Fernando de Castro and the discovery of the arterial chemoreceptors

Producción CientíficaWhen de Castro entered the carotid body(CB)field,the organ was considered to be a small autonomic ganglion,a gland,a glomusorglomerulus,or a paraganglion. In his 1928 paper,de Castro concluded:“Insum,the Glomuscarotic umisinnervated by centripetal fibers,whose trophic center sare located in thesensory ganglia of the glossopharyngeal, and not by centrifugal[efferent] or secret o motor fibers a sisthe case for glands ; these are precisely the facts which lead to suppose that the Glomuscaroticumisa sensory organ.”A few pages down,de Castro wrote:“The Glomus represents an organ with multiplereceptors furnished with specialized receptor cells like those of the sensory organs [tastebuds?]...As aplausible hypothesis we propos et hattheGlomuscaroti cum 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 are flex mechanism would have an effect on the functionalactivity of other organs... Therefore, thesensory fiber would not be directly stimulated by blood, but via the intermediation of the epithelial cell soft he organ, which, as their structures suggests, possess a secretory function which would participate in the stimulation of the centripetal fibers.”In our article we will recreat et he experiments that allowed Fernando de Castrotoreach this first conclusion. Also, we will scrutinize the natural endowment sand the scientific knowledge that drove de Castrotomaket the triple hypotheses : the CBaschemoreceptor (variationsinbloodcomposition),as a secondary sensory receptor which functioning involves a chemical synapse, and as a center, origin of systemicreflexes. After a brief account of the systemic reflex effects resulting from the CB stimulation, we wil lcomplete our article with a general view of the cellular-molecular mechanisms currently thought to be involved in the functionin go fthis arterial chemoreceptor

TP53 regulates human AlkB homologue 2 expression in glioma resistance to Photofrin-mediated photodynamic therapy

2010-2011 > Academic research: refereed > Publication in refereed journa

Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity

Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O(2)) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O(2)) and in response to hypoxias of different intensities (10, 5, and 2% O(2)) to study the release pathways. We found that ZM241385, an A(2) antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 30.8 and 72.5%, respectively. Suramin, a P(2)X antagonist, decreased the CSN discharges evoked by 0 and 7% O(2) by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O(2) levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.This work was supported by Portuguese Foundation for Science and Technology (PTDC/SAU-ORG/111417/2009), Spanish Micinn/Portugal CRUP 2009–0172, BFU2007–61848, and CIBERES.Peer Reviewe

Fernando de Castro and the discovery of the arterial chemoreceptors

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).Peer Reviewe

Chronic caffeine intake in adult rat inhibits carotid body sensitization produced by chronic sustained hypoxia but maintains intact chemoreflex output

Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A2B) was down-regulated and that in petrosal ganglion (A2A) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.The work was supported by Junta de Castilla y Leon [GR242]; Ciber de Enfermedades Respiratorias [CB06/06/0050 (FISS-ICIII)]; Dirección General de Investigación Científica y Tecnológica [BFU2007-61848]; Spanish MICINN/Portugal CRUP [2009-0172]; and Portuguese Foundation for Science and Technology [PTDC/SAU-ORG/111417/2009].Peer Reviewe

A revisit to O2 sensing and transduction in the carotid body chemoreceptors in the context of reactive oxygen species biology

14 páginas, 4 figuras, 2 tablas.-- This paper is part of a special issue entitled: “Physiological Redox: Regulation in Respiratory, Vascular, and Neural Cells”, guest-edited by Paul T. Schumacker and Jeremy P.T. Ward.Oxygen-sensing and transduction in purposeful responses in cells and organisms is of great physiological and medical interest. All animals, including humans, encounter in their lifespan many situations in which oxygen availability might be insufficient, whether acutely or chronically, physiologically or pathologically. Therefore to trace at the molecular level the sequence of events or steps connecting the oxygen deficit with the cell responses is of interest in itself as an achievement of science. In addition, it is also of great medical interest as such knowledge might facilitate the therapeutical approach to patients and to design strategies to minimize hypoxic damage. In our article we define the concepts of sensors and transducers, the steps of the hypoxic transduction cascade in the carotidbodychemoreceptor cells and also discuss current models of oxygen- sensing (bioenergetic, biosynthetic and conformational) with their supportive and unsupportive data from updated literature. We envision oxygen-sensing in carotidbodychemoreceptor cells as a process initiated at the level of plasma membrane and performed by a hemoprotein, which might be NOX4 or a hemoprotein not yet chemically identified. Upon oxygen-desaturation, the sensor would experience conformational changes allosterically transmitted to oxygen regulated K+ channels, the initial effectors in the transduction cascade. A decrease in their opening probability would produce cell depolarization, activation of voltage dependent calcium channels and release of neurotransmitters. Neurotransmitters would activate the nerve endings of the carotidbody sensory nerve to convey the information of the hypoxic situation to the central nervous system that would command ventilation to fight hypoxia.Supported Grants: BFU2007-61848 (DGICYT), CIBER CB06/06/0050 (FISS-ICiii) and JCyL-GR242.Peer reviewe

Biogeochemical flux and phytoplankton succession : a year-long sediment trap record in the Australian sector of the Subantarctic Zone

The Subantarctic Zone (SAZ) plays a crucial role in global carbon cycling as a significant sink for atmospheric CO2. In the Australian sector, the SAZ exports large quantities of organic carbon from the surface ocean, despite lower algal biomass accumulation in surface waters than other Southern Ocean sectors. We present the first analysis of diatom and coccolithophore assemblages and seasonality, as well as the first annual quantification of bulk organic components of captured material at the base of the mixed layer (500 m depth) in the SAZ. Sediment traps were moored in the SAZ southwest of Tasmania as part of the long-term SAZ Project for one year (September 2003 to September 2004). Annual mass flux at 500 m and 2000 m was composed mainly of calcium carbonate, while biogenic silica made up on average <10% of material captured in the traps. Organic carbon flux was estimated at 1.1 g m⁻² y⁻¹ at 500 m, close to the estimated global mean carbon flux. Low diatom fluxes and high fluxes of coccoliths were consistent with low biogenic silica and high calcium carbonate fluxes, respectively. Diatoms and coccoliths were identified to species level. Diatom and coccolithophore sinking assemblages reflected some seasonal ecological succession. A theoretical scheme of diatom succession in live assemblages is compared to successional patterns presented in sediment traps. This study provides a unique, direct measurement of the biogeochemical fluxes and their main biological carbon vectors just below the winter mixed layer depth at which effective sequestration of carbon occurs. Comparison of these results with previous sediment trap deployments at the same site at deeper depths (i.e. 1000, 2000 and 3800 m) documents the changes particle fluxes experience in the lower “twilight zone” where biological processes and remineralisation of carbon reduce the efficiency of carbon sequestration.17 page(s