los ritmos biológicos y circadianos de los seres vivos y su adaptación a cambios externos. Los ritmos biológicos pueden afectar a muchos procesos fisiológicos como la producción de hormonas y los ciclos sueño/vigilia o hambre/saciedad. Los horarios en los que nos alimentamos y el estilo de vida que llevamos influencian los procesos fisiológicos, y tienen gran impacto en la aparición de problemas metabólicos como la obesidad o la diabetes. Numerosos estudios han demostrado como los ritmos biológicos son alterados por los horarios del sueño y de las comidas, y se encuentran a merced del estilo de vida de cada persona., Máster en Nutrición Geriátrica

The association between obstructive sleep apnea (OSA) and metabolic disorders is well-established; however, the underlying mechanisms that elucidate this relationship remain incompletely understood. Since the liver is a major organ in the maintenance of metabolic homeostasis, we hypothesize that liver dysfunction plays a crucial role in the pathogenesis of metabolic dysfunction associated with obstructive sleep apnea (OSA). Herein, we explored the underlying mechanisms of this association within the liver. Experiments were performed in male Wistar rats fed with a control or high fat (HF) diet (60% lipid-rich) for 12 weeks. Half of the groups were exposed to chronic intermittent hypoxia (CIH) (30 hypoxic (5% O2) cycles, 8 h/day) that mimics OSA, in the last 15 days. Insulin sensitivity and glucose tolerance were assessed. Liver samples were collected for evaluation of lipid deposition, insulin signaling, glucose homeostasis, hypoxia, oxidative stress, antioxidant defenses, mitochondrial biogenesis and inflammation. Both the CIH and HF diet induced dysmetabolism, a state not aggravated in animals submitted to HF plus CIH. CIH aggravates hepatic lipid deposition in obese animals. Hypoxia-inducible factors levels were altered by these stimuli. CIH decreased the levels of oxidative phosphorylation complexes in both groups and the levels of SOD-1. The HF diet reduced mitochondrial density and hepatic antioxidant capacity. The CIH and HF diet produced alterations in cysteine-related thiols and pro-inflammatory markers. The results obtained suggest that hepatic mitochondrial dysfunction and oxidative stress, leading to inflammation, may be significant factors contributing to the development of dysmetabolism associated with OSA.

Obstructive sleep apnea (OSA) during pregnancy is characterized by episodes of intermittent hypoxia (IH) during sleep, resulting in adverse health outcomes for mother and offspring. Despite a prevalence of 8-20% in pregnant women, this disorder is often underdiagnosed.We have developed a murine model of gestational OSA to study IH effects on pregnant mothers, placentas, fetuses, and offspring. One group of pregnant rats was exposed to IH during the last 2 weeks of gestation (GIH). One day before the delivery date, a cesarean section was performed. Other group of pregnant rats was allowed to give birth at term to study offspring's evolution.Preliminary results showed no significant weight differences in mothers and fetuses. However, the weight of GIH male offspring was significantly lower than the controls at 14 days (p < 0.01). The morphological study of the placentas showed an increase in fetal capillary branching, expansion of maternal blood spaces, and number of cells of the external trophectoderm in the tissues from GIH-exposed mothers. Additionally, the placentas from the experimental males were enlarged (p < 0.05). Further studies are needed to follow the long-term evolution of these changes to relate the histological findings of the placentas with functional development of the offspring in adulthood.

This work analyzes the impact of two conditions, intermittent hypoxia exposure and high-fat diet in rats as models of sleep apnea. We studied the autonomic activity and histological structure of the rat jejunum and whether the overlapping of both conditions, as often observed in patients, induces more deleterious effects on the intestinal barrier. We found alterations in jejunum wall histology, predominantly in HF rats, based on increased crypt depth and submucosal thickness, as well as decreased muscularis propria thickness. These alterations were maintained with the IH and HF overlap. An increase in the number and size of goblet cells in the villi and crypts and the infiltration of eosinophils and lymphocytes in the lamina propria suggest an inflammatory status, confirmed by the increase in plasma CRP levels in all experimental groups. Regarding the CAs analysis, IH, alone or combined with HF, causes a preferential accumulation of NE in the catecholaminergic nerve fibers of the jejunum. In contrast, serotonin increases in all three experimental conditions, with the highest level in the HF group. It remains to be elucidated whether the alterations found in the present work could affect the permeability of the intestinal barrier, promoting sleep apnea-induced morbidities.

Metformin is a glucose-lowering, insulin-sensitizing drug that is commonly used in the treatment of type 2 diabetes (T2D). In the last decade, the carotid body (CB) has been described as a metabolic sensor implicated in the regulation of glucose homeostasis, being CB dysfunction crucial for the development of metabolic diseases, such as T2D. Knowing that metformin could activate AMP-activated protein kinase (AMPK) and that AMPK has been described to have an important role in CB hypoxic chemotransduction, herein we have investigated the effect of chronic metformin administration on carotid sinus nerve (CSN) chemosensory activity in basal and hypoxic and hypercapnic conditions in control animals. Experiments were performed in male Wistar rats subjected to 3 weeks of metformin (200 mg/kg) administration in the drinking water. The effect of chronic metformin administration was tested in spontaneous and hypoxic (0% and 5% O2) and hypercapnic (10% CO2) evoked CSN chemosensory activity. Metformin administration for 3 weeks did not modify the basal CSN chemosensory activity in control animals. Moreover, the CSN chemosensory response to intense and moderate hypoxia and hypercapnia was not altered by the chronic metformin administration. In conclusion, chronic metformin administration did not modify chemosensory activity in control animals.

Despite the great advances in macroautophagy/autophagy research in the last years, the in vivo role of the different members of the four mammalian orthologs of yeast Atg4 protease (ATG4A-D) remain unclear. To gain further insights into the functional relevance of Atg4 orthologs, we have generated mutant mice deficient in Atg4c. These mice are viable and fertile, and do not display any obvious abnormalities, indicating that they are able to develop the autophagic response required during the early neonatal period. However, they show tissue-specific autophagy alterations, including reduced autophagic flux in diaphragm and show decreased breathing and locomotor activity after fasting. In addition, atg4c-/- mice show reduced number of circulating T and B lymphocytes, which is associated with accumulation of apoptotic cells in the spleen and an increased susceptibility to develop chemically-induced fibrosarcomas. Moreover, through the analysis of cells and mice simultaneously deficient for ATG4C and ATG4D proteases we also reveal a role for ATG4C in mATG8 proteins delipidation.

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

Carotid body (CB) chemoreceptor cells sense arterial blood PO2, generating a neurosecretory response proportional to the intensity of hypoxia. Hydrogen sulfide (H2S) is a physiological gaseous messenger that is proposed to act as an oxygen sensor in CBs, although this concept remains controversial. In the present study we have used the H2S scavenger and vitamin B12 analog hydroxycobalamin (Cbl) as a new tool to investigate the involvement of endogenous H2S in CB oxygen sensing. We observed that the slow-release sulfide donor GYY4137 elicited catecholamine release from isolated whole carotid bodies, and that Cbl prevented this response. Cbl also abolished the rise in [Ca2+]i evoked by 50 µM NaHS in enzymatically dispersed CB glomus cells. Moreover, Cbl markedly inhibited the catecholamine release and [Ca2+]i rise caused by hypoxia in isolated CBs and dispersed glomus cells, respectively, whereas it did not alter these responses when they were evoked by high [K+]e. The L-type Ca2+ channel blocker nifedipine slightly inhibited the rise in CB chemoreceptor cells [Ca2+]i elicited by sulfide, whilst causing a somewhat larger attenuation of the hypoxia-induced Ca2+ signal. We conclude that Cbl is a useful and specific tool for studying the function of H2S in cells. Based on its effects on the CB chemoreceptor cells we propose that endogenous H2S is an amplifier of the hypoxic transduction cascade which acts mainly by stimulating non-L-type Ca2+ channels.

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.

Desde un enfoque integrador, que combina estudios funcionales in vivo e in vitro, se ha probado la hipótesis de que el efecto hipertensivo arterial sistémico de la hipoxia crónica intermitente, producido en la enfermedad respiratoria de la apnea obstructiva del sueño, se atenuaría o eliminaría debido a una respuesta quimiorreceptora menor en las ratas viejas y por falta de capacidad de respuesta del cuerpo carotídeo en los cobayas. Los datos muestran que la hipoxia crónica intermitente produce sensibilización del cuerpo carotídeo en la rata vieja sin modificaciones cardiovasculares aparentes. Por el contrario, la hipoxia crónica intermitente en el cobaya modifica parámetros cardiovasculares y metabólicos sin cambios en la funcionalidad del cuerpo carotídeo., Departamento de Bioquímica y Biología Molecular y Fisiología, Doctorado en Investigación Biomédica

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.

El cuerpo carotídeo (CC) tiene un papel fundamental en la génesis de las modificaciones que participan en el síndrome de apnea obstructiva del sueño debido a la activación y sensibilización de este órgano quimiorreceptor por la hipoxia crónica intermitente (HCI). Dichos fenómenos conducen a la activación secuencial de centros nerviosos troncoencefálicos y del simpático que tratarán de mantener la homeostasis del organismo al aumentar la ventilación y generar una respuesta vasopresora. Sin embargo, su activación permanente produce efectos adversos que conducen a la hipertensión sistémica. Por otra parte, otros mecanismos independientes de la sensibilización del CC se han propuesto como mecanismos patogénicos que también conducen a la hipertensión a través fundamentalmente de la disfunción endotelial. En esta tesis se han utilizado dos modelos animales de HCI, rata joven y vieja y cobaya joven, con el objetivo de avanzar en el conocimiento sobre los efectos de la HCI mediados y no mediados por el CC. Los principales resultados encontrados en el modelo de HCI de rata joven y vieja son la sensibilización del CC similar en ambas edades después de 15 días de exposición a HCI. Estos resultados no se correlacionan con una sensibilización del reflejo respiratorio, medido como aumento de la respuesta ventilatoria hipóxica en ninguna de las edades analizadas. Las ratas jóvenes muestran una alteración hemodinámica presentando hipertensión. Estos resultados se ajustan en parte a las características de los pacientes que sufren AOS, los cuales muestran un aumento en la respuesta respiratoria y una actividad nerviosa simpática elevada frente a la hipoxia aguda, lo que les hace propensos a desarrollar hipertensión sistémica. El envejecimiento produce un declive gradual en la función de los órganos y sistemas corporales; en este sentido la edad per se en las ratas produce hipertensión sin que la HCI lo modifique. Estos animales presentan una tendencia a sufrir disfunción endotelial e

[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.

[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.

[Aims/hypothesis] A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents., [Methods] Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT., [Results] KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks., [Conclusions/interpretation] KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O2) and hypercapnia (5% CO2) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH promoted

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.

[Background & Aims]: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD). [Methods]: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects. [Results]: CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10 days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD+/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK. [Conclusions]: rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD. © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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.

Previously we have reported that association of cigarette smoke (CS) and chronic hypoxia (CH) interact positively to physiopathologically remodel pulmonary circulation. In present study we have exposed guinea pigs to CS smoke (four cigarettes/day; 3 months; CS) and to chronic hypoxia (12% O2, 15 days; CH) alone or in combination (CSCH animals) and evaluated airways remodeling and resistance assessed as Penh (enhance pause). We measured Penh while animals breathe air, 10% O2 and 5% CO2 and found that CS and CH animals have higher Penh than controls; Penh was even larger in CSCH animals. A rough parallelism between Penh and thickness of bronchiolar wall and muscular layer and Goblet cell number was noticed. We conclude that CS and CH association accelerates CS-induced respiratory system damage, evidenced by augmented airway resistance, bronchial wall thickness and muscularization and Goblet cell number. Our findings would suggest that appearance of hypoxia would aggravate any preexisting pulmonary pathology by increasing airways resistance and reactivity. © 2011 Elsevier B.V.

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.

Hypoxia-induced dopamine (DA) release from carotid body (CB) glomus cells and activation of postsynaptic D2 receptors have been proposed to play an important role in the neurotransmission process between the glomus cells and afferent nerve endings. To better resolve the role of D2 receptors, we examined afferent nerve activity, catecholamine content and release, and ventilation of genetically engineered mice lacking D2 receptors (D2 -/- mice). Single-unit afferent nerve activities of D2 -/- mice in vitro were significantly reduced by 45% and 25% compared with wild-type (WT) mice during superfusion with saline equilibrated with mild hypoxia (PO2 ∼50 Torr) or severe hypoxia (PO2 ∼20 Torr), respectively. Catecholamine release in D2 -/- mice was enhanced by 125% in mild hypoxia and 75% in severe hypoxia compared with WT mice, and the rate of rise was increased in D2 -/- mice. We conclude that CB transduction of hypoxia is still present in D2 -/- mice, but the response magnitude is reduced. However, the ventilatory response to acute hypoxia is maintained, perhaps because of an enhanced processing of chemoreceptor input by brain stem respiratory nuclei. Copyright © 2007 the American Physiological Society.