Correlation Between Adenosine Triphosphate Levels, Dopamine Release and Electrical Activity in the Carotid Body: Support for the Metabolic Hypothesis of Chemoreception

Producción CientíficaAn unsolved issue for the arterial chemoreceptors is the mechanism by which hypoxia and other natural stimuli lead to an increase of activity in the carotid sinus nerve. According to the 'metabolic hypothesis', the hypoxic activation of the carotid body (CB) is mediated by a decrease of the ATP levels in the type I cells, which then release a neurotransmitter capable of exciting the sensory nerve endings. Using an in vitro preparation of cat CB, we report that ATP levels in the CB do in fact decrease when the organs are exposed to moderate, short lasting hypoxia (5 min 20% 02). Additionally, we found that decreases in ATP levels induced by 2-deoxyglucose (2 mM) or sodium cyanide (0.1 raM) are closely correlated with dopamine release from type I cells and electrical activity in the carotid sinus nerve elicited by these agents. The possible cause-effect relationship of these events is discusse

Effects of 2-Deoxy-D-Glucose on In Vitro Cat Carotid Body

Producción CientíficaThe process of chemosensory transduction in the arterial chemoreceptors is not well understood. According to the metabolic hypothesis of chemoreception, a decrease in arterial pO 2 will produce a decrease in the adenosine triphosphate (ATP) content in the chcmosensory type I cells, leading to release of a neurotransmitter and increased sensory neural activity. There is a paucity of direct experimental support for this hypothesis, and in the present work, we have tested the postulates of the metabolic hypothesis in an in vitro preparation of cat carotid body using 2-deoxy-D-glucose as an ATP-depleting agent. This preparation, when superfused with Tyrode containing 5 mM Na+-pyruvate instead of glucose, responds normally to hypoxia, low pH and acetylcholinc, and maintains normal ATP levels. Under these conditions, 2-deoxy-D-glucose is a chemostimulant, i.e. electrical activity in the carotid sinus nerve is increased, with a threshold concentration of 0.25 mM and a maximum response at about 2-4 raM. These concentrations of 2-deoxyglucose evoke a dose-dependent release of [3H]dopamine (synthesized from pH]tyrosine) from the carotid bodies which parallels the electrical activity. The 2-deoxy-D-glucose-evoked release and electrical activity is dependent on the presence of extracellular Ca 2+ . These same concentrations of 2-deoxy-D-glucose significantly reduce the ATP content of the carotid bodies. The events postulated bv the metabolic hypothesis, i.e. decrease in ATP content, release of a putative neurotransminer and activation of the sensory nerve endings are found to occur simultaneously. A possible cause-effect relationship between these three events is discussed

Marketing turístico: El caso del Caixa Forum

EL TFG titulado Marketing Touristico: El caso del Caisa Forum, consiste en una ionvestigación de mercado acerca del centro, para poder conocer los puntos fuertes y debiles y asi mejorar estos último

The role of dihydropydine-sensitive Ca2 + channels in stimulus-evoked catecholamine release from chemoreceptor cells of the carotid body

Producción CientíficaAhatraet-The present study utilized an in vitro preparation of the rabbit carotid body, with tissue catecholamine stores labeled by incubation with ‘H-tyrosine. The goal was to characterize pharmacologically the vol~g~~n&nt Ca*+ channels present in the type I (glomus) cells of this arterial chemoreceptor organ, and to elucidate their role as pathways for Ca2+ entry. We found that release of ‘H-dopamine induced by high external potassium was over 95% dependent on external cakium concentration and that this release was 9&100% inhibited by the dihydropy~~ne antagonists, nisoldipine and nitrendipine, and was potentiated by the dihydropyridine agonist, BayK 8444. Therefore, any stimulus-induced, cakiumdependent release of 3H-dopamine that was inhibited by nisoldipine and potentiated by BayK 8644, was considered to be supported by Ca2+ entry into the cells via voltage-dependent Ca2+ channels. Significant differences were observed in the release of ‘H-dopamine induced by 75 vs 25mM K+. On prolonged stimulation, release induced by 75 mM K+ was large and transient, whilst that induced by 25 mM K+, although more moderate, was sustained. The release elicited by 75 mM K+ was inhibited approximately 90% by 1.5 mM Co2+ or 625 nM nisoldipine, while release by 25 mM K+ was completely blocked by 0.6 mM Co*+ or 125 nM nisoldipine. Low PO,-induced release of 3H-dopamine was 95% dependent on Ca*+, and was inhibited by nisoldipine (625 nM) in a manner inversely proportional to the intensity of hypoxic stimulation, i.e. 79% inhibition at a PO, of 49 Torr, and 20% inhibition at PO2 of 0 Torr. BayK 8644 potentiatcd the release induced by moderate hypoxic stimuli. Release elicited by high PCOJlow pH, or by Na+-propionate or dinitrophenol~n~ining solutions, was approximately 80% Ca’+-dependent, and the ~hyd~y~din~ failed to modify this release. It is concluded that type I mlls possess vol~~de~nd~t Ca ‘+ channels sensitive to the dihydropy~dines, which in agreement with previous el~trophysiolo~~l data should be defined as L-type Ca*+ channels. Calcium entry which supports the release of 3H-dopamine elicited by moderate hypoxia should occur mainly through these channels while the release induced by strong hypoxic stimuli will be SetNed by Ca2+ entry which occurs in part via voltage-dependent Ca2+ channels, and in part through an additional pathway, probably a Na+/Ca2+ exchanger. The insensitivity to dihydropyridines of the release of )H-dopamine induced by high 1DC02/low pH, Na+-propionate and dinitrophenol may indicate a complete loss of efficacy of the drugs to modulate Ca 2+ channels under these conditions or more likely, that other mechanisms are activated, probably the Na+-Ca’+ exchanger. Carotid body (CB) chemoreceptors are thought to be composite receptors in which the type I (glomus) cells detect changes in blood PO,, PCO, and pH and respond with the release of neurotransmitt~ to activate the closely apposed chemosensory nerve terminals.~** One such neurotransmitter that has received considerable attention in recent years and is known to be released by the type I cells is dopamine (DA). This biogenic amine has been shown to be released in proportion to both the intensity of stimulation and the resultant sensory discharge recorded from the carotid sinus nerve $To whom correspondence should be addressed. Abbr~~~~~~ CB, carotid body; CSN, carotid sinus nerve; DA, dopamine; DHMA, dihydrox~~delic acid, DOPAC, dihydroxyphenyl acetic acid; NE, norepinephrine. (CSN). This relationship between stimulu

Adicción a videojuegos y agresividad en estudiantes de secundaria de una institución educativa particular de Chimbote, 2022

El propósito del estudio fue determinar la relación entre la adicción a los videojuegos y la agresividad en estudiantes de secundaria de una Institución Educativa Particular de Chimbote, 2022. El tipo de investigación fue básica y de diseño fue no experimental, enfoque cuantitativo, transversal y de tipo correlacional. Se evalúo a toda la población de 85 estudiantes con el Test de dependencia a los videojuegos (TDV) de Cholíz y Marco (2011) y el Cuestionario de Agresividad (AQ) de Buss y Perry (1992). Los resultados mostraron una relación significativa y directa entre ambas variables analizadas; lo cual quiere decir, que cuando existe mayor adicción a los videojuegos existe un nivel de agresividad elevada en el estudiante. Además, se encontró la prevalencia del nivel bajo en adicción a los videojuegos y en lo que corresponde a agresividad un nivel medio. Finalmente, se encontró una relación significativa y directa entre las dimensiones de la adicción a los videojuegos (Abstinencia, Dificultad para el control, Abuso y tolerancia y Problemas ocasionados por los videojuegos) con la agresivida

Exploring the mediators that promote carotid body dysfunction in type 2 diabetes and obesity related syndromes

Carotid bodies (CBs) are peripheral chemoreceptors that sense changes in blood O2, CO2, and pH levels. Apart from ventilatory control, these organs are deeply involved in the homeostatic regulation of carbohydrates and lipid metabolism and inflammation. It has been described that CB dysfunction is involved in the genesis of metabolic diseases and that CB overactivation is present in animal models of metabolic disease and in prediabetes patients. Additionally, resection of the CB-sensitive nerve, the carotid sinus nerve (CSN), or CB ablation in animals prevents and reverses diet-induced insulin resistance and glucose intolerance as well as sympathoadrenal overactivity, meaning that the beneficial effects of decreasing CB activity on glucose homeostasis are modulated by target-related efferent sympathetic nerves, through a reflex initiated in the CBs. In agreement with our pre-clinical data, hyperbaric oxygen therapy, which reduces CB activity, improves glucose homeostasis in type 2 diabetes patients. Insulin, leptin, and pro-inflammatory cytokines activate the CB. In this manuscript, we review in a concise manner the putative pathways linking CB chemoreceptor deregulation with the pathogenesis of metabolic diseases and discuss and present new data that highlight the roles of hyperinsulinemia, hyperleptinemia, and chronic inflammation as major factors contributing to CB dysfunction in metabolic disorders.publishersversionpublishe

Guinea Pig Oxygen-Sensing and Carotid Body Functional Properties

Mammals have developed different mechanisms to maintain oxygen supply to cells in response to hypoxia. One of those mechanisms, the carotid body (CB) chemoreceptors, is able to detect physiological hypoxia and generate homeostatic reflex responses, mainly ventilatory and cardiovascular. It has been reported that guinea pigs, originally from the Andes, have a reduced ventilatory response to hypoxia compared to other mammals, implying that CB are not completely functional, which has been related to genetically/epigenetically determined poor hypoxia-driven CB reflex. This study was performed to check the guinea pig CB response to hypoxia compared to the well-known rat hypoxic response. These experiments have explored ventilatory parameters breathing different gases mixtures, cardiovascular responses to acute hypoxia, in vitro CB response to hypoxia and other stimuli and isolated guinea pig chemoreceptor cells properties. Our findings show that guinea pigs are hypotensive and have lower arterial pO2 than rats, probably related to a low sympathetic tone and high hemoglobin affinity. Those characteristics could represent a higher tolerance to hypoxic environment than other rodents. We also find that although CB are hypo-functional not showing chronic hypoxia sensitization, a small percentage of isolated carotid body chemoreceptor cells contain tyrosine hydroxylase enzyme and voltage-dependent K+ currents and therefore can be depolarized. However hypoxia does not modify intracellular Ca2+ levels or catecholamine secretion. Guinea pigs are able to hyperventilate only in response to intense acute hypoxic stimulus, but hypercapnic response is similar to rats. Whether other brain areas are also activated by hypoxia in guinea pigs remains to be studied

Effects of Gestational Intermittent Hypoxia on Placental Morphology and Fetal Development in a Murine Model of Sleep Apnea

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.Ayudas para la realización de proyectos de investigación UVa 2021 (PROYEMER 57-E.O.

Intracellular Ca2 + deposits and catecholamine secretion by chemoreceptor cells of the rabbit carotid body

Producción CientíficaThe pívotal role of íntracellular free [Ca2+] fluctuatíons in the control of cellular functíons such as contraction and secretíon, íncludíng the release of neurotransmítters, was recognized many decades ago (see Rubín, 1982). More recently, the list of cellular functíons tríggered or modulated by the levels of Ca2+¡ has grown enormously. Addítional functíons regulated by [Ca2+)¡ include neuronal excítabílity, synaptic plastícíty, gene ex­ pressíon, cellular metabolísm, cell dívísíon and dífferentíatíon, and programmed cell dead (Míller, 1991; Clapham, 1995). Parallelíng the growth in this líst of Ca2+-controlled func­ tíons, a multíplicity of cellular mechanísms aimed at maintaining resting free [Ca2+)¡ in the range of l 00 nM for most cells has been described, allowing increases in Ca2+¡ levels that are specific in their magnitude, time course and spatial distributíon, accordíng to the cell function activated (Toescu, 1995). Since Ca2+ cannot be metabolized, cells regulate theír cytoplasmic levels of free Ca2+ through numerous bínding proteíns and influx and efflux mechanisms (Fíg 1). Ca2+ ínflux to cell cytoplasm from the extracellular milieu occurs vía voltage or receptor operated channels or vía yet ill-defined capacítatíve pathways; the Na+/Ca 2+ exchanger can also produce in sorne círcumstances net ínflux of Ca2+ (Míller, 1991; Clapham, 1995). Ca2+ ef­ flux to the extracellular space occurs against electrochemical gradíents, and thereby the pumpíng out of Ca2+ is directly (Caz+ pump) or indirectly (Na+/Ca2+) coupled to the hy­ drolysis of ATP

Effects of mitochondrial poisons on glutathione redox potential and carotid body chemoreceptor activity

Producción CientíficaLowoxygen sensing in chemoreceptor cells involves the inhibition of specific plasma membrane K+ channels, suggesting that mitochondria-derived reactive oxygen species (ROS) link hypoxia to K+ channel inhibition, subsequent cell depolarization and activation of neurotransmitter release.We have used several mitochondrial poisons, alone and in combination with the antioxidant N-acetylcysteine (NAC), and quantify their capacity to alter GSH/GSSG levels and glutathione redox potential (EGSH) in rat diaphragm. Selected concentrations of mitochondrial poisons with or without NAC were tested for their capacity to activate neurotransmitter release in chemoreceptor cells and to alter ATP levels in intact rat carotid body (CB).We found that rotenone (1 M), antimycin A (0.2 g/ml) and sodium azide (5mM) decreased EGSH; NAC restored EGSH to control values. At those concentrations mitochondrial poisons activated neurotransmitter release from CB chemoreceptor cells and decreased CB ATP levels, NAC being ineffective to modify these responses. Additional experiments with 3-nitroprionate (5 mM), lower concentrations of rotenone and dinitrophenol revealed variable relationships between EGSH and chemoreceptor cell neurotransmitter release responses and ATP levels. These findings indicate a lack of correlation between mitochondrialgenerated modifications of EGSH and chemoreceptor cells activity. This lack of correlation renders unlikely that alteration of mitochondrial production of ROS is the physiological pathway chemoreceptor cells use to signal hypoxia