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1.
Front Mol Neurosci ; 15: 1062410, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36704328

RESUMO

Oxygen breathing at elevated partial pressures (PO2's) at or more than 3 atmospheres absolute (ATA) causes a reduction in brain γ-aminobutyric acid (GABA) levels that impacts the development of central nervous system oxygen toxicity (CNS-OT). Drugs that increase brain GABA content delay the onset of CNS-OT, but it is unknown if oxidant damage is lessened because brain tissue PO2 remains elevated during hyperbaric oxygen (HBO2) exposures. Experiments were performed in rats and mice to measure brain GABA levels with or without GABA transporter inhibitors (GATs) and its influence on cerebral blood flow, oxidant damage, and aspects of mitochondrial quality control signaling (mitophagy and biogenesis). In rats pretreated with tiagabine (GAT1 inhibitor), the tachycardia, secondary rise in mean arterial blood pressure, and cerebral hyperemia were prevented during HBO2 at 5 and 6 ATA. Tiagabine and the nonselective GAT inhibitor nipecotic acid similarly extended HBO2 seizure latencies. In mice pretreated with tiagabine and exposed to HBO2 at 5 ATA, nuclear and mitochondrial DNA oxidation and astrocytosis was attenuated in the cerebellum and hippocampus. Less oxidant injury in these regions was accompanied by reduced conjugated microtubule-associated protein 1A/1B-light chain 3 (LC3-II), an index of mitophagy, and phosphorylated cAMP response element binding protein (pCREB), an initiator of mitochondrial biogenesis. We conclude that GABA prevents cerebral hyperemia and delays neuroexcitation under extreme HBO2, limiting oxidant damage in the cerebellum and hippocampus, and likely lowering mitophagy flux and initiation of pCREB-initiated mitochondrial biogenesis.

2.
Neurotox Res ; 36(4): 788-795, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31148118

RESUMO

Hyperbaric oxygen (HBO2) is acutely toxic to the central nervous system, culminating in EEG spikes and tonic-clonic convulsions. GABA enhancers and sodium channel antagonists improve seizure latencies in HBO2 when administered individually, while combining antiepileptic drugs from different functional classes can provide greater seizure latency. We examined the combined effectiveness of GABA enhancers (tiagabine and gabapentin) with sodium channel antagonists (carbamazepine and lamotrigine) in delaying HBO2-induced seizures. A series of experiments in C57BL/6 mice exposed to 100% oxygen at 5 atmospheres absolute (ATA) were performed. We predicted equally effective doses from individual drug-dose response curves, and the combinations of tiagabine + carbamazepine or lamotrigine were tested to determine the maximally effective combined doses to be used in subsequent experiments designed to identify the type of pharmacodynamic interaction for three fixed-ratio combinations (1:3, 1:1, and 3:1) using isobolographic analysis. For both combinations, the maximally effective combined doses increased seizure latency over controls > 5-fold and were determined to interact synergistically for fixed ratios 1:1 and 3:1, additive for 1:3. These results led us to explore whether the benefits of these drug combinations could be extended to the lungs, since a centrally mediated mechanism is believed to mediate hyperoxic-induced cardiogenic lung injury. Indeed, both combinations attenuated bronchoalveolar lavage protein content by ~ 50%. Combining tiagabine with carbamazepine or lamotrigine not only affords greater antiseizure protection in HBO2 but also allows for lower doses to be used, minimizing side effects, and attenuating acute lung injury.


Assuntos
Anticonvulsivantes/administração & dosagem , Oxigenoterapia Hiperbárica , Oxigênio/toxicidade , Convulsões/induzido quimicamente , Bloqueadores dos Canais de Sódio/administração & dosagem , Tiagabina/administração & dosagem , Animais , Carbamazepina/administração & dosagem , Gabapentina/administração & dosagem , Lamotrigina/administração & dosagem , Camundongos Endogâmicos C57BL , Convulsões/tratamento farmacológico
3.
J Appl Physiol (1985) ; 125(4): 1296-1304, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30024340

RESUMO

Exposure to extreme hyperbaric oxygen (HBO2) >5-6 atmospheres absolute (ATA) produces baroreflex impairment, sympathetic hyperactivation, hypertension, tachycardia, and cerebral hyperemia, known as phase II, culminating in seizures. We hypothesized that attenuation of the effects of high sympathetic outflow would preserve regional cerebral blood flow (rCBF) and protect against HBO2-induced seizures. To explore this possibility, we tested four adrenoceptor antagonists in conscious and anesthetized rats exposed to HBO2 at 5 and 6 ATA, respectively: phentolamine (nonselective α1 and α2), prazosin (selective α1), propranolol (nonselective ß1 and ß2), and atenolol (selective ß1). In conscious rats, four drug doses were administered to rats before HBO2 exposures, and seizure latencies were recorded. Drug doses that provided similar protection against seizures were administered before HBO2 exposures in anesthetized rats to determine the effects of adrenoceptor blockade on mean arterial pressure, heart rate, rCBF, and EEG spikes. All four drugs modified cardiovascular and rCBF responses in HBO2 that aligned with epileptiform discharges, but only phentolamine and propranolol effectively increased EEG spike latencies by ~20 and 36 min, respectively. When phentolamine and propranolol were delivered during HBO2 at the onset of phase II, only propranolol led to sustained reductions in heart rate and rCBF, preventing the appearance of epileptiform discharges. The enhanced effectiveness of propranolol may extend beyond ß-adrenoceptor blockade, i.e., membrane stability and reduced metabolic activity. These results indicate that adrenoceptor drug pretreatment will minimize the effects of excessive sympathetic outflow on rCBF and extend HBO2 exposure time.NEW & NOTEWORTHY Blocking adrenergic receptors with phentolamine (nonselective α1 and α2), prazosin (selective α1), propranolol (nonselective ß1 and ß2), and atenolol (selective ß1) modified cardiovascular and regional cerebral blood flow (rCBF) responses in hyperbaric oxygen (HBO2) at 6 atmospheres absolute (ATA); however, only phentolamine and propranolol extended EEG spike latencies. When these two agents were delivered at the onset of sympathetic hyperactivation, only propranolol reduced heart rate and rCBF throughout the exposure and prevented epileptiform discharges. These data validate the strong role of adrenergic control of cardiovascular function and rCBF in extreme HBO2 and the potential use of antiadrenergic drugs to prevent seizures.

4.
Neurosci Lett ; 653: 283-287, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28579483

RESUMO

Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2.


Assuntos
4-Aminobutirato Transaminase/metabolismo , Glutamato Descarboxilase/metabolismo , Oxigenoterapia Hiperbárica/efeitos adversos , Óxido Nítrico/metabolismo , Oxigênio/metabolismo , Oxigênio/toxicidade , Ácido gama-Aminobutírico/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL
5.
Brain Res ; 1657: 347-354, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28057450

RESUMO

Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore, we tested the hypothesis that pre-treatment with FDA-approved antiepileptic drugs could prevent seizure onset in hyperoxia at 5 atmospheres absolute. We selected drugs from two putative functional categories, Na+-channel antagonists and GABA enhancers, each administered intraperitoneally at four doses in separate groups of C57BL/6 mice. The drugs varied in efficacy at the doses used. Of the five tested Na+-channel antagonists, carbamazepine and lamotrigine more than tripled seizure latency compared to values seen in vehicle controls. Primidone, zonisamide and oxcarbazepine were less effective. Of the four GABA reuptake inhibitors, tiagabine and vigabatrin also increased seizure latency by more than three times control values; valproic acid was less effective, and the GABA synthesis promoter gabapentin was intermediate in effectiveness. We infer that Na+-channel function and GABA neurotransmission may be critical targets in the pathophysiology of CNS O2 toxicity. Because these essential components of neuronal excitation and inhibition are also implicated in the pathogenesis of other seizure disorders, including generalized epilepsy, we propose that, at some level, common pathways are involved in these pathologies, although the initiating insults differ. Furthermore, hyperoxic exposures are not known to cause the spontaneously-recurring seizures that characterize true clinical epilepsy. Nonetheless, experimental studies of hyperbaric oxygen toxicity could provide new insights into molecular mechanisms of seizure disorders of various etiologies. In addition, the neuropathology of hyperbaric oxygen is particularly relevant to the hypothesis held by some investigators that oxidative stress is an etiological factor in clinical epilepsies.


Assuntos
Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Oxigenoterapia Hiperbárica , Convulsões/prevenção & controle , Animais , Relação Dose-Resposta a Droga , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Inibidores da Captação de GABA/farmacologia , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Convulsões/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
J Appl Physiol (1985) ; 119(11): 1282-8, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26338456

RESUMO

The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hyperemia, sympathoexcitation, and seizures induced by hyperbaric oxygen (HBO2) at or above 3 atmospheres absolute (ATA). It is unknown whether these events in the onset of central nervous system oxygen toxicity originate within specific brain structures and whether blood flow is diverted to the brain from peripheral organs with high basal flow, such as the kidney. To explore these questions, total and regional cerebral blood flow (CBF) were measured in brain structures of the central autonomic network in anesthetized rats in HBO2 at 6 ATA. Electroencephalogram (EEG) recordings, cardiovascular hemodynamics, and renal blood flow (RBF) were also monitored. As expected, mean arterial blood pressure and total and regional CBF increased preceding EEG spikes while RBF was unaltered. Of the brain structures examined, the earliest rise in CBF occurred in the striatum, suggesting increased neuronal activation. Continuous unilateral or bilateral striatal infusion of the nitric oxide synthase inhibitor N(ω)-nitro-L-arginine methyl ester attenuated CBF responses in that structure, but global EEG discharges persisted and did not differ from controls. Our novel findings indicate that: 1) cerebral hyperemia in extreme HBO2 in rats does not occur at the expense of renal perfusion, highlighting the remarkable autoregulatory capability of the kidney, and 2) in spite of a sentinel increase in striatal blood flow, additional brain structure(s) likely govern the pathogenesis of HBO2-induced seizures because EEG discharge latency was unchanged by local blockade of striatal nitric oxide production and concomitant hyperemia.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Hiperóxia/fisiopatologia , Neostriado/irrigação sanguínea , Neostriado/metabolismo , Óxido Nítrico/biossíntese , Convulsões/fisiopatologia , Animais , Sistema Nervoso Autônomo/fisiopatologia , Eletroencefalografia , Inibidores Enzimáticos/farmacologia , Hemodinâmica/fisiologia , Oxigenoterapia Hiperbárica , Hiperóxia/complicações , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Sprague-Dawley , Circulação Renal , Convulsões/etiologia
7.
J Appl Physiol (1985) ; 117(5): 525-34, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24994889

RESUMO

Unexplained adjustments in baroreflex sensitivity occur in conjunction with exposures to potentially toxic levels of hyperbaric oxygen. To investigate this, we monitored central nervous system, autonomic and cardiovascular responses in conscious and anesthetized rats exposed to hyperbaric oxygen at 5 and 6 atmospheres absolute, respectively. We observed two contrasting phases associated with time-dependent alterations in the functional state of the arterial baroreflex. The first phase, which conferred protection against potentially neurotoxic doses of oxygen, was concurrent with an increase in baroreflex sensitivity and included decreases in cerebral blood flow, heart rate, cardiac output, and sympathetic drive. The second phase was characterized by baroreflex impairment, cerebral hyperemia, spiking on the electroencephalogram, increased sympathetic drive, parasympatholysis, and pulmonary injury. Complete arterial baroreceptor deafferentation abolished the initial protective response, whereas electrical stimulation of intact arterial baroreceptor afferents prolonged it. We concluded that increased afferent traffic attributable to arterial baroreflex activation delays the development of excessive central excitation and seizures. Baroreflex inactivation or impairment removes this protection, and seizures may follow. Finally, electrical stimulation of intact baroreceptor afferents extends the normal delay in seizure development. These findings reveal that the autonomic nervous system is a powerful determinant of susceptibility to sympathetic hyperactivation and seizures in hyperbaric oxygen and the ensuing neurogenic pulmonary injury.


Assuntos
Encéfalo/fisiologia , Oxigenoterapia Hiperbárica/efeitos adversos , Neurônios Aferentes/fisiologia , Oxigênio/toxicidade , Pressorreceptores/fisiologia , Animais , Estimulação Elétrica , Hemodinâmica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia
8.
J Appl Physiol (1985) ; 115(6): 819-28, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23823147

RESUMO

The cardiovascular system responds to hyperbaric hyperoxia (HBO2) with vasoconstriction, hypertension, bradycardia, and reduced cardiac output (CO). We tested the hypothesis that these responses are linked by a common mechanism-activation of the arterial baroreflex. Baroreflex function in HBO2 was assessed in anesthetized and conscious rats after deafferentation of aortic or carotid baroreceptors or both. Cardiovascular and autonomic responses to HBO2 in these animals were compared with those in intact animals at 2.5 ATA for conscious rats and at 3 ATA for anesthetized rats. During O2 compression, hypertension was greater after aortic or carotid baroreceptor deafferentation and was significantly more severe if these procedures were combined. Similarly, the hyperoxic bradycardia observed in intact animals was diminished after aortic or carotid baroreceptor deafferentation and replaced by a slight tachycardia after complete baroreceptor deafferentation. We found that hypertension, bradycardia, and reduced CO--the initial cardiovascular responses to moderate levels of HBO2--are coordinated through a baroreflex-mediated mechanism initiated by HBO2-induced vasoconstriction. Furthermore, we have shown that baroreceptor activation in HBO2 inhibits sympathetic outflow and can partially reverse an O2-dependent increase in arterial pressure.


Assuntos
Barorreflexo/fisiologia , Sistema Cardiovascular/fisiopatologia , Oxigenoterapia Hiperbárica/efeitos adversos , Animais , Pressão Arterial/fisiologia , Denervação Autônoma , Sistema Nervoso Autônomo/fisiopatologia , Bradicardia/etiologia , Bradicardia/fisiopatologia , Hemodinâmica , Hiperóxia/complicações , Hiperóxia/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Vasoconstrição/fisiologia
9.
Proc Natl Acad Sci U S A ; 110(28): 11529-34, 2013 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-23798386

RESUMO

From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO2, but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.


Assuntos
Transfusão de Sangue , Compostos Nitrosos/metabolismo , Oxigênio/metabolismo , Anemia/terapia , Animais , Hemorragia/terapia , Camundongos , Ratos , Ovinos
10.
J Appl Physiol (1985) ; 113(2): 224-31, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22556400

RESUMO

Intravenous perfluorocarbon (PFC) emulsions, administered with supplemental inspired O(2), are being evaluated for their ability to eliminate N(2) from blood and tissue prior to submarine escape, but these agents can increase the incidence of central nervous system (CNS) O(2) toxicity, perhaps by enhancing O(2) delivery to the brain. To assess this, we infused a PFC emulsion (Oxycyte, 6 ml/kg iv) into anesthetized rats and measured cerebral Po(2) and regional cerebral blood flow (rCBF) in cortex, hippocampus, hypothalamus, and striatum with 100% O(2) at 1, 3, or 5 atmospheres absolute (ATA). At 1 ATA, brain Po(2) stabilized at >20 mmHg higher in animals infused with PFC emulsion than in control animals infused with saline, and rCBF fell by ~10%. At 3 ATA, PFC emulsion raised brain Po(2) >70 mmHg above control levels, and rCBF decreased by as much as 25%. At 5 ATA, brain Po(2) was ≥159 mmHg above levels in control animals for the first 40 min but then rose sharply; rCBF showed a similar profile, reflecting vasoconstriction followed by hyperemia. Conscious rats were also pretreated with PFC emulsion at 3 or 6 ml/kg iv and exposed to 100% O(2) at 5 ATA. At the lower dose, 80% of the animals experienced seizures by 33 min compared with 50% of the control animals. At the higher dose, seizures occurred in all rats within 25 min. At these doses, administration of PFC emulsion poses a clear risk of CNS O(2) toxicity in conscious rats exposed to hyperbaric O(2) at 5 ATA.


Assuntos
Encéfalo/fisiopatologia , Circulação Cerebrovascular/efeitos dos fármacos , Fluorocarbonos/toxicidade , Consumo de Oxigênio/efeitos dos fármacos , Oxigênio/metabolismo , Convulsões/induzido quimicamente , Convulsões/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Fluorocarbonos/administração & dosagem , Infusões Intravenosas , Masculino , Ratos , Ratos Sprague-Dawley
11.
J Appl Physiol (1985) ; 112(11): 1814-23, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22442027

RESUMO

In hyperbaric oxygen (HBO(2)) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO(2) exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO(2) from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with central NOS inhibition. In inhibitor-treated animals, autonomic discharges, cardiovascular pressures, catecholamine release, and cerebral blood flow all remained below baseline throughout exposure to HBO(2). In control animals, however, initial declines in these parameters were followed by significant increases above their baselines. In awake animals, central NOS inhibition significantly decreased the incidence of clonic-tonic convulsions or delayed their onset, compared with controls. The novel findings of this study are that NO produced by nNOS in the periventricular regions of the brain plays a critical role in the events leading to both CNS toxicity in HBO(2) and to the associated sympathetic hyperactivation involved in pulmonary injury.


Assuntos
Fibras Adrenérgicas/fisiologia , Sistema Nervoso Central/fisiopatologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/fisiopatologia , Óxido Nítrico/fisiologia , Oxigênio/toxicidade , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Fibras Adrenérgicas/efeitos dos fármacos , Animais , Sistema Nervoso Central/efeitos dos fármacos , Oxigenoterapia Hiperbárica/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Oxigênio/administração & dosagem , Ratos , Ratos Sprague-Dawley
12.
Stroke ; 42(2): 471-6, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21193749

RESUMO

BACKGROUND AND PURPOSE: S-nitrosylated hemoglobin (S-nitrosohemoglobin) has been implicated in the delivery of O(2) to tissues through the regulation of microvascular blood flow. This study tested the hypothesis that enhancement of S-nitrosylated hemoglobin by ethyl nitrite inhalation improves outcome after experimental subarachnoid hemorrhage (SAH). METHODS: A preliminary dosing study identified 20 ppm ethyl nitrite as a concentration that produced a 4-fold increase in S-nitrosylated hemoglobin concentration with no increase in methemoglobin. Mice were subjected to endovascular perforation of the right anterior cerebral artery and were treated with 20 ppm ethyl nitrite in air, or air alone for 72 hours, after which neurologic function, cerebral vessel diameter, brain water content, cortical tissue Po(2), and parenchymal red blood cell flow velocity were measured. RESULTS: At 72 hours after hemorrhage, air- and ethyl nitrite-exposed mice had similarly sized blood clots. Ethyl nitrite improved neurologic score and rotarod performance; abated SAH-induced constrictions in the ipsilateral anterior, middle cerebral, and internal carotid arteries; and prevented an increase in ipsilateral brain water content. Ethyl nitrite inhalation increased red blood cell flow velocity and cortical tissue Po(2) in the ipsilateral cortex with no effect on systemic blood pressure. CONCLUSIONS: Targeted S-nitrosylation of hemoglobin improved outcome parameters, including vessel diameter, tissue blood flow, cortical tissue Po(2), and neurologic function in a murine SAH model. Augmenting endogenous Po(2)-dependent delivery of NO bioactivity to selectively dilate the compromised cerebral vasculature has significant clinical potential in the treatment of SAH.


Assuntos
Adjuvantes Farmacêuticos/administração & dosagem , Hemoglobinas/administração & dosagem , Nitritos/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Hemorragia Subaracnóidea/tratamento farmacológico , Adjuvantes Farmacêuticos/uso terapêutico , Administração por Inalação , Animais , Sinergismo Farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hemorragia Subaracnóidea/fisiopatologia
13.
Am J Physiol Lung Cell Mol Physiol ; 300(1): L102-11, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20971806

RESUMO

Breathing hyperbaric oxygen (HBO2), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO2, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO2 at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO2 is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO2 exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO2-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.


Assuntos
Circulação Cerebrovascular/efeitos dos fármacos , Oxigenoterapia Hiperbárica/efeitos adversos , Lesão Pulmonar/induzido quimicamente , Oxigênio/toxicidade , Animais , Eletroencefalografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Parada Cardíaca/induzido quimicamente , Hemodinâmica/efeitos dos fármacos , Oxigenoterapia Hiperbárica/métodos , Pulmão/efeitos dos fármacos , Circulação Pulmonar/efeitos dos fármacos , Ratos , Sistema Nervoso Simpático/efeitos dos fármacos
14.
J Appl Physiol (1985) ; 106(4): 1234-42, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19179645

RESUMO

Oxygen is a potent cerebral vasoconstrictor, but excessive exposure to hyperbaric oxygen (HBO(2)) can reverse this vasoconstriction by stimulating brain nitric oxide (NO) production, which increases cerebral blood flow (CBF)-a predictor of O(2) convulsions. We tested the hypothesis that phosphodiesterase (PDE)-5 blockers, specifically sildenafil and tadalafil, increase CBF in HBO(2) and accelerate seizure development. To estimate changes in cerebrovascular responses to hyperoxia, CBF was measured by hydrogen clearance in anesthetized rats, either control animals or those pretreated with one of these blockers, with the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME), with the NO donor S-nitroso-N-acetylpenicillamine (SNAP), or with a blocker combined with l-NAME. Animals were exposed to 30% O(2) at 1 atm absolute (ATA) ("air") or to 100% O(2) at 4 or 6 ATA. EEG spikes indicated central nervous system CNS O(2) toxicity. The effects of PDE-5 blockade varied as a positive function of ambient Po(2). In air, CBF did not increase significantly, except after pretreatment with SNAP. However, at 6 ATA O(2), mean values for CBF increased and values for seizure latency decreased, both significantly; pretreatment with l-NAME abolished these effects. Conscious rats treated with sildenafil before HBO(2) were also more susceptible to CNS O(2) toxicity, as demonstrated by significantly shortened convulsive latency. Decreases in regional CBF reflect net vasoconstriction in the brain regions studied, since mean arterial pressures remained constant or increased throughout. Thus PDE-5 blockers oppose the protective vasoconstriction that is the initial response to hyperbaric hyperoxia, decreasing the safety of HBO(2) by hastening onset of CNS O(2) toxicity.


Assuntos
Oxigenoterapia Hiperbárica , Hiperóxia/fisiopatologia , Inibidores da Fosfodiesterase 5 , Inibidores de Fosfodiesterase/farmacologia , Convulsões/induzido quimicamente , Vasoconstrição/efeitos dos fármacos , Anestesia , Animais , Gasometria , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , GMP Cíclico/fisiologia , Guanilato Ciclase/fisiologia , Hiperóxia/tratamento farmacológico , Infusões Intravenosas , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Inibidores de Fosfodiesterase/administração & dosagem , Ratos , Ratos Sprague-Dawley , Convulsões/fisiopatologia , Transdução de Sinais/fisiologia
15.
J Appl Physiol (1985) ; 106(2): 662-7, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18845774

RESUMO

Recent investigations have elucidated some of the diverse roles played by reactive oxygen and nitrogen species in events that lead to oxygen toxicity and defend against it. The focus of this review is on toxic and protective mechanisms in hyperoxia that have been investigated in our laboratories, with an emphasis on interactions of nitric oxide (NO) with other endogenous chemical species and with different physiological systems. It is now emerging from these studies that the anatomical localization of NO release, which depends, in part, on whether the oxygen exposure is normobaric or hyperbaric, strongly influences whether toxicity emerges and what form it takes, for example, acute lung injury, central nervous system excitation, or both. Spatial effects also contribute to differences in the susceptibility of different cells in organs at risk from hyperoxia, especially in the brain and lungs. As additional nodes are identified in this interactive network of toxic and protective responses, future advances may open up the possibility of novel pharmacological interventions to extend both the time and partial pressures of oxygen exposures that can be safely tolerated. The implications of a better understanding of the mechanisms by which NO contributes to central nervous system oxygen toxicity may include new insights into the pathogenesis of seizures of diverse etiologies. Likewise, improved knowledge of NO-based mechanisms of pulmonary oxygen toxicity may enhance our understanding of other types of lung injury associated with oxidative or nitrosative stress.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Encéfalo/metabolismo , Hiperóxia/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/toxicidade , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/fisiopatologia , Animais , Antioxidantes/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/fisiopatologia , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Mergulho/efeitos adversos , Humanos , Oxigenoterapia Hiperbárica/efeitos adversos , Hiperóxia/etiologia , Hiperóxia/fisiopatologia , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo , Ácido Peroxinitroso/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
16.
Am J Physiol Lung Cell Mol Physiol ; 294(5): L984-90, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18326824

RESUMO

Reactive species of oxygen and nitrogen have been collectively implicated in pulmonary oxygen toxicity, but the contributions of specific molecules are unknown. Therefore, we assessed the roles of several reactive species, particularly nitric oxide, in pulmonary injury by exposing wild-type mice and seven groups of genetically altered mice to >98% O2 at 1, 3, or 4 atmospheres absolute. Genetically altered animals included knockouts lacking either neuronal nitric oxide synthase (nNOS(-/-)), endothelial nitric oxide synthase (eNOS(-/-)), inducible nitric oxide synthase (iNOS(-/-)), extracellular superoxide dismutase (SOD3(-/-)), or glutathione peroxidase 1 (GPx1(-/-)), as well as two transgenic variants (S1179A and S1179D) having altered eNOS activities. We confirmed our earlier finding that normobaric hyperoxia (NBO2) and hyperbaric hyperoxia (HBO2) result in at least two distinct but overlapping patterns of pulmonary injury. Our new findings are that the role of nitric oxide in the pulmonary pathophysiology of hyperoxia depends both on the specific NOS isozyme that is its source and on the level of hyperoxia. Thus, iNOS predominates in the etiology of lung injury in NBO2, and SOD3 provides an important defense. But in HBO2, nNOS is a major contributor to pulmonary injury, whereas eNOS is protective. In addition, we demonstrated that nitric oxide derived from nNOS is involved in a neurogenic mechanism of HBO2-induced lung injury that is linked to central nervous system oxygen toxicity through adrenergic/cholinergic pathways.


Assuntos
Hiperóxia/metabolismo , Pneumopatias/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Comportamento Animal , Glutationa Peroxidase/metabolismo , Oxigenoterapia Hiperbárica , Hiperóxia/patologia , Pulmão/enzimologia , Pneumopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo III , Oxigênio/toxicidade , Oxiemoglobinas/metabolismo , Superóxido Dismutase/metabolismo , Glutationa Peroxidase GPX1
17.
J Neurosci ; 28(9): 2015-24, 2008 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-18305236

RESUMO

The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, during hypoxic preconditioning, are coordinated in part by nitric oxide (NO). We tested the hypothesis that acute transient hypoxia stimulates NO synthase (NOS)-activated mechanisms of mitochondrial biogenesis in the hypoxia-sensitive subcortex of wild-type (Wt) and neuronal NOS (nNOS) and endothelial NOS (eNOS)-deficient mice. Mice were exposed to hypobaric hypoxia for 6 h, and changes in immediate hypoxic transcriptional regulation of mitochondrial biogenesis was assessed in relation to mitochondrial DNA (mtDNA) content and mitochondrial density. There were no differences in cerebral blood flow or hippocampal PO2 responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1 alpha), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, localized in reporter mice expressing mitochondrial green fluorescence protein, were seen primarily in hippocampal neurons. eNOS-/- mice displayed lower basal levels but maintained hypoxic induction of these transcripts. In contrast, nuclear transcriptional regulation of mitochondrial biogenesis in nNOS-/- mice was normal at baseline but did not respond to hypoxia. After hypoxia, subcortical mtDNA content increased in Wt and eNOS-/- mice but not in nNOS-/- mice. Hypoxia stimulated PGC-1alpha protein expression and phosphorylation of protein kinase A and cAMP response element binding (CREB) protein in Wt mice, but CREB only was activated in eNOS-/- mice and not in nNOS-/- mice. These findings demonstrate that hypoxic preconditioning elicits subcortical mitochondrial biogenesis by a novel mechanism that requires nNOS regulation of PGC-1alpha and CREB.


Assuntos
Encéfalo/ultraestrutura , DNA Mitocondrial/fisiologia , Hipóxia/patologia , Hipóxia/fisiopatologia , Mitocôndrias/fisiologia , Óxido Nítrico Sintase Tipo I/deficiência , Análise de Variância , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Proteína de Ligação a CREB/metabolismo , Inibidores Enzimáticos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/biossíntese , Hipóxia/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo II/deficiência , Óxido Nítrico Sintase Tipo III , Proteínas Nucleares/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição
18.
Am J Physiol Lung Cell Mol Physiol ; 293(1): L229-38, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17416738

RESUMO

Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O(2) at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O(2) pressures, 2-3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral transection of the vagus nerve. We propose that extrapulmonary, neurogenic events predominate in the pathogenesis of acute pulmonary oxygen toxicity in hyperbaric oxygenation, as nNOS activity drives lung injury by modulating the output of central autonomic pathways.


Assuntos
Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Óxido Nítrico/metabolismo , Oxigênio/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Gasometria , Líquidos Corporais/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/química , Hiperóxia/patologia , L-Lactato Desidrogenase/metabolismo , Pulmão/patologia , Pulmão/ultraestrutura , Pneumopatias/patologia , Masculino , Nitratos/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Nitritos/metabolismo , Pneumonia/patologia , Edema Pulmonar/sangue , Edema Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Análise de Sobrevida , Tirosina/análogos & derivados , Tirosina/metabolismo , Vagotomia
19.
J Cereb Blood Flow Metab ; 25(10): 1288-300, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15789033

RESUMO

Hyperbaric oxygen (HBO(2)) increases oxygen tension (PO(2)) in blood but reduces blood flow by means of O(2)-induced vasoconstriction. Here we report the first quantitative evaluation of these opposing effects on tissue PO(2) in brain, using anesthetized rats exposed to HBO(2) at 2 to 6 atmospheres absolute (ATA). We assessed the contribution of regional cerebral blood flow (rCBF) to brain PO(2) as inspired PO(2) (PiO(2)) exceeds 1 ATA. We measured rCBF and local PO(2) simultaneously in striatum using collocated platinum electrodes. Cerebral blood flow was computed from H(2) clearance curves in vivo and PO(2) from electrodes calibrated in vitro, before and after insertion. Arterial PCO(2) was controlled, and body temperature, blood pressure, and EEG were monitored. Scatter plots of rCBF versus PO(2) were nonlinear (R(2)=0.75) for rats breathing room air but nearly linear (R(2)=0.88-0.91) for O(2) at 2 to 6 ATA. The contribution of rCBF to brain PO(2) was estimated at constant inspired PO(2), by increasing rCBF with acetazolamide (AZA) or decreasing it with N-nitro-L-arginine methyl ester (L-NAME). At basal rCBF (78 mL/100 g min), local PO(2) increased 7- to 33-fold at 2 to 6 ATA, compared with room air. A doubling of rCBF increased striatal PO(2) not quite two-fold in rats breathing room air but 13- to 64-fold in those breathing HBO(2) at 2 to 6 ATA. These findings support our hypothesis that HBO(2) increases PO(2) in brain in direct proportion to rCBF.


Assuntos
Encéfalo/metabolismo , Circulação Cerebrovascular , Oxigenoterapia Hiperbárica , Oxigênio/análise , Fluxo Sanguíneo Regional , Animais , Corpo Estriado/irrigação sanguínea , Corpo Estriado/química , Hidrogênio/análise , Masculino , Pressão Parcial , Ratos , Ratos Sprague-Dawley , Respiração
20.
Neurosci Lett ; 344(1): 53-6, 2003 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-12781920

RESUMO

Nitric oxide (NO) from endothelial or neuronal NO synthases (eNOS or nNOS) may contribute both to the cerebrovascular responses to oxygen and potentially to the peroxynitrite-mediated toxic effects of hyperbaric oxygen (HBO(2)) on the central nervous system (CNS O(2) toxicity). In mice lacking eNOS or nNOS (-/-), regional cerebral blood flow (rCBF) and 3-nitrotyrosine (3-NT), a biochemical marker for peroxynitrite (ONOO(-)) formation, were measured in the brain during HBO(2) exposure. These variables were then correlated with EEG spiking activity related to CNS O(2) toxicity. In wild-type (WT) mice, HBO(2) exposure transiently reduced rCBF, but by 60 min rCBF was restored to baseline levels and above, followed by EEG spikes. Mice lacking nNOS also showed initial depression of rCBF followed by hyperemia but the delay in the onset of EEG discharges was greater. In contrast, in eNOS-deficient mice rCBF did not decrease and hyperemia was less pronounced during HBO(2). EEG spike latency was longer in eNOS(-/-) compared to WT or nNOS(-/-) mice. 3-NT gradually increased in all strains during HBO(2) but accumulation was slower in nNOS(-/-) mice, consistent with less ONOO(-) production. These results indicate that NOS-deficient mice have different cerebrovascular responses and tolerance to HBO(2) depending on which enzyme isoform is affected. The data suggest a key role for eNOS-dependent NO production in cerebral vasoconstriction and in the development of hyperoxic hyperemia preceding O(2) seizures, whereas neuronal NO may mediate toxic effects of HBO(2) mainly by its reaction with superoxide to generate the stronger oxidant, peroxynitrite.


Assuntos
Oxigenoterapia Hiperbárica/efeitos adversos , Óxido Nítrico Sintase/metabolismo , Oxigênio/toxicidade , Convulsões/induzido quimicamente , Telencéfalo/irrigação sanguínea , Telencéfalo/metabolismo , Animais , Circulação Cerebrovascular/fisiologia , Eletroencefalografia/efeitos dos fármacos , Hiperemia , Isoenzimas , Camundongos , Camundongos Knockout , Microdiálise , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/análise , Ácido Peroxinitroso/metabolismo , Telencéfalo/efeitos dos fármacos
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