RESUMO
The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity of nuclear and mitochondrial transcription factors for mitochondrial DNA replication was tested in the in vivo rat brain. Mitochondrial reactive oxygen species generation was stimulated using pre-convulsive doses of hyperbaric oxygen and hippocampal mitochondrial DNA content and neuronal and mitochondrial morphology and cell proliferation were evaluated at 1, 5 and 10 days. Gene expression was subsequently evaluated to assess nuclear and mitochondrial-encoded respiratory genes, mitochondrial transcription factor A, and nuclear respiratory transcription factors-1 and -2. After 1 day, a mitochondrial DNA deletion emerged involving Complex I and IV subunit-encoding regions that was independent of overt neurological or cytological O(2) toxicity, and resolved before the onset of cell proliferation. This damage was attenuated by blockade of neuronal nitric oxide synthase. Compensatory responses were found in nuclear gene expression for manganese superoxide dismutase, mitochondrial transcription factor A, and nuclear respiratory transcription factor-2. Enhanced nuclear respiratory transcription factor-2 binding activity in hippocampus was accompanied by a nearly three-fold boost in mitochondrial DNA content over 5 days. The finding that O(2) activates regional mitochondrial DNA transcription, replication, and mitochondrial biogenesis in the hippocampus may have important implications for maintaining neuronal viability after brain injury.
Assuntos
DNA Mitocondrial/metabolismo , Hipocampo/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Forma Celular/efeitos dos fármacos , Forma Celular/fisiologia , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/fisiologia , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/genética , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/genética , Fator de Transcrição de Proteínas de Ligação GA/efeitos dos fármacos , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Deleção de Genes , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Hipocampo/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I/metabolismo , Fator 1 Nuclear Respiratório/efeitos dos fármacos , Fator 1 Nuclear Respiratório/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Oxigênio/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/farmacologia , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
The hypothesis that in conditions of hyperbaric oxygenation, nitric oxide (NO) modulates the vasodilatory effect of CO2 in the brain and thus accelerates the neurotoxic action of oxygen was verified experimentally. Conscious rats breathed atmospheric air or oxygen at 5 atm and blood flow in the striatum was measured before and after inhibition of carbonic anhydrase with acetazolamide, which causes retention of CO2 in the brain. Acetazolamide (35 mg/kg) increased blood flow in the animals when breathing air by 38 +/- 7.4% (p < 0.01), while preliminary inhibition of NO synthase with N(omega)-nitro-L-arginine-methyl ester (L-NAME, 30 mg/kg) significantly weakened its vasodilatory action. Inhibition of carbonic anhydrase in animals breathing hyperbaric oxygen at 5 atm prevented cerebral vasoconstriction, increased brain blood flow, and accelerated the development of oxygen convulsions. The vasodilatory effect of acetazolamide in hyperbaric oxygenation was significantly reduced in animals pretreated with the NO synthase inhibitor, such that the latent period of convulsions increased. The results obtained here provide evidence that in conditions of extreme hyperoxia, NO modulates the cerebral hyperemia developing in conditions of CO2 retention in the brain and accelerates the development of the neurotoxic actions of hyperbaric oxygen.
Assuntos
Encéfalo/fisiologia , Dióxido de Carbono/metabolismo , Óxido Nítrico/fisiologia , Oxigênio/efeitos adversos , Pressão , Acetazolamida/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Inibidores da Anidrase Carbônica/farmacologia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletroencefalografia/métodos , Inibidores Enzimáticos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The hypothesis that decreases in brain blood flow during respiration of hyperbaric oxygen result from inactivation of nitric oxide (NO) by superoxide anions (O2(-)) is proposed. Changes in brain blood flow were assessed in conscious rats during respiration of atmospheric air or oxygen at a pressure of 4 atm after dismutation of O2(-) with superoxide dismutase or suppression of NO synthesis with the NO synthase inhibitor L-NAME. I.v. administration of superoxide dismutase increased brain blood flow in rats breathing air but was ineffective after previous inhibition of NO synthase. Hyperbaric oxygenation at 4 atm induced decreases in brain blood flow, though prior superoxide dismutase prevented hyperoxic vasoconstriction and increased brain blood flow in rats breathing hyperbaric oxygen. The vasodilatory effect of superoxide dismutase in hyperbaric oxygenation was not seen in animals given prior doses of the NO synthase inhibitor. These results provide evidence that one mechanism for hyperoxic vasoconstriction in the brain consists of inactivation of NO by superoxide anions, decreasing its basal vasorelaxing action.
Assuntos
Encéfalo/irrigação sanguínea , Hiperóxia/fisiopatologia , Óxido Nítrico/metabolismo , Superóxidos/metabolismo , Vasoconstrição , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sequestradores de Radicais Livres/farmacologia , Oxigenoterapia Hiperbárica , Masculino , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Superóxido Dismutase/farmacologiaRESUMO
Studies on conscious rats with inhibition of NO synthase were used to assess the dynamics of brain blood flow and EEG traces during hyperbaric oxygenation at 4 or 5 atm. Oxygen at a pressure of 4 atm induced cerebral vasoconstriction in intact animals and decreased blood flow by 11-18% (p < 0.05) during 60-min exposure to hyperbaric oxygenation. Paroxysmal EEG activity and oxygen convulsions did not occur in rats at 4 atm of O2. At 5 atm, convulsive activity appeared on the EEG at 41 +/- 1.9 min, and blood flow decreased significantly during the first 20 min; blood flow increased by 23 +/- 9%, as compared with controls, (p < 0.01) before the appearance of convulsions on the EEG. Prior inhibition of NO synthase I (NOS I) and NO synthase III (NOS III) with N(omega)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg) or inhibition only of NOS I with 7-nitroindazole (7-NI, 50 mg/kg) prevented the development of hyperoxic hyperemia and paroxysmal spikes on the EEG during hyperbaric oxygenation at 5 atm. These results show that hyperbaric oxygen induces changes in cerebral blood flow which modulate its neurotoxic action via nitric oxide synthesized both in neurons and in cerebral vessels.
Assuntos
Encéfalo/irrigação sanguínea , Circulação Cerebrovascular/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Oxigenoterapia Hiperbárica/efeitos adversos , Óxido Nítrico Sintase/efeitos dos fármacos , Oxigênio/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Corpo Estriado/irrigação sanguínea , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/enzimologia , Eletroencefalografia , Endotélio Vascular/metabolismo , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo III , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Convulsões/induzido quimicamente , Vasoconstrição/efeitos dos fármacosRESUMO
With cholestatic hepatite, the relationship between acid-alkaline condition of blood and electrophoretic mobility of erythrocytes was studied. It is shown that changes in parameters of the individual mobility distribution are translated into reality independently, and are directed to maintain the steadiness of the index middle level. Dependence of this sign on the pH value, hemoglobin content and bicarbonate-ion concentrating in blood, an on partial pressure of oxygen and carbonic gas was discovered. The intravenous infusion of patients with hemodese restored the middle level of cell electrophoretic mobility previously reduced due to liver pathology. Membrane mechanisms controlling stability of erythrocyte electrokinetic characteristics are discussed.
Assuntos
Equilíbrio Ácido-Base/fisiologia , Colestase/sangue , Eritrócitos/fisiologia , Hepatite/sangue , Equilíbrio Ácido-Base/efeitos dos fármacos , Colestase/tratamento farmacológico , Eletroforese , Eritrócitos/efeitos dos fármacos , Hepatite/tratamento farmacológico , Humanos , Substitutos do Plasma/administração & dosagem , Povidona/administração & dosagem , Processamento de Sinais Assistido por ComputadorRESUMO
A study was made of the influence of psycho-emotional strain, experienced by students when taking examinations, on the erythrocyte electrophoretic mobility (EPM). It has been shown that students under psycho-emotional strain the mean value of EPM remains the same, but changes were observed in the form of EPM distribution, while estimated by asymmetry and excession coefficients. Similar results were obtained when adrenalin was added to the blood.
Assuntos
Eritrócitos/fisiologia , Estresse Psicológico/sangue , Avaliação Educacional , Eletroforese , Eletrofisiologia , Epinefrina/farmacologia , Eritrócitos/efeitos dos fármacos , Humanos , Cinética , Estudantes/psicologia , Propriedades de SuperfícieRESUMO
The physiological role of extracellular superoxide dismutase (SOD3) has received insufficient study. We investigated the hypothesis that SOD3, which neutralizes superoxide anions (O2(-)) in the intercellular space of the brain, prevents the inactivation of nitric oxide (NO) and is thus involved in regulating cerebral vascular tone. Local brain blood flow was measured in the striatum of anesthetized rats during administration of various combinations of a SOD mimetic, a SOD inhibitor, an NO donor, and an NOS inhibitor into the striatum using a Hamilton syringe. In normal conditions, SOD3 was found to minimize O2(-) levels, protecting endogenously produced NO at a sufficient level to maintain cerebral vascular tone and reactivity. SOD3 was found to increase the vasodilatory effect of endogenously produced NO in the brain. SOD3 was found to neutralize superoxide anions produced in the brain during respiration of 100% O2 and to maintain basal NO levels and its vasodilatory potential in normobaric hyperoxia.
Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Superóxido Dismutase/metabolismo , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/fisiologia , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Corpo Estriado/irrigação sanguínea , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Inibidores Enzimáticos/farmacologia , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/fisiologia , Hiperóxia/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ratos , S-Nitroso-N-Acetilpenicilamina/farmacologia , Superóxido Dismutase/antagonistas & inibidores , Superóxidos/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaAssuntos
Adaptação Fisiológica , Oxigenoterapia Hiperbárica/efeitos adversos , Óxido Nítrico/fisiologia , Animais , Animais Recém-Nascidos , Arginina/farmacologia , Encéfalo/metabolismo , Síndromes Neurotóxicas , Doadores de Óxido Nítrico/farmacologia , Nitroglicerina/farmacologia , Ratos , Ratos WistarAssuntos
Eritrócitos/fisiologia , Adulto , Fatores Etários , Eletroforese , Feminino , Humanos , Masculino , Fatores SexuaisRESUMO
Physiological role of extracellular superoxide dismutase (SOD3) remains obscure. We tested the hypothesis that SOD3 regulates the equilibrium between superoxide (O2-) and nitric oxide (NO), thereby controlling vascular tone and cerebrovascular reactivity. In anesthetized rats local blood flow was measured in the striatum after intracerebral delivery of SOD-mimetic, SOD-inhibitor, NO-donor and NOS-inhibitor by microdialysis. We have found that SOD3 minimizes O2- levels preserving NO availability at resting conditions. SOD3 promotes NO mediated vasodilatation by scavenging O2- and basal SOD3 levels is able to inactivate O2- produced by 100% oxygen breathing preserving vasodilator effect of NO.
Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Superóxido Dismutase/farmacologia , Superóxidos/metabolismo , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
Hyperbaric oxygenation modulates cerebral blood flow affecting the development of oxygen convulsions. Before hyperbaric oxygenation-induced convulsions in rats the initial decrease in blood flow gave place to hyperemia, Po(2) increased. In rats receiving cyclooxygenase inhibitor indomethacin no convulsions were observed, blood flow and Po(2)were lower than in controls. Our results indicate that indomethacin prevents hyperemia and alleviates oxygen convulsions under conditions of hyperbaric oxygenation.
Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Oxigenoterapia Hiperbárica/efeitos adversos , Hiperemia/prevenção & controle , Indometacina/farmacologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Telencéfalo/irrigação sanguínea , Telencéfalo/efeitos dos fármacos , Animais , Inibidores de Ciclo-Oxigenase/uso terapêutico , Indometacina/uso terapêutico , Masculino , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Convulsões/tratamento farmacológicoRESUMO
We tested a hypothesis that the cerebral blood flow (CBF) is reduced at hyperbaric oxygen due to inactivation of nitric oxide (NO) by superoxide anions (O2). In our experiments, the CBF was measured under hyperbaric oxygenation (HBO) 4ATA after inhibition of NO synthesis and inactivation of O2. The CBF was reduced at HBO exposure. Inhibition of NO--synthase type I and III (NOS) by L-NAME in the air caused the same decreasing of the CBF as at 4 ATA HBO. Hyperbaric vasoconstriction was diminished after NOS inhibition. Intravenous injection of superoxide dismutase (CuZn SOD) increased the CBF in the air and HBO exposure. This effect disappeared at preliminary NOS inhibition. These data suggest that inactivation of NO by O2 is a more effective mechanism of HBO vasoconstriction.
Assuntos
Circulação Cerebrovascular , Óxido Nítrico/metabolismo , Oxigênio/farmacologia , Superóxidos/metabolismo , Vasoconstrição , Animais , Inibidores Enzimáticos/farmacologia , Oxigenoterapia Hiperbárica , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Superóxido Dismutase/farmacologiaRESUMO
Hyperbaric oxygen (HBO2) causes CO2 retention in the brain that leads to the increase in cerebral blood flow (CBF) by poorly understood mechanisms. We have tested the hypothesis that NO is implicated in CBF-responses to hypercapnia under hyperoxic conditions. Alert rats were exposed to HBO2 at 5 ata and blood flow in the striatum measured by H2 clearance every 10 min. Acetazolamide, the inhibitor of carbonic anhydrase, was used to increase brain PCO2. CBF responses to acetazolamide administration (30 mg/kg, i.p.) were assessed in rats breathing air at 1 ata or oxygen at 5 ata with and without NOS inhibition (L-NAME, 30 mg/kg, i.p.). In rats breathing air, acetazolamide increased CBF by 34 +/- 7.4% over 30 min and by 28 +/- 12% over 3 hours while NOS inhibition with L-NAME attenuated acetazolamide-induced cerebral vasodilatation. HBO2 at 5 ata reduced CBF during the first 30 min hyperoxia, after that CBF increased by 55 +/- 19% above pre-exposure levels. In acetazolamide-treated animals, no HBO, induced vasoconstricton was observed and striatal blood flow increased by 53 +/- 18% within 10 min of hyperbaric exposure. After NOS inhibition, cerebral vasodilatation in response to acetazolamide during HBO2 exposure was significantly attenuated. The study demonstrates that NO is implicated in acetazolamide (CO2)-induced cerebral hyperemia under hyperbaric oxygen exposure.
Assuntos
Dióxido de Carbono/fisiologia , Corpo Estriado/efeitos dos fármacos , Óxido Nítrico/fisiologia , Oxigênio/toxicidade , Vasodilatação/efeitos dos fármacos , Acetazolamida/farmacologia , Animais , Inibidores da Anidrase Carbônica/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Corpo Estriado/irrigação sanguínea , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Pressão , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/fisiopatologiaRESUMO
High pressure oxygen evokes a cerebral vasoconstriction and diminishes cerebral blood flow with the aid of mechanisms which are not yet sufficiently studied. We were checking a hypothesis that the hyperbaric oxygen (HBO2) inactivates cerebral nitrogen oxide (NO), interrupts its basal relaxing effect, and evokes a vasoconstriction. In our experiments, HBO2 decreased cerebral blood flow depending on the pressure. Inhibiting the NO-synthase weakened basal vasorelaxation in breathing with atmosphere air and eliminated the vasoconstriction in exposure to the HBO2. Inactivation of O2 prevented the HBO2-induced vasoconstriction. The data obtained reveal that diminishing of cerebral blood flow in HBO is related to the NO inactivation and weakening of its basal vasorelaxing effect. Possible mechanisms of the NO inactivation may involve its reaction with oxygen and superoxide anion which lead to diminishing of the tissue NO concentration and weakening of its vasorelaxing effect.
Assuntos
Circulação Cerebrovascular/fisiologia , Óxido Nítrico/fisiologia , Oxigênio/farmacologia , Vasoconstrição/fisiologia , Anestesia , Animais , Inibidores Enzimáticos/farmacologia , Óxido Nítrico/biossíntese , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Pressão , Ratos , Ratos Sprague-Dawley , Ratos Wistar , VigíliaRESUMO
The goal of work was to reveal changes in microcirculation of the rat brain and the role of nitric oxide (NO) in development of seizures at hyperbaric oxygen exposure. The Wistar rats with implanted paired platinum electrodes in left and right striatum were used for experiments. The latency of seizures was defined by the EEG, the cerebral blood flow (CBF) was measured by hydrogen clearance. One group of animals was exposed to a 5-ata oxygen, while the others before oxygen treatment were injected with: Nw-nitro-L-arginine methyl ester (L-NAME), blockator of constitutive NO synthase; 7-nitroindozol (7NI), specific inhibitor of neural NO synthase. The latency of seizures was 41 +/- 1.9 min at 5 ata oxygen exposure. CBF was decreased to 10-14% but before seizures it increased to 23 +/- 9%. L-NAME and 7NI prevented development of hyperoxygen hyperemia and onset of seizures. The results indicate occurrence of hyperbaric oxygen changes of the CBF that modulate neurotoxic effects of NO in neurons as well as in cerebral vessels.