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Aging cell (1)
Cardiovascular Research (1)
Respiratory Research (1)
The Journal of General Physiology (1)
González, Constancio (5)
Allhorn, Maria (1)
Almendros, Isaac (1)
Bastiani, Michael J. (1)
Batuca, Joana Rita (1)
Castañeda, Javier (1)
Cogolludo, Angel (1)
Do Carmo, Sonia (1)
Farré, Ramon (1)
Frazziano, Giovanna (1)
Ganfornina, Maria D. (1)
Lora, Jose M. (1)
López-López, José Ramón (1)
Menendez, Carmen (1)
Monteiro, Emília Carreira (1)
Monteiro, Teresa Castro (1)
Montserrat, Josep M (1)
Moral-Sanz, Javier (1)
Moreno, Laura (1)
Navajas, Daniel (1)
Obeso, Ana (1)
Perez-Vizcaino, Francisco (1)
Pérez-García, María Teresa (1)
Rassart, Eric (1)
Sanchez, Diego (1)
Torres, Marta (1)
Torres-Schumann, Sonia (1)
Villamor, Eduardo (1)
Vogel, Marci (1)
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Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine
Monteiro, Teresa Castro
Batuca, Joana Rita
Monteiro, Emília Carreira
The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A2-adenosine receptors stimulation and attenuated by D2-dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3′,5′-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A2A-adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB’s peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-010-9187-z) contains supplementary material, which is available to authorized users.
Aging; Peripheral chemoreceptors; Ventilation; Domperidone; cAMP; Adenosine A2A receptors
Changes in oxygen partial pressure of brain tissue in an animal model of obstructive apnea
Montserrat, Josep M
Cognitive impairment is one of the main consequences of obstructive sleep apnea (OSA) and is usually attributed in part to the oxidative stress caused by intermittent hypoxia in cerebral tissues. The presence of oxygen-reactive species in the brain tissue should be produced by the deoxygenation-reoxygenation cycles which occur at tissue level during recurrent apneic events. However, how changes in arterial blood oxygen saturation (SpO2) during repetitive apneas translate into oxygen partial pressure (PtO2) in brain tissue has not been studied. The objective of this study was to assess whether brain tissue is partially protected from intermittently occurring interruption of O2 supply during recurrent swings in arterial SpO2 in an animal model of OSA.
Twenty-four male Sprague-Dawley rats (300-350 g) were used. Sixteen rats were anesthetized and non-invasively subjected to recurrent obstructive apneas: 60 apneas/h, 15 s each, for 1 h. A control group of 8 rats was instrumented but not subjected to obstructive apneas. PtO2 in the cerebral cortex was measured using a fast-response oxygen microelectrode. SpO2 was measured by pulse oximetry. The time dependence of arterial SpO2 and brain tissue PtO2 was carried out by Friedman repeated measures ANOVA.
Arterial SpO2 showed a stable periodic pattern (no significant changes in maximum [95.5 ± 0.5%; m ± SE] and minimum values [83.9 ± 1.3%]). By contrast, brain tissue PtO2 exhibited a different pattern from that of arterial SpO2. The minimum cerebral cortex PtO2 computed during the first apnea (29.6 ± 2.4 mmHg) was significantly lower than baseline PtO2 (39.7 ± 2.9 mmHg; p = 0.011). In contrast to SpO2, the minimum and maximum values of PtO2 gradually increased (p < 0.001) over the course of the 60 min studied. After 60 min, the maximum (51.9 ± 3.9 mmHg) and minimum (43.7 ± 3.8 mmHg) values of PtO2 were significantly greater relative to baseline and the first apnea dip, respectively.
These data suggest that the cerebral cortex is partially protected from intermittently occurring interruption of O2 supply induced by obstructive apneas mimicking OSA.
Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress
Ganfornina, Maria D.
Do Carmo, Sonia
Lora, Jose M.
Bastiani, Michael J.
Many nervous system pathologies are associated with increased levels of Apolipoprotein D (ApoD), a lipocalin also expressed during normal development and aging. An ApoD homologous gene in Drosophila, Glial Lazarillo, regulates resistance to stress, and neurodegeneration in the aging brain. Here we study for the first time the protecting potential of ApoD in a vertebrate model organism. Loss of mouse ApoD function increases the sensitivity to oxidative stress and the levels of brain lipid peroxidation, and impairs locomotor and learning abilities. Human ApoD over-expression in the mouse brain produces opposite effects, increasing survival and preventing the raise of brain lipid peroxides after oxidant treatment. These observations, together with its transcriptional up-regulation in the brain upon oxidative insult, identify ApoD as an acute response protein with a protective and therefore beneficial function mediated by the control of peroxidated lipids.
lipocalin; oxidative stress; learning; locomotor behavior; paraquat; lipid peroxidation
Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV.
Methods and results
Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of KV currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response.
nSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.
Hypoxic pulmonary vasoconstriction; Neutral sphingomyelinase; Protein kinase C ζ; Pulmonary arteries
Kvβ1.2 Subunit Coexpression in HEK293 Cells Confers O2 Sensitivity to Kv4.2 but not to Shaker Channels
Pérez-García, María Teresa
López-López, José Ramón
The Journal of General Physiology
Voltage-gated K+ (KV) channels are protein complexes composed of ion-conducting integral membrane α subunits and cytoplasmic modulatory β subunits. The differential expression and association of α and β subunits seems to contribute significantly to the complexity and heterogeneity of KV channels in excitable cells, and their functional expression in heterologous systems provides a tool to study their regulation at a molecular level. Here, we have studied the effects of Kvβ1.2 coexpression on the properties of Shaker and Kv4.2 KV channel α subunits, which encode rapidly inactivating A-type K+ currents, in transfected HEK293 cells. We found that Kvβ1.2 functionally associates with these two α subunits, as well as with the endogenous KV channels of HEK293 cells, to modulate different properties of the heteromultimers. Kvβ1.2 accelerates the rate of inactivation of the Shaker currents, as previously described, increases significantly the amplitude of the endogenous currents, and confers sensitivity to redox modulation and hypoxia to Kv4.2 channels. Upon association with Kvβ1.2, Kv4.2 can be modified by DTT (1,4 dithiothreitol) and DTDP (2,2′-dithiodipyridine), which also modulate the low pO2 response of the Kv4.2+β channels. However, the physiological reducing agent GSH (reduced glutathione) did not mimic the effects of DTT. Finally, hypoxic inhibition of Kv4.2+β currents can be reverted by 70% in the presence of carbon monoxide and remains in cell-free patches, suggesting the presence of a hemoproteic O2 sensor in HEK293 cells and a membrane-delimited mechanism at the origin of hypoxic responses. We conclude that β subunits can modulate different properties upon association with different KV channel subfamilies; of potential relevance to understanding the molecular basis of low pO2 sensitivity in native tissues is the here described acquisition of the ability of Kv4.2+β channels to respond to hypoxia.
potassium channels; β subunit; hypoxia
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