ubiquinone and Hypoxia

Hypoxia promotes physiological processes such as energy metabolism, angiogenesis, cell proliferation, and cell viability through the transcription factor Hypoxia Inducible Factor (HIF). Hypoxia also diminishes the activity of ATP consuming processes to promote cell survival. The mechanism(s) by which hypoxia activates HIF and diminishes ATP demand are a subject of intensive research. Here we outline the model in which mitochondrial complex III regulate the activity of HIF and diminish ATP utilization processes through the increased production of ROS during hypoxia.

Topics: Adenosine Triphosphate; Animals; Electron Transport; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondria; Oxygen; Procollagen-Proline Dioxygenase; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Ubiquinone

Topics: Amino Acids; Animals; Cerebral Cortex; Citric Acid Cycle; Cytochromes; Fatty Acids; Flavoproteins; Glycolysis; Hypoxia; Lactates; Mitochondria; Mixed Function Oxygenases; Muscles; Myocardium; NAD; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Polarography; Pyruvates; Serotonin; Spectrophotometry; Ubiquinone

To explore the presence and consequences of tissue hypoxia in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).. EAE was induced in Dark Agouti rats by immunization with recombinant myelin oligodendrocyte glycoprotein and adjuvant. Tissue hypoxia was assessed in vivo using 2 independent methods: an immunohistochemical probe administered intravenously, and insertion of a physical, oxygen-sensitive probe into the spinal cord. Indirect markers of tissue hypoxia (eg, expression of hypoxia-inducible factor-1α [HIF-1α], vessel diameter, and number of vessels) were also assessed. The effects of brief (1 hour) and continued (7 days) normobaric oxygen treatment on function were evaluated in conjunction with other treatments, namely administration of a mitochondrially targeted antioxidant (MitoQ) and inhibition of inducible nitric oxide synthase (1400W).. Observed neurological deficits were quantitatively, temporally, and spatially correlated with spinal white and gray matter hypoxia. The tissue expression of HIF-1α also correlated with loss of function. Spinal microvessels became enlarged during the hypoxic period, and their number increased at relapse. Notably, oxygen administration significantly restored function within 1 hour, with improvement persisting at least 1 week with continuous oxygen treatment. MitoQ and 1400W also caused a small but significant improvement.. We present chemical, physical, immunohistochemical, and therapeutic evidence that functional deficits caused by neuroinflammation can arise from tissue hypoxia, consistent with an energy crisis in inflamed central nervous system tissue. The neurological deficit was closely correlated with spinal white and gray matter hypoxia. This realization may indicate new avenues for therapy of neuroinflammatory diseases such as MS.

Topics: Amidines; Animals; Benzylamines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Micronutrients; Organophosphorus Compounds; Oxygen; Rats; Recovery of Function; Severity of Illness Index; Single-Blind Method; Spinal Cord Diseases; Ubiquinone

Progressive augmentation (PA) and ventilatory long-term facilitation (vLTF) of respiratory motor output are forms of respiratory plasticity that are initiated during exposure to intermittent hypoxia. The present study was designed to determine whether PA and vLTF are enhanced in obstructive sleep apnoea (OSA) participants compared to matched healthy controls. The study was also designed to determine whether administration of an antioxidant cocktail mitigates PA and vLTF. Thirteen participants with sleep apnoea and 13 controls completed two trials. During both trials participants were exposed to intermittent hypoxia which included twelve 4-min episodes of hypoxia (P(ETCO(2)), 50 mmHg; P(ETCO(2)), 4 mmHg above baseline) followed by 30 min of recovery. Prior to exposure to intermittent hypoxia, participants were administered, in a randomized fashion, either an antioxidant or a placebo cocktail. Baseline measures of minute ventilation during the placebo and antioxidant trials were not different between or within groups. During the placebo trial, PA was evident in both groups; however it was enhanced in the OSA group compared to control (last hypoxic episode 36.9 +/- 2.8 vs. 27.7 +/- 2.2 l min(-1); P

Topics: Adult; Antioxidants; Humans; Hypoxia; Male; Oxidative Stress; Polysomnography; Pulmonary Ventilation; Sleep Apnea, Obstructive; Superoxide Dismutase; Time Factors; Ubiquinone; Vitamin E

Most monotherapies available against glioblastoma multiforme (GBM) target individual hallmarks of this aggressive brain tumor with minimal success. In this article, we propose a therapeutic strategy using coenzyme Q. Xenografts of U251 cells in nu/nu mice were used to assay tumor growth, hypoxia, angiogenesis, and inflammation. An orthotopic model was used to explore microglial infiltration, tumor growth, and invasion into the brain parenchyma. Cell proliferation, migration, invasion, proteome remodeling, and secretome were assayed in vitro. Conditioned media were used to assay angiogenesis, monocyte chemoattraction, and differentiation into macrophages in vitro.. CoQ

Topics: Animals; Antioxidants; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Humans; Hypoxia; Inflammation; Mice; Proteome; Ubiquinone

[Figure: see text].

Topics: Animals; Antioxidants; Biomarkers; Blood Pressure; Female; Heart Rate; Hypoxia; Male; Organophosphorus Compounds; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Ubiquinone

Neonatal intermittent hypoxia (IH) results in oxidative distress in preterm infants with immature antioxidant systems, contributing to lung injury. Coenzyme Q10 (CoQ10) and fish oil protect against oxidative injury. We tested the hypothesis that CoQ10 is more effective than fish oil for prevention of IH-induced lung injury in neonatal rats.. Newborn rats were exposed to two clinically relevant IH paradigms at birth (P0): (1) 50% O. Of the two neonatal IH paradigms 21%/12% O. Data suggest that higher FiO

Topics: Animals; Animals, Newborn; Female; Fish Oils; Hypoxia; Lung; Male; Oxidative Stress; Pregnancy; Rats; Rats, Sprague-Dawley; Ubiquinone

The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10) supplementation on oxidative stress engendered from hypoxia in population live at high altitude.. This is an intervention study in which 50 females of volunteers population-36 of them who live at high altitude compared with the placebo group (14 from the total population that live at sea level). Blood samples were collected in -anticoagulant tubes from control and high altitude before and after CoQ10 supplementation (150 mg/day for 2, 4 and 8 weeks). Plasma was separated and used for the determination of malondialdehyde (MDA), nitric oxide (NOx), total antioxidant capacity (TAC), paraoxonase (PON1) by spectrophotometer, CoQ10 and vitamin E by high performance liquid chromatography (HPLC).. Our results appeared that TAC, PON1, vitamin E and CoQ10 concentrations were significantly decreased in population at high altitude at base line compared to placebo group population at sea level. Whereas, administration of CoQ10 attenuated all measured parameters especially after eight weeks of administration.. We concluded that coenzyme Q10 supplement at a dose of 150 mg/day has a powerful effect in oxidative stress parameters and increased antioxidant parameters included vitamin E in population with hypoxia after 4 and 8 weeks. So that supplementation positively affects oxidative stress and is recommended CoQ10 supplementation in population who live at high altitude.

Topics: Altitude; Aryldialkylphosphatase; Dietary Supplements; Female; Humans; Hypoxia; Oxidative Stress; Random Allocation; Ubiquinone

Reactive oxygen species (ROS), mitochondrial dysfunction, and excessive vasoconstriction are important contributors to chronic hypoxia (CH)-induced neonatal pulmonary hypertension. On the basis of evidence that PKCβ and mitochondrial oxidative stress are involved in several cardiovascular and metabolic disorders, we hypothesized that PKCβ and mitochondrial ROS (mitoROS) signaling contribute to enhanced pulmonary vasoconstriction in neonatal rats exposed to CH. To test this hypothesis, we examined effects of the PKCβ inhibitor LY-333,531, the ROS scavenger 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (TEMPOL), and the mitochondrial antioxidants mitoquinone mesylate (MitoQ) and (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) on vasoconstrictor responses in saline

Topics: Animals; Animals, Newborn; Chronic Disease; Cyclic N-Oxides; Enzyme Inhibitors; Female; Free Radical Scavengers; Hypoxia; Indoles; Maleimides; Organophosphorus Compounds; Oxidative Stress; Pregnancy; Protein Kinase C beta; Pulmonary Artery; Pulmonary Circulation; Rats; Reactive Oxygen Species; Spin Labels; Ubiquinone; Vasoconstriction; Vasoconstrictor Agents

In human blood, oxygen is mainly transported by red blood cells. Accordingly, the dissolved oxygen level in plasma is expected to be limited, although it has not been quantified yet. Here, by developing dedicated methods and tools, we determined that human plasma pO

Topics: Animals; Ascorbic Acid; Cell Line; Cell Lineage; Erythrocytes; Guinea Pigs; HEK293 Cells; Hep G2 Cells; Humans; Hypoxia; Oxidation-Reduction; Oxygen; Plasma; Solubility; Ubiquinone

What is the central question of this study? Does treatment of hypoxic dams with a placenta-targeted antioxidant prevent the release of placenta-derived factors that impair maturation or growth of fetal cardiomyocytes in vitro? What is the main finding and its importance? Factors released from hypoxic placentae impaired fetal cardiomyocyte maturation (induced terminal differentiation) and growth (increased cell size) in vitro, which was prevented by maternal treatment with a placenta-targeted antioxidant (nMitoQ). Moreover, there were no sex differences in the effects of placental factors on fetal cardiomyocyte maturation and growth. Overall, our data suggest that treatment targeted against placental oxidative stress could prevent fetal programming of cardiac diseases via the release of placental factors.. Pregnancy complications associated with placental oxidative stress may impair fetal organ development through the release of placenta-derived factors into the fetal circulation. We assessed the effect of factors secreted from placentae previously exposed to prenatal hypoxia on fetal cardiomyocyte development and developed a treatment strategy that targets placental oxidative stress by encapsulating the antioxidant MitoQ into nanoparticles (nMitoQ). We used a rat model of prenatal hypoxia (gestational day (GD) 15-21), which was treated with saline or nMitoQ on GD15. On GD21, placentae were harvested, placed in culture, and conditioned medium (containing placenta-derived factors) was collected after 24 h. This conditioned medium was then added to cultured cardiomyocytes from control dam fetuses. Conditioned medium from prenatally hypoxic placentae increased the percentage of binucleated cardiomyocytes (marker of terminal differentiation) and the size of mononucleated and binucleated cardiomyocytes (sign of hypertrophy), effects that were prevented by nMitoQ treatment. Our data suggest that factors derived from placentae previously exposed to prenatal hypoxia lead to abnormal fetal cardiomyocyte development, and show that treatment against placental oxidative stress may prevent fetal programming of cardiac disease.

Topics: Animals; Antioxidants; Cells, Cultured; Culture Media, Conditioned; Female; Fetal Development; Hypoxia; Male; Myocytes, Cardiac; Organophosphorus Compounds; Oxidative Stress; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Ubiquinone

Myopathy is a well-known adverse effect of statins, affecting a large sector of statins users. The reported experimental data emphasized on mechanistic study of statin myopathy on large muscles. Clinically, both large muscles and respiratory muscles are reported to be involved in the myotoxic profile of statins. However, the experimental data investigating the myopathic mechanism on respiratory muscles are still lacking. The present work aimed to study the effect of atorvastatin treatment on respiratory muscles using rat isolated hemidiaphragm in normoxic & hypoxic conditions. The contractile activity of isolated hemidiaphragm in rats treated with atorvastatin for 21 days was investigated using nerve stimulated technique. Muscle twitches, train of four and tetanic stimulation was measured in normoxic, hypoxic and reoxygenation conditions. Atorvastatin significantly increased the tetanic fade, a measure of muscle fatigability, in hypoxic conditions. Upon reoxygenation, rat hemidiaphragm regains its normal contractile profile. Co-treatment with coenzyme Q10 showed significant improvement in defective diaphragmatic contractility in hypoxic conditions. This work showed that atorvastatin treatment rapidly deteriorates diaphragmatic activity in low oxygen environment. The mitochondrial respiratory dysfunction is probably the mechanism behind such finding. This was supported by the improvement of muscle contractile activity following CoQ10 co-treatment.

Topics: Animals; Anticholesteremic Agents; Atorvastatin; Hypoxia; Male; Muscle Contraction; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Ubiquinone

Therapeutic hypothermia is commonly used during cardiopulmonary bypass (CPB) to protect the heart against myocardial injury in cardiac surgery. Patients who suffer from chronic hypoxia (CH), such as those with certain heart or lung conditions, are at high risk of severe myocardial injury after cardiac surgery, but the underlying mechanisms are unknown. This study tested whether CH attenuates hypothermic cardioprotection during CPB. Using a rat model of CPB, we found that hypothermic cardioprotection was impaired in CH rats but was preserved in normoxic rats. Cardiac proteomes showed that cold-inducible RNA binding protein (CIRBP) was significantly (

Topics: Animals; Antioxidants; DNA Methylation; Female; Humans; Hypoxia; In Situ Nick-End Labeling; Male; Mice, Knockout; Myocytes, Cardiac; Promoter Regions, Genetic; Rats; RNA-Binding Proteins; Ubiquinone

Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism - this requires rhodoquinone (RQ), an electron carrier that is made by very few animal species. Crucially RQ is not made or used by any parasitic hosts and RQ synthesis is thus an ideal target for anthelmintics. However, little is known about how RQ is made and no drugs are known to block RQ synthesis.

Topics: Anaerobiosis; Animals; Caenorhabditis elegans; Hypoxia; Kynurenine; Metabolic Networks and Pathways; Survival Analysis; Ubiquinone

Topics: Animals; Carotid Body; Electron Transport Complex I; Electron Transport Complex II; Hypoxia; Ion Channels; Mice; NAD; NADH Dehydrogenase; Oxygen; Reactive Oxygen Species; Ubiquinone

Casuso, Rafael A., Jerónimo Aragón-Vela, Gracia López-Contreras, Silvana N. Gomes, Cristina Casals, Yaira Barranco-Ruiz, Jordi J. Mercadé, and Jesus R. Huertas. Does swimming at a moderate altitude favor a lower oxidative stress in an intensity-dependent manner? Role of nonenzymatic antioxidants. High-Alt Med Biol. 18:46-55, 2017.-we aimed to describe oxidative damage and enzymatic and nonenzymatic antioxidant responses to swimming at different intensities in hypoxia. We recruited 12 highly experienced swimmers who have been involved in competitive swimming for at least 9 years. They performed a total of six swimming sessions carried out at low (LOW), moderate (MOD), or high (HIGH) intensity at low altitude (630 m) and at 2320 m above sea level. Blood samples were collected before the session (Pre), after the cool down (Post), and after 15 minutes of recovery (Rec). Blood lactate (BL) and heart rate were recorded throughout the main part of the session. Average velocities did not change between hypoxia and normoxia. We found a higher BL in response to MOD intensity in hypoxia. Plasmatic hydroperoxide level decreased at all intensities when swimming in hypoxia. This effect coincided with a lower glutation peroxidase activity and a marked mobilization of the circulating levels of α-tocopherol and coenzyme Q10 in an intensity-dependent manner. Our results suggest that, regardless of the intensity, no oxidative damage is found in response to hypoxic swimming in well-trained swimmers. Indeed, swimmers show a highly efficient antioxidant system by stimulating the mobilization of nonenzymatic antioxidants.

Topics: Adult; alpha-Tocopherol; Altitude; Antioxidants; Athletes; Exercise Tolerance; Female; Heart Rate; Humans; Hypoxia; Male; Oxidation-Reduction; Oxidative Stress; Peroxidase; Swimming; Ubiquinone; Young Adult

The present study aims to clarify the protective effect of supplementation with some antioxidants, such as idebenone (200 mg/kg, ip), melatonin (10 mg/kg, ip) and arginine (200 mg/kg, ip) and their combination, on liver function (T. protein, albumin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase), energetic parameters (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, inorganic phosphate, total adenylate, adenylate energy charge and potential phosphate). The effect on glycolytic and glycogenolytic enzymes (glucose, glycogen, glycogen phosphorylase, pyruvate kinase and phosphofructokinase against hypoxia) was also studied. The drugs were administered 24 and 1 h prior sodium nitrite intoxication. All biochemical parameters were estimated 1 h after sodium nitrite injection. Injection of sodium nitrite (75 mg/kg, sc) produced a significant disturbance in all biochemical parameters of liver function, energetic parameters and glycolytic and glycogenolytic enzymes. Hepatic damage was confirmed by histopathological examination of the liver as compared to controls. The marked changes in hepatic cells induced by sodium nitrite were completely abolished by pretreatment with the drug combination, suggesting potential protection against sodium nitrite-induced hypoxia. It could be concluded that a combination of both idebenone and melatonin or idebenone and arginine provides potential protection against sodium nitrite-induced hypoxia by improving biochemical parameters and preserving liver histology.

Topics: Animals; Antioxidants; Arginine; Chemical and Drug Induced Liver Injury; Cytoprotection; Dietary Supplements; Disease Models, Animal; Drug Therapy, Combination; Energy Metabolism; Hypoxia; Liver; Male; Melatonin; Oxidative Stress; Rats; Reactive Oxygen Species; Sodium Nitrite; Time Factors; Ubiquinone

Sleep apnea associated with chronic intermittent hypoxia (IH) impairs hippocampal functions but the pathogenic mechanisms involving dysfunction of nitric oxide (NO) and ionic channels remain unclear. We examined the hypothesis that hippocampal NO deficit impairs the activity of large conductance calcium-activated potassium (BK) channels in rats with chronic IH, mimicking conditions in patients with sleep apnea. A patch-clamp study was performed on hippocampal CA1 neurons acutely dissociated from IH and control rats. The levels of endogenous NO and intracellular calcium in the CA1 region of the hippocampal slices were measured respectively by electrochemical microsensors and spectrofluorometry. We found that the open probability of BK channels remarkably decreased in the CA1 pyramidal neurons in a time-dependent manner with the IH treatment, without changes in the unitary conductance and reversal potential. NO donors, SNP or DETA/NO, significantly restored the activity of BK channels in the IH neurons, which was prevented by blockade of S-nitrosylation with NEM or MTSES but not by inhibition of the cGMP pathway with ODQ or 8-bromo-cGMP. Endogenous NO levels were substantially lowered in the IH hippocampus during resting and hypoxia. Also, the level of protein expression of neuronal NO synthase was markedly lessened in the IH neurons with decreased intracellular calcium response to hypoxia. Collectively, the results suggest that the IH-induced NO deficit mediated by a down-regulation of the expression of neuronal NO synthase plays a causative role in the impaired activity of BK channels, which could account for the hippocampal injury in patients with sleep apnea.

Topics: Animals; Calcium; Chronic Disease; Coenzymes; Hippocampus; Hypoxia; Large-Conductance Calcium-Activated Potassium Channels; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type I; Oxidative Stress; Rats; Rats, Sprague-Dawley; Ubiquinone

In present research the action of coenzyme Q10 on energetic metabolism and antioxidant system at different temperature conditions has been studied. It was established that the addition of coenzyme Q10 caused inadequate stimulation of main metabolic systems that could lead to running out of functional reserves of cardiomyocytes. The use of coenzyme Q10 helped to optimize intracellular compensating mechanisms supplying the defense of myocardium. Introduction in a diet coenzyme Q10 in conditions of a temperature's comfort threshold excess and development of a histic hypoxia can promote the decrease of gravity of hypoxic myocardium's lesions and to glycogenolysis' amplification that promotes maintenance of an energy homeostasis of a myocardium in posthypoxia term. It is possible to assume, that the augmentation of duration of reception coenzyme Q10 or its dosages can render more expressed protective effect.

Topics: Adaptation, Physiological; Animals; Coenzymes; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Housing, Animal; Hypoxia; Male; Myocardium; Rats; Temperature; Ubiquinone

Prophylactic dietary intake of synthetic ubiquinone-10, succinic acid, or mixture of these substances prevented disturbances in aggregation and electrophoretic mobility of erythrocytes and inhibited lipid peroxidation in cells of rats with experimental epinephrine-induced toxemia.

Topics: Animals; Epinephrine; Erythrocyte Aggregation; Erythrocytes; Female; Hypoxia; Lipid Peroxidation; Models, Biological; Rats; Succinic Acid; Toxemia; Ubiquinone

Coenzyme Q10 (CoQ10, ubiquinone) is a highly mobile electron carrier in the mitochondrial respiratory chain that also acts as an antioxidant. We evaluated the cardiovascular protective efficacy of CoQ10 at the rostral ventrolateral medulla (RVLM), a medullary site where sympathetic vasomotor tone originates and where the organophosphate poison mevinphos (Mev) acts to elicit cardiovascular intoxication. Experiments were carried out in adult male Sprague-Dawley rats that were maintained under propofol anesthesia. Microinjection bilaterally of Mev (10 nmol) into the RVLM induced progressive hypotension and minor bradycardia, alongside significant depression of the activity of NADH cytochrome c reductase (enzyme marker for Complexes I and III) or cytochrome c oxidase (enzyme marker for Complex IV) in the mitochondrial respiratory chain, reduction in ATP concentration, or tissue hypoxia in the RVLM. On the other hand, the activity of succinate cytochrome c reductase (enzyme marker for Complexes II and III) remained unaltered. The Mev-induced hypotension, bioenergetic failure, or hypoxia was significantly reversed when CoQ10 (4 microg) was coadministered bilaterally into the RVLM with the organophosphate poison. We conclude that CoQ10 confers cardiovascular protection against acute Mev intoxication by acting on the RVLM, whose neuronal activity is intimately related to the "life-and-death" process. We also showed that amelioration of the selective dysfunction of respiratory enzyme Complexes I and IV in the mitochondrial respiratory chain, the reduced ATP level, and the induced tissue hypoxia in the RVLM are among some of the underlying mechanisms for the elicited protection.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Cardiovascular System; Coenzymes; Electron Transport Complex IV; Hypotension; Hypoxia; Male; Medulla Oblongata; Mevinphos; Mitochondria; NADH Dehydrogenase; Oxygen; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Succinate Cytochrome c Oxidoreductase; Succinic Acid; Time Factors; Ubiquinone

The properties of coenzymes Q (CoQ9 and CoQ10) are closely linked to their redox state (CoQox/total CoQ) x 100. In this work, CoQ redox state was biologically validated by high performance liquid chromatography-electrochemical measurement after modulation of mitochondrial electron flow of cultured cells by molecules increasing (rotenone, carbonyl cyanide chlorophenylhydrazone) or decreasing (antimycin) CoQ oxidation. The tissue specificity of CoQ redox state and content were investigated in control and hypoxic rats. In control rats, there was a strong negative linear regression between tissular CoQ redox state and CoQ content. Hypoxia increased CoQ9 redox state and decreased CoQ9 content in a negative linear relationship in the different tissues, except the heart and lung. This result demonstrates that, under conditions of mitochondrial impairment, CoQ redox control is tissue-specific.

Topics: 3T3 Cells; Animals; Chromatography, High Pressure Liquid; Electron Transport; Hypoxia; Male; Mice; Mitochondria; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Regression Analysis; Reproducibility of Results; Sensitivity and Specificity; Tissue Distribution; Ubiquinone

Chronic hypoxia (CH) is believed to induce myocardial protection, but this is in contrast with clinical evidence. Here, we test the hypothesis that repeated brief reoxygenation episodes during prolonged CH improve myocardial tolerance to hypoxia-induced dysfunction. Male 5-week-old Sprague-Dawley rats (n = 7-9/group) were exposed for 2 weeks to CH (F(I)O(2) = 0.10), intermittent hypoxia (IH, same as CH, but 1 hr/day exposure to room air), or normoxia (N, F(I)O(2) = 0.21). Hearts were isolated, Langendorff perfused for 30 min with hypoxic medium (Krebs-Henseleit, PO(2) = 67 mmHg), and exposed to hyperoxia (PO(2) = 670 mm Hg). CH hearts displayed higher end-diastolic pressure, lower rate x pressure product, and higher vascular resistance than IH. During hypoxic perfusion, anaerobic mechanisms recruitment was similar in CH and IH hearts, but less than in N. Thus, despite differing only for 1 hr daily exposure to room air, CH and IH induced different responses in animal homeostasis, markers of oxidative stress, and myocardial tolerance to reoxygenation. We conclude that the protection in animals exposed to CH appears conferred by the hypoxic preconditioning due to the reoxygenation rather than by hypoxia per se.

Topics: alpha-Tocopherol; Animals; Heart; Hypoxia; Male; Myocardium; Oxidative Stress; Perfusion; Rats; Rats, Sprague-Dawley; Time Factors; Ubiquinone

Coenzyme Q10 (CoQ10) is a natural mitochondrial respiratory chain constituent with antioxidant properties. This study tests the hypothesis that CoQ10 administered before the onset of reoxygenation on cardiopulmonary bypass, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass. The antioxidant properties of CoQ10 were confirmed by an in vitro study in which normal myocardial homogenates were incubated with the oxidant, t-butylhydroperoxide. Fifteen immature piglets (< 3 weeks old) were placed on 60 minutes of cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (oxygen tension about 400 mm Hg). Ten others became hypoxemic on cardiopulmonary bypass for 30 minutes by lowering oxygen tension to approximately 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 30 minutes. In five piglets, CoQ10 (45 mg/kg) was added to the cardiopulmonary bypass circuit 15 minutes before reoxygenation, and five others were not treated (no treatment). Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance (conductance catheter), oxidant damage (lipid peroxidation) was assessed by measuring conjugated diene levels in coronary sinus blood, and antioxidant reserve capacity was determined by measuring malondialdehyde in myocardium after cardiopulmonary bypass incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant damage and allowed complete functional recovery. Reoxygenated hearts (no treatment) showed a progressive increase in conjugated diene levels in coronary sinus blood after reoxygenation (2.3 +/- 0.6 A233 nm/0.5 ml plasma at 30 minutes after reoxygenation) and reduced antioxidant reserve capacity (malondialdehyde: 1219 +/- 157 nmol/g protein at 4.0 mmol/L t-butylhydroperoxide), resulting in severe postbypass dysfunction (percent end-systolic elastance = 38 +/- 6). Conversely, CoQ10 treatment avoided the increase in conjugated diene levels (2.1 +/- 0.6 vs 1.1 +/- 0.3, p < 0.05 vs no treatment), retained normal antioxidant reserve (896 +/- 76 nmol/g protein, p < 0.05 vs no treatment), and allowed nearly complete recovery of function (94% +/- 7%, p < 0.05 vs no treatment). We conclude that reoxygenation of the hypoxemic immature heart on cardiopulmonary bypass causes oxygen-mediated myocardial injury, which can be limited by CoQ10 treatment before reoxygenation. These findings imply

Topics: Animals; Cardiopulmonary Bypass; Coenzymes; Hemodynamics; Hypoxia; In Vitro Techniques; Lipid Peroxidation; Myocardial Contraction; Myocardial Reperfusion Injury; Peroxides; Reactive Oxygen Species; Swine; tert-Butylhydroperoxide; Ubiquinone; Ventricular Function, Left

The effects of cerebral metabolism-improving drugs on NADPH diaphorase activity in the mouse brain were studied, and we found that diaphorase activity in the post-mitochondrial fraction of brain homogenate was enhanced by idebenone in a concentration-dependent manner. Histochemical studies also indicated that diaphorase staining was intensified by idebenone at the same concentration. These results suggest that idebenone may stimulate the production of nitric oxide, probably through its direct action on nitric oxide synthase, thus producing its protective action on neurological disorders due to cerebral hypoxia or ischemia as a consequence of dilating the cerebral blood vessels.

Topics: Amino Acid Oxidoreductases; Animals; Benzoquinones; Brain; Brain Ischemia; Cerebral Cortex; Choroid Plexus; Dose-Response Relationship, Drug; Histocytochemistry; Hypoxia; In Vitro Techniques; Male; Mice; NADPH Dehydrogenase; Nitric Oxide; Nitric Oxide Synthase; Ubiquinone

2-Oxoglutarate-supported rat liver mitochondria were loaded with moderate amounts of calcium and submitted to O2 deprivation and reoxygenation. In the presence of acetoacetate, anaerobic energy production maintained Ca2+ retention by mitochondria during the anoxia period unless the Pi concentration of the incubation solution was raised to 4-6 mM. Acetoacetate prompted Ca2+ release from O2-deprived mitochondria at elevated Pi levels, presumably due to occurrence of a permeability transition of the inner membrane. Providing 3-hydroxybutyrate and malate, together with acetoacetate, was found to delay the permeability transition until O2 was reintroduced, i.e., O2 triggered a paradoxical release of Ca2+ from mitochondria under these conditions. Whether initiated by O2 in the presence of Pi or by Pi under aerobic conditions, Ca2+ release was initially activated and subsequently inhibited or reversed in the presence of alpha-tocopherol (10-90 mumol.g protein-1). Similar effects were exerted by alpha-tocopherol during Pi-induced Ca2+ release from oligomycin-treated mitochondria supported by succinate (+ rotenone). In addition, the permeability transition was delayed by retinol (3-30 mumol.g protein-1) while beta-carotene, ubiquinone, and water-soluble antioxidants, including Trolox C, were ineffective. Other observations suggest that the Ca(2+)-releasing and/or -retaining effects of alpha-tocopherol and retinol may be independent from pro- and/or antioxidant activities. Effects resembling those of alpha-tocopherol were exerted by alpha-tocopherol succinate, which is devoid of antioxidant activity. Our data indicate that the permeability transition of Ca(2+)-loaded liver mitochondria may be triggered by O2, in the presence of ketone bodies, and affected by lipid-soluble antioxidants through mechanisms seemingly unrelated to free-radical generation or scavenging.

Topics: Acetoacetates; Anaerobiosis; Animals; Antioxidants; beta Carotene; Calcium; Carotenoids; Chromans; Hypoxia; Kinetics; Mitochondria, Liver; Oligomycins; Oxygen; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Ubiquinone; Vitamin A; Vitamin E

Effect of WEB 1881 FU (nebracetam) on hypoxia and ischemia-induced impairment of 2-deoxyglucose (2DG) uptake and CA1 field potentials induced by hypoxia and hypoxia/hypoglycemia (ischemia) in rat brain slices was evaluated and compared to the findings obtained with pentobarbital and idebenone. Hippocampal and cortical slices were exposed to 15-20 min of ischemia, and then these slices were returned to oxygenated and glucose-containing buffer for 6 hr. Ischemia reduced both 30 mM KCl-induced 2DG uptake and CA1 field potentials elicited by the stimulation of Schaffer collaterals in the hippocampus. Pretreatment of nebracetam at 1 mM or pentobarbital at 0.1 mM attenuated a decline of 2DG uptake and CA1 field potentials under the condition of ischemia. In addition, nebracetam and pentobarbital relatively recovered the increase of 2DG uptake in the hippocampus under hypoxia for 45 min. Furthermore, these drugs also attenuated the decline of 2DG uptake induced by 10 mM glutamate for 20 min. However, treatment with idebenone did not recover the deficit of 2DG uptake and CA1 field potential. The present result suggests that nebracetam and pentobarbital exert neuroprotective actions against not only ischemia but also glutamate toxicity.

Topics: Animals; Benzoquinones; Brain Ischemia; Cerebral Cortex; Deoxyglucose; Electrophysiology; Evoked Potentials; Glutamates; Glutamic Acid; Hippocampus; Hypoxia; In Vitro Techniques; Male; Parasympathomimetics; Pentobarbital; Pyrrolidinones; Rats; Rats, Inbred Strains; Ubiquinone

1. The biosynthesis of ubiquinone (UQ) in isolated rat heart under ischemic and hypoxic conditions was investigated. 2. Under ischemic perfusion, a greater amount of biosynthetic intermediates, 3-nonaprenyl and 3-decaprenyl-4-hydroxybenzoate (PPHBs) was accumulated and a smaller amount of UQ-9 and -10 was synthesized when compared with normal conditions. 3. The accumulation of PPHBs was observed without forming UQs during anaerobic perfusion. 4. Hydroxylation which is the following reaction of PPHBs for the biosynthesis of UQ in rat heart, was proceeded by the monooxygenase(s) depending upon the oxygen concentrations.

Topics: Animals; Chromatography, High Pressure Liquid; Coronary Disease; Hydroxylation; Hypoxia; Male; Mitochondria, Heart; Myocardium; Oxygen; Parabens; Pyridines; Rats; Rats, Inbred Strains; Rotenone; Terpenes; Ubiquinone

Effect of WEB 1881 FU on hypoglycemia/hypoxia-induced brain damage in rats was evaluated and compared to findings obtained with idebenone. We used an in vitro model that facilitated the direct monitoring of dopamine release from striatal slices. The response to high K+ stimulation under perfusion of the slices with D-glucose-free Ringer solution (hypoglycemia) decreased at 40 min, and then practically disappeared. WEB 1881 FU at 10(-6) M or idebenone at 10(-6) M significantly protected against impairment of the striatal responses under the conditions of hypoglycemia. Hypoglycemic injury, evidenced by a remarkable neuron loss, necrosis and spongyosis was also ameliorated by these drugs. WEB 1881 FU at 10(-6) M had a protective action against the impairment of striatal responses evoked by NaCN (electron transport inhibitor at site 3) and oligomycin (inhibitor of mitochondrial ATP synthesis), but idebenone at 10(-6) M did not. In light of these observations, the possibility that WEB 1881 FU and idebenone exert neuroprotective actions against hypoglycemic/hypoxic brain injury by activating energy metabolism with different mechanisms from each other has to be considered.

Topics: Animals; Benzoquinones; Brain Diseases; Corpus Striatum; Cyanides; Dopamine; Hypoglycemia; Hypoxia; In Vitro Techniques; Male; Neurons; Oligomycins; Parasympatholytics; Potassium; Pyrrolidinones; Quinones; Rats; Rats, Inbred Strains; Ubiquinone

The effects of idebenone on survival time of mice subjected to hypoxia induced by N2 and CO2 inhalation and KCN injection were studied. Idebenone (10, 20, 50 and 100 mg/kg, i.p.) prolonged the survival time of mice exposed to a hypoxic condition (98% N2, 2% O2) in a dose-dependent manner: significant prolongations were observed at doses higher than 20 mg/kg. The drug also exerted a similar elongation effect at the same doses under conditions of 100% CO2 gas inhalation and KCN injection (3 mg/kg, i.v.). The results suggest that idebenone protects against hypoxia by improving cerebral energy metabolism.

Topics: Animals; Benzoquinones; Cerebral Cortex; Energy Metabolism; Hypoxia; Mice; Mice, Inbred ICR; Quinones; Ubiquinone

Topics: Animals; Brain; Coenzymes; Energy Metabolism; Hypoxia; Rabbits; Ubiquinone

We have studied the effects of reoxygenation on hypoxia-induced changes in contents of high energy phosphate compounds in pacemaker cells of nodal tissues excised from the rabbit heart, and effects of coenzyme Q10 on the electrical activity and metabolite contents in the tissue exposed to hypoxia and then reoxygenated. The contents of ATP and creatine phosphate (CP) in the sinoatrial node tissue were markedly reduced within 15-30 min after exposure to hypoxic Tyrode's solution. Reoxygenation produced almost complete recovery of the tissue ATP, but not of CP. After 60-120 min of hypoxia, the tissue ATP and CP decreased to about 60-30% of the initial value, but were not recovered by reoxygenation. Coenzyme Q10 (CoQ) at concentrations of 10(-6)-10(-5) g/ml did not produce changes in action potential parameters in the normal Tyrode's solution. CoQ (10(-5) g/ml) did not prevent the decreases in tissular ATP and CP in the initial period of hypoxia (30-60 min), but the ATP content at 120 min of hypoxia in the presence of CoQ was higher than the control. CoQ promoted recovery of tissular ATP after reoxygenation. Our results provide direct evidence that generation of action potentials in the sinoatrial nodal cells can be maintained by a small amount of ATP produced by the anaerobic glycolytic pathway. The present results suggest that exogenous CoQ would facilitate resynthesis of ATP in the functionally impaired mitochondria.

Topics: Action Potentials; Adenosine Triphosphate; Aerobiosis; Animals; Coenzymes; Hypoxia; In Vitro Techniques; Myocardium; Oxygen; Phosphocreatine; Rabbits; Sinoatrial Node; Ubiquinone

Topics: Animals; Cell Survival; Cells, Cultured; Coenzymes; Heart; Hypoxia; Male; Myocardium; Rats; Rats, Inbred Strains; Time Factors; Ubiquinone

To investigate the protective effect of coenzyme Q10 on left ventricular function during ischaemia and reperfusion, we studied isolated working rat hearts contracting 300 times per min perfused with Krebs-Henseleit solution at 37 degrees C. There was no significant difference in left ventricular end-diastolic pressure and left ventricular dP/dt between the coenzyme Q10-treated group (intravenous injection of 0.0115 mmol per kg of body weight, n = 7) and the vehicle-treated control group (n = 7) throughout 45 min of ischaemia and 30 min of reperfusion. The left ventricular peak systolic pressure in the coenzyme Q10-treated group was higher than in the vehicle-treated control group (48.7 +/- 10.9 versus 29.7 +/- 10.0 mmHg, p less than 0.05) after 30 min of reperfusion, although there was no significant difference between the two groups before and during ischaemia (45 min). During 5 to 30 min of the recovery period, the coronary sinus flow in the coenzyme Q10-treated group was greater than in the control group (5.4 +/- 1.8 versus 3.1 +/- 0.5 ml X min-1 after 30 min of recovery, p less than 0.05). It was concluded that coenzyme Q10 improved recovery of the left ventricular peak systolic pressure and the coronary sinus flow. Although it is possible that coenzyme Q10 facilitated ATP production and improved recovery, it is more likely that coenzyme Q10, which is an antioxidant, protected the myocardium against free radical damage during reperfusion.

Topics: Animals; Blood Pressure; Coenzymes; Heart; Heart Ventricles; Hypoxia; Ischemia; Male; Perfusion; Rats; Rats, Inbred Strains; Ubiquinone

Topics: Animals; Coenzymes; Energy Metabolism; Hypoxia; Lactates; Lactic Acid; Rabbits; Resuscitation; Ubiquinone

Topics: Animals; Hypoxia; Lactates; Liver; Rabbits; Ubiquinone

Topics: Animals; Benzoquinones; Cardiovascular Agents; Citric Acid Cycle; Coronary Circulation; Coronary Disease; Electron Transport; Hypoxia; Malates; Mice; Myocardium; Quinones; Rats; Succinates; Ubiquinone

The content of ubiquinone and vitamin E in liver, heart, kidney and muscle tissues has been found to vary in experimental focal myocarditis and acute hypoxic hypoxia. These compounds have been demonstrated to accumulate in myocardial mitochondria, which is likely to be related to both interstitial and inter-organ redistribution having a compensatory-adaptation importance. In the pathology under study, the myocardium demonstrates a greater intensity and more remarkable line of changes in the content of vitamin E and ubiquinone. It is suggested that these substances contribute to the increased body resistance to hypoxic exposures of varying genesis.

Topics: Animals; Hypoxia; Kidney; Liver; Male; Mitochondria, Heart; Muscles; Myocarditis; Myocardium; Rats; Ubiquinone; Vitamin E

As one of the factors contributing to the intractability of chronic gastric ulcer, the effect of hypoxia is examined in this paper, based upon the experimental acetic acid ulcer in the stomach of Wistar rats. Results indicate that hypoxia has a harmful influence on the healing process of chronic, gastric ulcer in rats, and also that this effect of hypoxia can be prevented by administration of Coenzyme Q10 in diet.

Topics: Acetates; Animals; Gastric Mucosa; Hypoxia; Male; Pylorus; Rats; Stomach Ulcer; Time Factors; Ubiquinone

Rabbits were kept for 2 and 4 hours in a chamber containing a gas mixture of 92% N2 and 8% O2. The ubiquinone level in the musculus quadriceps femoris of the animals was determined. Rabbits after 4 hours hypoxia were retaken into normal conditions for 2 hours before killing. Biochemical findings revealed a significant decrease in the ubiquinone activity during hypoxia independently from duration of hypoxia. 2 hours after hypoxia the ubiquinone activity became normal. The slight alterations biochemically determined can not be followed unambiguously by histochemical methods, but the microscopic studies have revealed that the red fibres of mixed musculus quadriceps femoris are responsible for the quantitative changes.

Topics: Animals; Histocytochemistry; Hypoxia; Male; Muscles; Rabbits; Ubiquinone

The content and biosynthesis of ubiquinone-9 in the thin slices of the liver of rats was studied during altitude adaptation. There was a three-fold acceleration of ubiquinone biosynthesis during the first period of altitude adaptation. Acceleration of biosynthesis of ubiquinone-9 in rat liver was insignificant after two weeks of adaptation. The content of ubiquinone-9 in rat liver changed but insignificantly in the course of one month of altitude adaptation.

Topics: Adaptation, Physiological; Altitude; Animals; Hypoxia; Liver; Male; Rats; Time Factors; Ubiquinone

Exposure of rats to hypobaric stress for periods of up to 36 h caused a consistent change in the succinate-NT reductase activity of the heart mitochondria whereas there was no significant change in the activities of either succinate dehydrogenase and succinate-NT reductase of the brain and the kidney. Mitochondrial succinate dehydrogenase of the heart, the brain and the kidney was activated 2- to 7-fold with the substrate and malonate. The activations obtained with oxalate, citrate and dinitrophenol were relatively lower in comparison to succinate and malonate. Benzohydroquinone and 2-nitrophenol had no stimulatory effect on the heart, the brain and the kidney mitochondria. THE ACTIVATIONS OBTAINED WITH THE VARIOUS EFFECTORS PARTIALLY (OR COMPLETELY IN THE CASE OF SUCCINATE) REVERSED ON WASHING THE MITOCHONDRIAL SAMPLES WITH THE SUCROSE HOMOGENIZING MEDIUM. The effect of ubiquinol, which also activated the enzyme, was only partially reversed after the second preincubation with succinate in the brain and the kidney whereas in the heart the activity was fully reversed. The increased activity of succinate dehydrogenase obtained with ATP and ADP was further enhanced by Mg2+ exclusively in the brain mitochondria, suggesting the possibility of Mg2+-AIP complex as the active species. Succinate-NT reductase of the heart, the brain and the kidney mitochondria showed a high activation with ubiquinone whereas its reduced form had no stimulatory effect.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Atmospheric Pressure; Brain; Diphosphates; Hypoxia; Kidney; Magnesium; Male; Malonates; Mitochondria; Myocardium; Oxidoreductases; Rats; Stimulation, Chemical; Stress, Physiological; Succinates; Tetrazolium Salts; Ubiquinone

Topics: Adaptation, Physiological; Altitude; Animals; Female; Guinea Pigs; Hypoxia; Male; Myocardium; Rats; Ubiquinone

Topics: Animals; Binding Sites; Diphosphates; Enzyme Activation; Hypoxia; Liver; Male; Malonates; Mitochondria, Liver; Nitrophenols; Oxaloacetates; Pressure; Protein Binding; Protein Denaturation; Quinones; Rats; Spectrophotometry; Succinate Dehydrogenase; Succinates; Time Factors; Ubiquinone

Topics: Amobarbital; Animals; Calcium; Electric Stimulation; Epinephrine; Freezing; Guinea Pigs; Heart; Heart Atria; Hypoxia; In Vitro Techniques; Male; Malonates; Mitochondria, Muscle; Myocardium; Ouabain; Oxidation-Reduction; Rotenone; Ubiquinone

Topics: Adaptation, Physiological; Animals; Cytochromes; Hypoxia; Male; Mitochondria, Liver; Muscles; Myocardium; Myoglobin; Rats; Ubiquinone

Topics: Anesthesia, Local; Animals; Blood Pressure; Carbohydrate Metabolism; Carbon Dioxide; Electrocardiography; Humans; Hypoxia; Oxygen; Rabbits; Ubiquinone