Ivan Demchenko - Academia.edu (original) (raw)
Papers by Ivan Demchenko
Neuroscience, 2006
The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity... more 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 threefold 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.
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, Jul 1, 2002
Elsevier eBooks, 1980
This chapter discusses the methods of investigation of the regional or total cerebral blood flow ... more This chapter discusses the methods of investigation of the regional or total cerebral blood flow from the point of view of systems analysis. The systems analysis approach means treating the object of investigation as a complex system. This approach involves the examination of the system as a whole while simultaneously giving due consideration to the interaction of all its functionally significant components. The systems analysis involves special principles and methods, one of which is mathematical modelling that has wide applications. It can be the most appropriate method where the activities of a particular functional unit are well-enough understood to predict their direction and to assess its functional state at any given time. The systems approach is based on a clear delineation of the functional system under investigation and the identification of the channels by which it communicates with other systems. The channels through which it receives external influences are its input; the results of its activities are its output.
Doklady Biological Sciences, 2005
PubMed, Jul 28, 2006
CNS O2 toxicity is manifested most profoundly by generalized motor convulsions. The hypothesis wa... more CNS O2 toxicity is manifested most profoundly by generalized motor convulsions. The hypothesis was tested that HBO2 triggers seizures by an excitatory to inhibitory neurotransmitter imbalance produced by neuronal nitric oxide (NO) activity. Anesthetized rats were exposed to 5 ATA HBO2 for 75 min with or without prior inhibition of nNOS. Interstitial NO and amino acids: aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) were determined in the striatum by microdialysis coupled with HPLC. Blood flow and EEG in the same striatal region were measured simultaneously. Rats treated with 7-NI showed no EEG spikes of O2 toxicity, while seizure latency for untreated rats was 63 +/- 7 min. Significant increases in NO metabolites and blood flow were observed in control rats before seizures. HBO2 did not change Glu significantly and increased Asp slightly whereas GABA decreased progressively by 37 +/- 7%. Pretreatment with 7-NI led to a significantly smaller decline in GABA. Overall, the simplified excitotoxicity index Glu/GABA increased significantly after 60 min of HBO2 in control but fell in rats treated with 7-NI. We conclude that HBO2-stimulated neuronal NO production promotes an imbalance between glutamatergic and GABAergic synaptic function implicated in the genesis of oxygen-induced seizures.
Neuroscience and Behavioral Physiology, Dec 22, 2009
The physiological role of extracellular superoxide dismutase (SOD3) has received insufficient stu... more 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.
Brain Research, Nov 1, 2001
Central nervous system oxygen toxicity (CNS O2 toxicity) is preceded by release of hyperoxic vaso... more Central nervous system oxygen toxicity (CNS O2 toxicity) is preceded by release of hyperoxic vasoconstriction, which increases regional cerebral blood flow (rCBF). These increases in rCBF precede the onset of O2-induced convulsions. We have tested the hypothesis that hyperbaric oxygen (HBO2) stimulates NO* production in the brain that leads to hyperemia and anticipates electrical signs of neurotoxicity. We measured rCBF and EEG responses in rats exposed at 4 to 6 atmospheres (ATA) of HBO2 and correlated them with brain interstitial NO* metabolites (NO(x)) as an index of NO* production. During exposures to hyperbaric oxygen rCBF decreased at 4 ATA, decreased for the initial 30 min at 5 ATA then gradually increased, and increased within 30 min at 6 ATA. Changes in rCBF correlated positively with NO(x) production; increases in rCBF during HBO2 exposure were associated with large increases in NO(x) at 5 and 6 ATA and always preceded EEG discharges as a sign of CNS O2 toxicity. In rats pretreated with L-NAME, rCBF remained maximally decreased throughout 75 min of HBO2 at 4, 5 and 6 ATA. These data provide the first direct evidence that increased NO* production during prolonged HBO2 exposure is responsible for escape from hyperoxic vasoconstriction. The finding suggests that NO* overproduction initiates CNS O2 toxicity by increasing rCBF, which allows excessive O2 to be delivered to the brain.
Fiziologicheskiĭ zhurnal, Jun 1, 2011
The data obtained demonstrated that NO restrains ET-1 production and blunts ET-1-mediated basal c... more The data obtained demonstrated that NO restrains ET-1 production and blunts ET-1-mediated basal cerebrovascular tone. Local hyperoxygenation of the brain tissue decreases NO availability, supeoxide production, suppresses NO-mediated vascular tone and facilitates ET-1-mediated vasoconstriction.
Bulletin of Experimental Biology and Medicine, Sep 1, 1999
Exposure to absolute oxygen pressure of 3 and 5 bar revealed hemispheric and interhemispheric dif... more Exposure to absolute oxygen pressure of 3 and 5 bar revealed hemispheric and interhemispheric differences in lipid peroxidation and the content of phospholipids in rat brain.
Journal of Evolutionary Biochemistry and Physiology, Sep 1, 2020
Journal of Evolutionary Biochemistry and Physiology, Sep 1, 2019
The cardiovascular system of vertebrates, including humans, is well known to respond to hyperoxia... more The cardiovascular system of vertebrates, including humans, is well known to respond to hyperoxia by vasoconstriction, bradycardia and decreased contractility of the left heart ventricle. We hypothesized that all of these responses are components of the baroreflex that regulates blood pressure and circulation in hyperoxia. To test this hypothesis, we carried out experiments on awake rats in which the dynamics of arterial blood pressure, organ blood flow (brain, kidney, lower limbs) and ECG was tracked in response to oxygen breathing at 1, 3 and 5 ATA. The afferent and efferent baroreflex pathways were studied using denervation of the carotid baroreceptors and transection of the aortic depressor nerves and vagus nerve. The baroreflex effectiveness was assessed using phenylephrine injections or spontaneous changes in blood pressure. To activate the GABAergic system, nipecotic acid was injected into the lateral ventricle of the brain. Our studies demonstrated the presence of all the baroreflex components in hyperoxia which were triggered by a sharp rise in blood pressure due to systemic vasoconstriction. Hyperoxic vasoconstriction, in turn, arose due to endothelium-derived nitric oxide (NO) which binds to superoxide anions followed by a loss of the vasodilator component of vascular tone. Aortic and carotid sinus baroreceptors with ascending nerve fibers were identified as an afferent component of the hyperoxic baroreflex. Bradycardia and a decrease in cardiac output, resulting from baroreflex activation by hyperoxia, are actualized via efferent sympathetic and parasympathetic pathways. At 1 and 3 ATA O 2 , the baroreflex effectiveness increased compared to atmospheric air breathing, but extreme hyperoxia (5 ATA) suppressed the baroreflex mechanism. Activation of the GABAergic system in the cerebral cortex by nipecotic acid prevented the loss of the hyperoxic baroreflex. In hyperoxia, the baroreflex mechanism realizes adaptive responses of the cardiovascular system aimed at restraining the delivery of excess oxygen to an organism and mitigates activation of the sympathetic nervous system.
The FASEB Journal, 2015
An imbalance between glutamatergic and g-aminobutyric acid (GABA)ergic synaptic transmission is a... more An imbalance between glutamatergic and g-aminobutyric acid (GABA)ergic synaptic transmission is associated with hyperbaric oxygen (HBO2) induced seizures. Here we explored the impact of S-nitrosyla...
Evolutionary Physiology and Biochemistry - Advances and Perspectives, Feb 19, 2018
For more than five decades, Hyperbaric Laboratory has conducted basic and applied researches deal... more For more than five decades, Hyperbaric Laboratory has conducted basic and applied researches dealt with CNS oxygen toxicity, the high pressure nervous syndrome and nitrogen narcosis. Main achievements of basic researches are as follows: identified key mechanisms of adaptive responses of CNS and cardiorespiratory systems to breathing gas mixtures at high pressure, neurophysiological mechanisms of CNS oxygen toxicity and high pressure nervous syndrome, and pathogenesis of nitrogen narcosis. Main achievements of the translation of hyperbaric researches are as follows: new technology for 1000 m dive of animals (monkeys) using the gas mixture (He-N 2-O 2), new compression and decompression profiles for free escape of monkey from a depth of 700 m, use preconditional hypoxia and hyperthermia for the protection of nitrogen narcosis. Currently, main researches are focusing on the evaluation of molecular and cellular mechanisms of biological responses to extreme hyperbaric environments.
Journal of Applied Physiology, 2000
We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbari... more We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but...
Brain research, Feb 15, 2017
Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore,... more 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 n...
Journal of Applied Physiology, 2015
The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hy... more 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 HBO2at 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 ...
Journal of applied physiology (Bethesda, Md. : 1985), 2014
Unexplained adjustments in baroreflex sensitivity occur in conjunction with exposures to potentia... more 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 respons...
The Journal of Neuroscience, 2008
The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, dur... more 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 PO2responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1 α), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, locali...
Neuroscience, 2006
The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity... more 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 threefold 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.
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, Jul 1, 2002
Elsevier eBooks, 1980
This chapter discusses the methods of investigation of the regional or total cerebral blood flow ... more This chapter discusses the methods of investigation of the regional or total cerebral blood flow from the point of view of systems analysis. The systems analysis approach means treating the object of investigation as a complex system. This approach involves the examination of the system as a whole while simultaneously giving due consideration to the interaction of all its functionally significant components. The systems analysis involves special principles and methods, one of which is mathematical modelling that has wide applications. It can be the most appropriate method where the activities of a particular functional unit are well-enough understood to predict their direction and to assess its functional state at any given time. The systems approach is based on a clear delineation of the functional system under investigation and the identification of the channels by which it communicates with other systems. The channels through which it receives external influences are its input; the results of its activities are its output.
Doklady Biological Sciences, 2005
PubMed, Jul 28, 2006
CNS O2 toxicity is manifested most profoundly by generalized motor convulsions. The hypothesis wa... more CNS O2 toxicity is manifested most profoundly by generalized motor convulsions. The hypothesis was tested that HBO2 triggers seizures by an excitatory to inhibitory neurotransmitter imbalance produced by neuronal nitric oxide (NO) activity. Anesthetized rats were exposed to 5 ATA HBO2 for 75 min with or without prior inhibition of nNOS. Interstitial NO and amino acids: aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) were determined in the striatum by microdialysis coupled with HPLC. Blood flow and EEG in the same striatal region were measured simultaneously. Rats treated with 7-NI showed no EEG spikes of O2 toxicity, while seizure latency for untreated rats was 63 +/- 7 min. Significant increases in NO metabolites and blood flow were observed in control rats before seizures. HBO2 did not change Glu significantly and increased Asp slightly whereas GABA decreased progressively by 37 +/- 7%. Pretreatment with 7-NI led to a significantly smaller decline in GABA. Overall, the simplified excitotoxicity index Glu/GABA increased significantly after 60 min of HBO2 in control but fell in rats treated with 7-NI. We conclude that HBO2-stimulated neuronal NO production promotes an imbalance between glutamatergic and GABAergic synaptic function implicated in the genesis of oxygen-induced seizures.
Neuroscience and Behavioral Physiology, Dec 22, 2009
The physiological role of extracellular superoxide dismutase (SOD3) has received insufficient stu... more 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.
Brain Research, Nov 1, 2001
Central nervous system oxygen toxicity (CNS O2 toxicity) is preceded by release of hyperoxic vaso... more Central nervous system oxygen toxicity (CNS O2 toxicity) is preceded by release of hyperoxic vasoconstriction, which increases regional cerebral blood flow (rCBF). These increases in rCBF precede the onset of O2-induced convulsions. We have tested the hypothesis that hyperbaric oxygen (HBO2) stimulates NO* production in the brain that leads to hyperemia and anticipates electrical signs of neurotoxicity. We measured rCBF and EEG responses in rats exposed at 4 to 6 atmospheres (ATA) of HBO2 and correlated them with brain interstitial NO* metabolites (NO(x)) as an index of NO* production. During exposures to hyperbaric oxygen rCBF decreased at 4 ATA, decreased for the initial 30 min at 5 ATA then gradually increased, and increased within 30 min at 6 ATA. Changes in rCBF correlated positively with NO(x) production; increases in rCBF during HBO2 exposure were associated with large increases in NO(x) at 5 and 6 ATA and always preceded EEG discharges as a sign of CNS O2 toxicity. In rats pretreated with L-NAME, rCBF remained maximally decreased throughout 75 min of HBO2 at 4, 5 and 6 ATA. These data provide the first direct evidence that increased NO* production during prolonged HBO2 exposure is responsible for escape from hyperoxic vasoconstriction. The finding suggests that NO* overproduction initiates CNS O2 toxicity by increasing rCBF, which allows excessive O2 to be delivered to the brain.
Fiziologicheskiĭ zhurnal, Jun 1, 2011
The data obtained demonstrated that NO restrains ET-1 production and blunts ET-1-mediated basal c... more The data obtained demonstrated that NO restrains ET-1 production and blunts ET-1-mediated basal cerebrovascular tone. Local hyperoxygenation of the brain tissue decreases NO availability, supeoxide production, suppresses NO-mediated vascular tone and facilitates ET-1-mediated vasoconstriction.
Bulletin of Experimental Biology and Medicine, Sep 1, 1999
Exposure to absolute oxygen pressure of 3 and 5 bar revealed hemispheric and interhemispheric dif... more Exposure to absolute oxygen pressure of 3 and 5 bar revealed hemispheric and interhemispheric differences in lipid peroxidation and the content of phospholipids in rat brain.
Journal of Evolutionary Biochemistry and Physiology, Sep 1, 2020
Journal of Evolutionary Biochemistry and Physiology, Sep 1, 2019
The cardiovascular system of vertebrates, including humans, is well known to respond to hyperoxia... more The cardiovascular system of vertebrates, including humans, is well known to respond to hyperoxia by vasoconstriction, bradycardia and decreased contractility of the left heart ventricle. We hypothesized that all of these responses are components of the baroreflex that regulates blood pressure and circulation in hyperoxia. To test this hypothesis, we carried out experiments on awake rats in which the dynamics of arterial blood pressure, organ blood flow (brain, kidney, lower limbs) and ECG was tracked in response to oxygen breathing at 1, 3 and 5 ATA. The afferent and efferent baroreflex pathways were studied using denervation of the carotid baroreceptors and transection of the aortic depressor nerves and vagus nerve. The baroreflex effectiveness was assessed using phenylephrine injections or spontaneous changes in blood pressure. To activate the GABAergic system, nipecotic acid was injected into the lateral ventricle of the brain. Our studies demonstrated the presence of all the baroreflex components in hyperoxia which were triggered by a sharp rise in blood pressure due to systemic vasoconstriction. Hyperoxic vasoconstriction, in turn, arose due to endothelium-derived nitric oxide (NO) which binds to superoxide anions followed by a loss of the vasodilator component of vascular tone. Aortic and carotid sinus baroreceptors with ascending nerve fibers were identified as an afferent component of the hyperoxic baroreflex. Bradycardia and a decrease in cardiac output, resulting from baroreflex activation by hyperoxia, are actualized via efferent sympathetic and parasympathetic pathways. At 1 and 3 ATA O 2 , the baroreflex effectiveness increased compared to atmospheric air breathing, but extreme hyperoxia (5 ATA) suppressed the baroreflex mechanism. Activation of the GABAergic system in the cerebral cortex by nipecotic acid prevented the loss of the hyperoxic baroreflex. In hyperoxia, the baroreflex mechanism realizes adaptive responses of the cardiovascular system aimed at restraining the delivery of excess oxygen to an organism and mitigates activation of the sympathetic nervous system.
The FASEB Journal, 2015
An imbalance between glutamatergic and g-aminobutyric acid (GABA)ergic synaptic transmission is a... more An imbalance between glutamatergic and g-aminobutyric acid (GABA)ergic synaptic transmission is associated with hyperbaric oxygen (HBO2) induced seizures. Here we explored the impact of S-nitrosyla...
Evolutionary Physiology and Biochemistry - Advances and Perspectives, Feb 19, 2018
For more than five decades, Hyperbaric Laboratory has conducted basic and applied researches deal... more For more than five decades, Hyperbaric Laboratory has conducted basic and applied researches dealt with CNS oxygen toxicity, the high pressure nervous syndrome and nitrogen narcosis. Main achievements of basic researches are as follows: identified key mechanisms of adaptive responses of CNS and cardiorespiratory systems to breathing gas mixtures at high pressure, neurophysiological mechanisms of CNS oxygen toxicity and high pressure nervous syndrome, and pathogenesis of nitrogen narcosis. Main achievements of the translation of hyperbaric researches are as follows: new technology for 1000 m dive of animals (monkeys) using the gas mixture (He-N 2-O 2), new compression and decompression profiles for free escape of monkey from a depth of 700 m, use preconditional hypoxia and hyperthermia for the protection of nitrogen narcosis. Currently, main researches are focusing on the evaluation of molecular and cellular mechanisms of biological responses to extreme hyperbaric environments.
Journal of Applied Physiology, 2000
We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbari... more We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but...
Brain research, Feb 15, 2017
Breathing oxygen at sufficiently elevated pressures can trigger epileptiform seizures. Therefore,... more 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 n...
Journal of Applied Physiology, 2015
The endogenous vasodilator and signaling molecule nitric oxide has been implicated in cerebral hy... more 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 HBO2at 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 ...
Journal of applied physiology (Bethesda, Md. : 1985), 2014
Unexplained adjustments in baroreflex sensitivity occur in conjunction with exposures to potentia... more 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 respons...
The Journal of Neuroscience, 2008
The adaptive mechanisms that protect brain metabolism during and after hypoxia, for instance, dur... more 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 PO2responses to acute hypoxia among these strains of mice. In Wt mice, hypoxia increased mRNA levels for peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1 α), nuclear respiratory factor-1, and mitochondrial transcription factor A. After 24 h, new mitochondria, locali...