ubiquinone and Ischemia

In this review we summarise the current state of knowledge of the therapeutic efficacy and mechanisms of action of CoQ(10) in cardiovascular disease. Our conclusions are: 1. There is promising evidence of a beneficial effect of CoQ(10) when given alone or in addition to standard therapies in hypertension and in heart failure, but less extensive evidence in ischemic heart disease. 2. Large scale multi-centre prospective randomised trials are indicated in all these areas but there are difficulties in funding such trials. 3. Presently, due to the notable absence of clinically significant side effects and likely therapeutic benefit, CoQ(10) can be considered a safe adjunct to standard therapies in cardiovascular disease.

Topics: Adenosine Triphosphate; Anthracyclines; Antioxidants; Cardiovascular Diseases; Clinical Trials as Topic; Coenzymes; Diet; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Ischemia; Mitochondria; Models, Biological; Ubiquinone

Co-enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trails worldwide.

Topics: Administration, Oral; Cardiovascular Diseases; Chemical Phenomena; Chemistry; Coenzymes; Doxorubicin; Free Radicals; Heart Arrest, Induced; Heart Failure; Humans; Hypertension; Ischemia; Reperfusion; Ubiquinone

Mitochondrial dysfunction is a critical factor contributing to oxidative stress and apoptosis in ischemia-reperfusion (I/R) diseases. Mitoquinone (MitoQ) is a mitochondria-targeted antioxidant whose potent anti-I/R injury capacity has been demonstrated in organs such as the heart and the intestine. In the present study, we explored the role of MitoQ in maintaining mitochondrial homeostasis and attenuating oxidative damage in renal I/R injury. We discovered that the decreased renal function and pathological damage caused by renal I/R injury were significantly ameliorated by MitoQ. MitoQ markedly reversed mitochondrial damage after I/R injury and inhibited renal reactive oxygen species production. In vitro, hypoxia/reoxygenation resulted in increased mitochondrial fission and decreased mitochondrial fusion in human renal tubular epithelial cells (HK-2), which were partially prevented by MitoQ. MitoQ treatment inhibited oxidative stress and reduced apoptosis in HK-2 cells by restoring mitochondrial membrane potential, promoting ATP production, and facilitating mitochondrial fusion. Deeply, renal I/R injury led to a decreased expression of sirtuin-3 (Sirt3), which was recovered by MitoQ. Moreover, the inhibition of Sirt3 partially eliminated the protective effect of MitoQ on mitochondria and increased oxidative damage. Overall, our data demonstrate a mitochondrial protective effect of MitoQ, which raises the possibility of MitoQ as a novel therapy for renal I/R.

Topics: Adenosine Triphosphate; Antioxidants; Homeostasis; Humans; Ischemia; Kidney Diseases; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Reactive Oxygen Species; Reperfusion; Reperfusion Injury; Sirtuin 3; Ubiquinone

Topics: Animals; Cytokines; Ischemia; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinases; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Spermatic Cord Torsion; Testis; Ubiquinone

Generation of toxic oxygen metabolites followed by oxidant- and inflammatory-mediated tissue injury plays a crucial role in the pathogenesis of ischemia and reperfusion (IR). Ubiquinol, the reduced form of coenzyme Q10, is recognized for its potent antioxidant and anti-inflammatory properties in biological membranes. The present study was established to examine the possible protective effect of ubiquinol against renal IR injury. Groups of male Wistar rats were assigned into sham, ubiquinol, IR (45-min bilateral renal ischemia followed by 24-h reperfusion), and ubiquinol+ IR (ubiquinol 300 mg/kg given orally for 7 consecutive days before IR induction). Renal morphology, function, oxidative stress, and inflammatory markers were evaluated at the end of reperfusion. IR caused renal dysfunction as shown by significant increases in blood urea nitrogen, plasma creatinine, and a decrease in creatinine clearance. Light and electron microscopic examinations exhibited severe tubular damages and abnormal mitochondrial structure. IR-induced renal injuries were associated with significant increases in malondialdehyde, nitric oxide, tumor necrosis factor-α, but decreases in antioxidant thiols and superoxide dismutase. Pretreatment with ubiquinol obviously attenuated all the changes caused by IR, whereas it had no considerable effect in the sham-operated rats. These findings indicate that supplementation of ubiquinol prior to IR incidence confers functional and morphological protection to the ischemic kidney by maintaining the redox balance and regulating the generation of inflammatory mediator. The outcomes suggest that ubiquinol may be a potential candidate to counteract organ dysfunction in conditions involving IR injury.

Topics: Animals; Antioxidants; Blood Urea Nitrogen; Dietary Supplements; Drug Evaluation, Preclinical; Ischemia; Kidney; Male; Malondialdehyde; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Sulfhydryl Compounds; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Ubiquinone

Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases. We tested whether a diet supplemented with CoQ10 ameliorates oxidative stress and mitochondrial alteration, as well as promotes retinal ganglion cell (RGC) survival in ischemic retina induced by intraocular pressure elevation. A CoQ10 significantly promoted RGC survival at 2 weeks after ischemia. Superoxide dismutase 2 (SOD2) and heme oxygenase-1 (HO-1) expression were significantly increased at 12 h after ischemic injury. In contrast, the CoQ10 significantly prevented the upregulation of SOD2 and HO-1 protein expression in ischemic retina. In addition, the CoQ10 significantly blocked activation of astroglial and microglial cells in ischemic retina. Interestingly, the CoQ10 blocked apoptosis by decreasing caspase-3 protein expression in ischemic retina. Bax and phosphorylated Bad (pBad) protein expression were significantly increased in ischemic retina at 12 h. Interestingly, while CoQ10 significantly decreased Bax protein expression in ischemic retina, CoQ10 showed greater increase of pBad protein expression. Of interest, ischemic injury significantly increased mitochondrial transcription factor A (Tfam) protein expression in the retina at 12 h, however, CoQ10 significantly preserved Tfam protein expression in ischemic retina. Interestingly, there were no differences in mitochondrial DNA content among control- or CoQ10-treated groups. Our findings demonstrate that CoQ10 protects RGCs against oxidative stress by modulating the Bax/Bad-mediated mitochondrial apoptotic pathway as well as prevents mitochondrial alteration by preserving Tfam protein expression in ischemic retina. Our results suggest that CoQ10 may provide neuroprotection against oxidative stress-mediated mitochondrial alterations in ischemic retinal injury.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-Associated Death Protein; Body Weight; Diet; DNA-Binding Proteins; Female; High Mobility Group Proteins; Intraocular Pressure; Ischemia; Mice; Mice, Inbred C57BL; Mitochondria; Neuroprotective Agents; Oxidative Stress; Phosphorylation; Retina; Retinal Ganglion Cells; Ubiquinone; Vitamins

The unique feature of mitochondrial complex I is the so-called A/D transition (active-deactive transition). The A-form catalyses rapid oxidation of NADH by ubiquinone (k ~104 min-1) and spontaneously converts into the D-form if the enzyme is idle at physiological temperatures. Such deactivation occurs in vitro in the absence of substrates or in vivo during ischaemia, when the ubiquinone pool is reduced. The D-form can undergo reactivation given both NADH and ubiquinone availability during slow (k ~1-10 min-1) catalytic turnover(s). We examined known conformational differences between the two forms and suggested a mechanism exerting A/D transition of the enzyme. In addition, we discuss the physiological role of maintaining the enzyme in the D-form during the ischaemic period. Accumulation of the D-form of the enzyme would prevent reverse electron transfer from ubiquinol to FMN which could lead to superoxide anion generation. Deactivation would also decrease the initial burst of respiration after oxygen reintroduction. Therefore the A/D transition could be an intrinsic protective mechanism for lessening oxidative damage during the early phase of reoxygenation. Exposure of Cys39 of mitochondrially encoded subunit ND3 makes the D-form susceptible for modification by reactive oxygen species and nitric oxide metabolites which arrests the reactivation of the D-form and inhibits the enzyme. The nature of thiol modification defines deactivation reversibility, the reactivation timescale, the status of mitochondrial bioenergetics and therefore the degree of recovery of the ischaemic tissues after reoxygenation.

Topics: Catalysis; Cell Hypoxia; Electron Transport Complex I; Energy Metabolism; Humans; Ischemia; Mitochondria; NAD; Nitric Oxide; Oxidation-Reduction; Oxygen; Reactive Oxygen Species; Ubiquinone

We investigated the protective effects of coenzyme Q10 on bladder dysfunction in a rat model of atherosclerosis induced chronic bladder ischemia.. A total of 24 male Sprague-Dawley® rats at age 16 weeks were divided into 4 groups of 6 each, including group 1--untreated, sham operated rats, group 2--coenzyme Q10 treated, sham operated rats, group 3--untreated rats with chronic bladder ischemia and group 4--coenzyme Q10 treated rats with chronic bladder ischemia. Groups 3 and 4 received an endothelial injury to the iliac arteries and were fed a 2% cholesterol diet for 8 weeks. Groups 2 and 4 were treated with coenzyme Q10 and the others were treated with vehicle for 4 weeks. Eight weeks postoperatively we performed continuous in vivo cystometry, an in vitro detrusor muscle strip study and a malondialdehyde assay. Histological examination of the bladder walls and iliac arteries was also done.. In vivo cystometry revealed that coenzyme Q10 administration after the induction of chronic bladder ischemia prolonged micturition frequency and the intercontraction interval, and increased bladder capacity compared to those in untreated rats with chronic bladder ischemia. In the detrusor muscle strip study coenzyme Q10 administration after the induction of chronic bladder ischemia increased contractile responses compared to those in untreated rats with chronic bladder ischemia. Rats with chronic bladder ischemia also showed higher malondialdehyde in bladder tissue and serum than the other groups. Chronic bladder ischemia induced submucosal fibrosis of the bladder walls and a degenerative change in the blood vessel tunical media, as shown on histological examination.. Our study suggests that coenzyme Q10 acts as an antioxidant to protect bladder function in this chronic bladder ischemia model.

Topics: Animals; Biopsy, Needle; Chronic Disease; Disease Models, Animal; Immunohistochemistry; Ischemia; Male; Malondialdehyde; Muscle Contraction; Oxidative Stress; Protective Agents; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Sensitivity and Specificity; Ubiquinone; Urinary Bladder; Urinary Bladder, Overactive; Urodynamics

To evaluate the protective effects of two naturally occurring antioxidants, α-Lipoic acid and coenzyme Q10 on the response to in vitro ischemia of the rabbit urinary bladder. We measured free fatty acid (FFA) content, phospholipid (PL) content, malondialdehyde (MDA) levels, and phospholipase A(2) activity (PLA) of subcellular compartments. Twenty New Zealand White male rabbits were separated into four groups of five rabbits each. The in vitro whole bladders from Groups 1 and 2 received a 3 h incubation under normal oxygenated physiological conditions. The bladders were stimulated by field stimulation at 1 and 3 h. The bladders from groups 3 and 4 underwent 1 h incubation time under normal oxygenated physiological conditions. After 1 h, the bladders were stimulated with field stimulation. After a maximal pressure response was recorded, the stimulation was turned off and the bath medium changed to one equilibrated with 95% nitrogen, 5% oxygen without glucose (ischemic medium) and incubated for 1 h with field stimulations occurring at 5 min intervals during this time. At the end of this hour of ischemia with repetitive stimulation, the bath was changed to an oxygenated medium with glucose for a 1-h reperfusion period after which the stimulation was repeated. The rabbits from groups 2 and 4 received α-Lipoic acid (10 mg/kg/day) + Coenzyme Q10 (3 mg/kg/day) by gavage for 4 weeks before the experiment. At the end of the experimental period, each bladder was opened longitudinally, and the muscle and mucosa separated by blunt dissection, frozen under liquid nitrogen, and stored at -80°C for biochemical analyses. Each tissue was fractionated by differential centrifugation into nuclear, mitochondrial, synaptosomal, and cytosol (supernatant) components. PL, FFA, MDA, and PLA were analyzed using standard biochemical techniques. Post-ischemic contractility only returned to 30% of control of the untreated group. However, post-ischemic contractility of the treated group returned to approximately 70% of control. PL loss in the muscle mitochondria and synaptosomes was prevented by antioxidant treatment, while the mucosal layer showed a significant drop in PL with antioxidants treatment. Administration of CoQ + LA significantly decreased MDA levels in both control and ischemic tissues in both the muscle and mucosal bladder layers, especially substantial in the microsomal and mitochondrial components. Treatment had variable effects on PLA(2) activity. Treatment of bladder d

Topics: Animals; Antioxidants; Fatty Acids, Nonesterified; Ischemia; Lipid Peroxidation; Male; Malondialdehyde; Mucous Membrane; Muscle, Smooth; Organ Size; Phospholipases A2; Phospholipids; Rabbits; Reperfusion Injury; Thioctic Acid; Ubiquinone; Urinary Bladder

Cardiomyopathy (CMP) is a common debilitating illness, associated with a high mortality and poor quality of life. There is extensive evidence from in vitro and animal experiments that CMP is a state of increased oxidative stress. Coenzyme Q10 (CoQ10) and high-sensitivity C-reactive protein (hs-CRP) are important markers to evaluate the oxidative stress and inflammatory status of patients with CMP.. A total of 28 patients with chronic stable heart failure (21 men and 7 women, ages 18-76 years) were included in the study. Causes of heart failure were ischemic CMP in 17 patients and idiopathic dilated CMP in 11 patients. A total of 28 patients (12 men and 16 women; ages 30-71 years) with normal coronary angiography were enrolled as a control group. Levels of CoQ10, albumin, total thiol groups (T-SH), bilirubin, uric acid as plasma antioxidants, hs-CRP as an inflammation marker and lipid profile were studied in patients and controls.. Plasma CoQ10, T-SH and albumin levels were significantly decreased in patients compared to controls. Uric acid, bilirubin and hs-CRP levels were found to be significantly increased compared to controls.. In this study, evidence of decreased antioxidant status was determined in CMP patients together with vascular inflammation. CoQ10, other plasma antioxidants and hs-CRP measured routinely can reflect decreased antioxidant status and inflammatory process in patients with dilated CMP. These markers can be used to monitor the status of patients with CMP.

Topics: Adolescent; Adult; Aged; Antioxidants; Biomarkers; C-Reactive Protein; Cardiomyopathy, Dilated; Case-Control Studies; Female; Humans; Ischemia; Male; Middle Aged; Substrate Specificity; Ubiquinone

To determine the efficacy of coenzyme Q10 (CoQ10) and alpha-lipoic acid (alpha-LA), either alone or in combination, to protect the contractile responses of the rabbit urinary bladder from damage caused by repetitive stimulation in the presence or absence of in vitro ischemia.. Four groups of New Zealand white rabbits (4 per group) were treated with vehicle (group 1), CoQ10 (group 2), alpha-LA (group 3), or CoQ10 plus alpha-LA (group 4) for 2 weeks. At the end of the treatment period, eight longitudinal strips from each rabbit bladder body were placed in oxygenated Tyrode's solution with glucose (normal physiologic medium). The strips were stimulated by field stimulation, carbachol, and KCl, and the responses were recorded. One half of the strips were switched for 1 hour to Tyrode's solution with no glucose equilibrated with nitrogen (ischemia medium). Simultaneously, all strips were subjected to 1 h of repetitive field stimulation followed by 1 hour of recovery in normal physiologic medium, and the responses to all stimuli were recorded again.. CoQ10 showed no protective effect. Alpha-LA resulted in increased contractile responses of the control bladder and showed a moderate protective effect for all forms of stimulation. The combination, however, showed a significantly greater increase in the contraction of the control bladder and a greater protective effect than alpha-LA alone.. The combination of alpha-LA and CoQ10 treatment enhanced the contractile response in normal medium and diminished the contractile dysfunction induced by repetitive field stimulation and ischemia.

Topics: Animals; Antioxidants; Carbachol; Electric Stimulation; Electron Transport Chain Complex Proteins; In Vitro Techniques; Ischemia; Male; Muscle Contraction; Potassium Chloride; Rabbits; Thioctic Acid; Ubiquinone; Urinary Bladder

This study was designed to test whether Coenzyme Q10 (CoQ10) supplementation has neuroprotective effect in aged, double-transgenic amyloid precursor protein (APP)/presenilin 1 (PS1), single transgenic APP and PS1 mice exposed to ischemic injury of the brain. Forty-eight mice (12 each of APP/PS1, APP, PS1 and wild-type) were studied. Half of each genotype groups (n=6 per group) was treated with CoQ10 (1200 mg/kg/day) after ischemic injury and the other half with placebo. Magnetic resonance (MR) images were used to measure the volume of induced infarction (IFV), as well as the volume of the hemispheres and hippocampi. Significantly greater volumes of infarction and lesser volumes of hemisphere/hippocampus on the ischemic side were observed in APP/PS1 and APP mice than in PS1 and wild-type mice. This is consistent with amplification of the effect of ischemia in APP carriers. After 28 days of CoQ10 treatment, APP/PS1 or APP mutations have smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo. No differences between CoQ10- and placebo-treated groups in volumes of infarct, hemisphere and hippocampus were observed in PS1 and wild-type mice. We conclude that CoQ10 has a protective effect on the brain from infarction and atrophy induced by ischemic injury in aged and susceptible transgenic mice.

Topics: Aging; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Coenzymes; Functional Laterality; Hippocampus; Humans; Ischemia; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroprotective Agents; Presenilin-1; Ubiquinone

Recent studies support a role for excitotoxicity in the development of retinal ganglion cell (RGC) damage in subjects suffering from glaucoma. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, has been reported to afford neuroprotection, preventing the formation of the mitochondrial permeability transition pore. Using an established animal model of retinal ischemia/reperfusion here, we show that synaptic glutamate increases at 130min from beginning of reperfusion and delayed apoptosis in the RGC layer is seen at 24h. Intraocular administration of CoQ10 minimizes glutamate increase and affords neuroprotection, suggesting that oxidative stress and energy failure might be implicated in the mechanisms of RGC death.

Topics: Administration, Topical; Animals; Coenzymes; Glutamic Acid; In Situ Nick-End Labeling; Intraocular Pressure; Ischemia; Male; Microdialysis; Rats; Rats, Wistar; Retinal Diseases; Retinal Ganglion Cells; Ubiquinone

To evaluate in vitro the effect of coenzyme Q10 (CoQ(10)) on ischemia-induced hair cell death.. Organotypic cochlear cultures of newborn rats were subjected to ischemia with and without CoQ(10).. Addition of CoQ(10) has not prevented HC loss.. CoQ(10) seems to protect against only certain modes of cell death.

Topics: Animals; Animals, Newborn; Carbon Dioxide; Cell Death; Cell Survival; Coenzymes; Electron Transport Chain Complex Proteins; Hair Cells, Auditory; Ischemia; Nitrogen; Organ Culture Techniques; Perilymph; Protective Agents; Rats; Rats, Wistar; Ubiquinone

Near-infrared spectrometry (NIRS) is a well-known method used to measure in vivo tissue oxygenation and hemodynamics. This method is used to derive relative measures of hemoglobin (Hb) + myoglobin (Mb) oxygenation and total Hb (tHb) accumulation from measurements of optical attenuation at discrete wavelengths. We present the design and validation of a new NIRS oxygenation analyzer for the measurement of muscle oxygenation kinetics. This design optimizes optical sensitivity and detector wavelength flexibility while minimizing component and construction costs. Using in vitro validations, we demonstrate 1) general optical linearity, 2) system stability, and 3) measurement accuracy for isolated Hb. Using in vivo validations, we demonstrate 1) expected oxygenation changes during ischemia and reactive hyperemia, 2) expected oxygenation changes during muscle exercise, 3) a close correlation between changes in oxyhemoglobin and oxymyoglobin and changes in deoxyhemoglobin and deoxymyoglobin and limb volume by venous occlusion plethysmography, and 4) a minimal contribution from movement artifact on the detected signals. We also demonstrate the ability of this system to detect abnormal patterns of tissue oxygenation in a well-characterized patient with a deficiency of skeletal muscle coenzyme Q(10). We conclude that this is a valid system design for the precise, accurate, and sensitive detection of changes in bulk skeletal muscle oxygenation, can be constructed economically, and can be used diagnostically in patients with disorders of skeletal muscle energy metabolism.

Topics: Coenzymes; Electronics; Equipment Design; Exercise; Hemoglobins; Humans; Hyperemia; Ischemia; Kinetics; Metabolism, Inborn Errors; Movement; Muscle, Skeletal; Myoglobin; Neuromuscular Diseases; Oxygen; Oxygen Consumption; Plethysmography; Reproducibility of Results; Sensitivity and Specificity; Spectroscopy, Near-Infrared; Ubiquinone

A role for the antioxidants vitamin E and idebenone in decreasing retinal cell injury, after metabolic inhibition induced by chemical ischemia and hypoglycemia, was investigated and compared with oxidative stress conditions. Preincubation of the antioxidants, vitamin E (20 microM) and idebenone (10 microM), effectively protected from retinal cell injury after oxidative stress or hypoglycemia, whereas the protection afforded after postincubation of both antioxidants was decreased. Delayed retinal cell damage, mediated by chemical ischemia, was attenuated at 10 or 12 h postischemia, only after exposure to the antioxidants during all the experimental procedure. An antagonist of the N-methyl-D-aspartate (NMDA) receptors, an inhibitor of nitric oxide synthase (NOS) or a blocker of L-type Ca2+ channels were ineffective in reducing cell injury induced by chemical ischemia, hypoglycemia or oxidative stress. Oxidative stress and hypoglycemia increased (about 1.2-fold) significantly the fluorescence of the probe DCFH2-DA, that is indicative of intracellular ROS formation. Free radical generation detected with the probe dihydrorhodamine 123 (DHR 123) was enhanced after oxidative stress, chemical ischemia or hypoglycemia (about 2-fold). Nevertheless, the antioxidants vitamin E or idebenone were ineffective against intracellular ROS generation. Cellular energy charge decreased greatly after chemical ischemia, was moderately affected after hypoglycemia, but no significant changes were observed after oxidative stress. Preincubation with vitamin E prevented the changes in energy charge upon 6 h posthypoglycemia. We can conclude that irreversible changes occurring during chemical ischemia mainly reflect the alterations taking place at the ischemic core, whereas hypoglycemia situations may reflect changes occurring at the penumbra area, whereby vitamin E or idebenone may help to increase cell survival, exerting a beneficial neuroprotective effect.

Topics: Animals; Antioxidants; Benzoquinones; Calcium Channel Blockers; Cells, Cultured; Chick Embryo; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Free Radicals; Hypoglycemia; Ischemia; Neurons; Oxidative Stress; Reactive Oxygen Species; Retina; Ubiquinone; Vitamin E

In a surgical model of liver ischemia lipid peroxidation occurs, as shown by increase of lipid peroxidation end products, endogenous CoQ9 is oxidized and mitochondrial respiration is lowered; however, pre-treatment of the rats by i.p. injection of CoQ10 for 14 days normalizes the above parameters, presumably by way of the observed high extent of reduction of the incorporated quinone; moreover, liver homogenates of the CoQ10-treated rats are more resistant than those of non-treated rats to oxidative stress induced by an azido free radical initiator. This preliminary study suggests that CoQ10 pre-treatment can be of beneficial effect against oxidative damage during liver surgery transplantation.

Topics: Amidines; Animals; Antioxidants; Ischemia; Lipid Peroxidation; Liver; Oxidants; Rats; Reperfusion; Reperfusion Injury; Ubiquinone; Vitamin A; Vitamin E

We examined whether pentoxifylline (PTX) and coenzyme Q10 (Q) pretreatment affect ischemia-reperfusion damage in the rat liver.. Twenty minutes of reflow following 30 min of ischemia was performed. Before the experiment, rats were treated PTX 50 mg/kg, IP or PTX 50 mg/kg IP + Q10 mg/kg, intragastric, or untreated. Rats were divided into four groups: control (C), ischemia-reperfusion (IR), PTX-treated (P), and Q+PTX-treated (QP) groups. Hepatic glutathione (GSH) and malondialdehyde (MDA) levels and catalase, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and reductase (GSSGR) activities were measured.. In IR group GSH levels decreased (p<0.01), conversely MDA levels increased (p<0.01). PTX pretreatment did not affect GSH and MDA values, but Q+PTX pretreatment improved of those (p<0.01). It was shown that catalase and GSH-Px activities increased during ischemia-reperfusion (p<0.01, both of), but PTX pretreatment did not significantly ameliorate those activities. GSSGR activity was higher in IR group than in basal levels (p<0.01). The decrease GSSGR activity that was observed in P group was not significant compared to IR group. During ischemia/reperfusion also SOD activity increased as compared with controls (p<0.05). In PTX-treated group, SOD activity was significantly higher than control and ischemia/reperfusion groups (p<0.01, both of). Q+PTX treatment ameliorated those enzyme activities to the control values.. Short-term hepatic ischemia-reperfusion diminished GSH, increased MDA levels and induced some antioxidant enzyme activities. Q+PTX pretreatment was useful in hepatic ischemia-reperfusion injury, but treatment of PTX alone did not cause beneficial effect in the present study.

Topics: Animals; Catalase; Coenzymes; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Hematologic Agents; Ischemia; Liver; Male; Malondialdehyde; Pentoxifylline; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase; Ubiquinone

The effect of energetic metabolism compromise, obtained by chemical induction of hypoglycaemia (glucose deprivation), hypoxia (mitochondrial respiratory chain inhibition), and ischaemia (hypoglycaemia plus hypoxia), on glutamate toxicity was analyzed on PC12 cells. The respiratory status of these cells, measured by the MTT [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assay, was significantly decreased after metabolic inhibition induced by ischaemia, but it was not affected by both hypoglycaemia and hypoxia. Under hypoglycaemia, but not under hypoxia, ATP levels were significantly reduced (from 12.67+/-0.48 to 5.38+/-1.41 nmol/mg protein). However, ischaemic-like conditions greatly potentiated the decline of ATP levels (95% decrease) observed after hypoglycaemia. The influence of metabolic inhibition on glutamate-induced cytotoxicity was also analyzed. When the cells were preincubated under conditions that deplete ATP (hypoglycaemia and ischaemia), the inhibition of MTT reduction, measured after glutamate incubation, was potentiated. This effect could be reverted when vitamin E and idebenone were present during the induction of metabolic inhibition. The ATP levels above which glutamate susceptibility was enhanced were also determined. These results indicate that glutamate toxicity on PC12 cells, which occurs by a mechanism independent of N-methyl-D-aspartate (NMDA) receptor activation, can be enhanced by the depletion of intracellular ATP upon metabolic stress; it is dependent on the extent of ATP depletion and seems to involve the generation of free radicals. It can be concluded that under ischaemic conditions, the deleterious effects of glutamate can be potentiated by the energetic compromise associated with this pathologic situation.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Benzoquinones; Cell Hypoxia; Disease Susceptibility; Energy Metabolism; Glutamic Acid; Hypoglycemia; Ischemia; Mitochondria; PC12 Cells; Rats; Receptors, N-Methyl-D-Aspartate; Tetrazolium Salts; Thiazoles; Ubiquinone; Vitamin E

Heat shock proteins (HSPs) are induced in the liver after warm ischemia/reperfusion and are thought to be markers of hepatocellular injury and oxidative stress.. The influence of variable periods of cold storage followed by reperfusion on the expression of HSP70 was studied in the isolated perfused pig liver. Organs were harvested and stored in histidine-tryptophan-ketoglutarate solution at 4 degrees C and then perfused (210 min) in a closed water bath (38 degrees C), which subjects the liver to fluctuating outer pressure. The role of energy depletion, reactive oxygen intermediates, Kupffer cells, and circulating leukocytes in HSP70 expression was determined.. HSP70 expression was not detectable in liver tissue before explantation or before reperfusion by Northern blot analysis using a pig HSP70 gene probe. HSP70 expression was observed after reperfusion depending on cold storage time. Kinetics of HSP70 expression monitored by reverse transcriptase polymerase chain reaction showed a rapid increase of mRNA within 1 hr, which was closely associated with delayed recovery of hepatocellular energy charge, as assessed by the ketone body ratio. The inactivation of Kupffer cells, the presence or absence of leukocytes, and the suppression of oxidative stress with the antioxidant idebenone, given during reperfusion, had no influence. However, feeding the animals with idebenone over 7 days before explantation led to a faster recovery of ketone body ratio, paralleled by a substantial suppression of HSP70 expression.. Our data show that HSP70 expression during reperfusion is mainly dependent on the preceding cold storage time and the consecutive delayed recovery of the hepatocellular energy charge.

Topics: Animals; Base Sequence; Benzoquinones; Cold Temperature; Conserved Sequence; DNA Primers; Energy Metabolism; Female; Gadolinium; Glucose; HSP70 Heat-Shock Proteins; Hypertonic Solutions; Ischemia; Ketone Bodies; Kinetics; Kupffer Cells; Liver; Male; Mannitol; Organ Preservation; Polymerase Chain Reaction; Potassium Chloride; Procaine; Reperfusion; RNA, Messenger; Swine; Transcription, Genetic; Ubiquinone

Topics: Animals; Blood Glucose; Coenzymes; Diabetes Mellitus, Experimental; Glucose Tolerance Test; Graft Survival; Ischemia; Male; Pancreas Transplantation; Rats; Rats, Inbred Lew; Temperature; Time Factors; Transplantation, Isogeneic; Ubiquinone

The authors prepared an experimental animal model of ischemia and reperfusion of the limbs to evaluate in vivo the reactive oxygen species involvement and protective role of coenzyme Q10 in reperfusion injury. A group of male rabbits (untreated group) underwent clamping of abdominal aorta for 3 hr and then declamping; at intervals blood sampling was drawn for coenzyme Q10, vitamin E, lactic acid and creatine kinase assays. Another group of male rabbits (treated group) underwent the same ischemia period but before declamping coenzyme Q10 was administered intra aorta. In untreated group, coenzyme Q10 and vitamin E plasma levels decreased while lactic acid and creatine kinase plasma levels increased during reperfusion. These data demonstrate that, after only 3 hr of ischemia, the extremities show a biochemical reperfusion injury, and this involves an increased consumption of antioxidants such as coenzyme Q10 and vitamin E. In the treated group, the increase of creatine kinase plasma levels during reperfusion was not significant, while the decrease in vitamin E was more marked.

Topics: Animals; Aorta, Abdominal; Coenzymes; Constriction; Creatine Kinase; Extremities; Ischemia; Isoenzymes; Lactates; Lactic Acid; Male; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Ubiquinone; Vitamin E

Topics: Animals; Free Radicals; Glutathione; Ischemia; Liver; Liver Diseases; Mitochondria, Liver; Rats; Reperfusion Injury; Ubiquinone; Vitamin E; Xanthine Dehydrogenase; Xanthine Oxidase

Metabolic disturbances in the canine liver during warm ischemia by Pringle's method for 60 minutes and the role of Coenzyme Q10 (CoQ10), Prostaglandin E1 (PGE1) and ONO-3708, TXA2 receptor antagonist, were studied. Mongrel dogs were divided into five groups; control group, group of liver ischemia without drugs, groups of liver ischemia with CoQ10, PGE1 and ONO-3708 pretreatment. Metabolic rates of PGI2, TXA2, insulin, glucagon and glucose and production of lipid peroxides in the five groups were measured at the points before Pringle's procedure, 5 minutes, 60 minutes and 120 minutes after declamping. In the group of ischemia without drug administration, the hepatic metabolism of PGI2, TXA2, insulin and glucose were decreased after declamping. The metabolism of glucagon, however, was not disturbed by warm ischemia. The production of lipid peroxides increased at 5 minutes after declamping. In the groups of CoQ10, PGE1 and ONO-3708 pretreatment, changes of PGI2, TXA2 and insulin metabolism in the liver were improved, and an increased production of lipid peroxides by warm ischemia was normalized. This study suggests that CoQ10, PGE1 and ONO-3708 protect liver damage by warm ischemia as results of improvement of metabolic disturbances of PGI2, TXA2, insulin and suppression of lipid peroxides production.

Topics: Alprostadil; Animals; Body Temperature; Dogs; Epoprostenol; Insulin; Ischemia; Lipid Peroxides; Liver; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Ubiquinone

Topics: Adenosine Triphosphate; Animals; Coenzymes; Intestine, Small; Ischemia; Kinetics; Rats; Rats, Inbred Strains; Reperfusion Injury; Time Factors; Ubiquinone

This study was made in a canine isolated gracilis muscle model to measure directly the free radicals, to predict the severity of ischemia and reperfusion injury of the skeletal muscle by measuring its surface pH (mspH), and to determine the effect of Coenzyme Q10 (CoQ10) in reducing the extent of muscle injury. Animals were divided into three groups: group A (control, n = 10), group B (untreated, n = 10), and group C (CoQ10 treated, n = 10). In both groups B and C, 5 hr ischemia followed by 40 min of reperfusion was made. Free radicals were measured directly by electron spin resonance spectrometer (ESR) and mspH was measured using a pH microprobe. Serum creatine phosphokinase (CPK) was estimated before ischemia, 5 and 30 min after reperfusion. The extent of muscle injury was evaluated morphologically by Evan's blue dye exclusion test. ESR intensity in group B was 0.55 +/- 0.19 and decreased to 0.30 +/- 0.04 in group C (P less than 0.01). Rate of recovery of mspH was higher in group C (7.16 +/- 0.06) compared to group B (6.88 +/- 0.11, P less than 0.01) and CPK in group C was less (847 +/- 381 IU/liter) than in group B (1356 +/- 519 IU/liter, P less than 0.05) after 30 min of reperfusion. In group C the morphological muscle injury was less (37.8 +/- 5%) compared to group B (56.7 +/- 3.6%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Coenzymes; Dogs; Electron Spin Resonance Spectroscopy; Female; Free Radicals; Hydrogen-Ion Concentration; Ischemia; Male; Muscles; Oxygen; Reperfusion Injury; Ubiquinone

Topics: Adenosine Triphosphate; Animals; Glutathione; Ischemia; Kidney; Lipid Peroxides; Liver; Liver Diseases; Male; Mice; Mice, Inbred ICR; Rats; Rats, Inbred Strains; Reperfusion Injury; Shock, Septic; Ubiquinone; Vitamin E

Topics: Animals; Coenzymes; Free Radicals; Glutathione; Glutathione Disulfide; Ischemia; Liver; Liver Circulation; Male; Models, Biological; Rats; Rats, Inbred Strains; Reperfusion; Ubiquinone; Vitamin E

This study was undertaken to determine whether pretreatment of the donor rat with coenzyme Q10 (CoQ10) would protect against hepatic ischemia induced for 30 minutes at normothermic body temperature. Fresh liver transplants were used as controls (minus warm ischemia of 30 minutes) and gave a 1-week survival rate of 84.6%. CoQ10 was administered intravenously (10 mg/kg body weight) to the donor rat 1 hour before induction of warm ischemia (group A). In another group (B), the same dose was given intravenously not only to the donor rat but also to the recipient rat 1 hour before grafting. None of the placebo group survived more than 2 days. The 1-week survival rates of the groups pretreated with CoQ10 were 45.5% for group A and 50% for group B. There was no significant difference between groups A and B. A statistically significant difference was demonstrated between the placebo group and both CoQ10-treated groups (p less than 0.05). It was therefore assumed that CoQ10, accumulated in the donor liver, was a primary factor in improving survival. Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), serum alkaline phosphatase (SALP), total bilirubin, and total protein were measured by means of light and electron microscopic examination of the liver 6 months after transplantation. Long-term-surviving rats with transplanted, ischemically damaged liver that was pretreated with CoQ10 showed a decrease in the activity of SGOT and SGPT and an increase in levels of total protein to the normal range (as well as to those levels exhibited by fresh-liver-transplanted rats) with practically no change in levels of SALP, total bilirubin, or in histologic findings. These results indicate that donor pretreatment with CoQ10 is useful for increasing survival after warm ischemic damage of rat liver grafts.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Bilirubin; Coenzymes; Disease Models, Animal; Ischemia; Liver; Liver Transplantation; Male; Mortality; Rats; Rats, Inbred Strains; Ubiquinone

Topics: Animals; Coenzymes; DNA; Hepatectomy; Ischemia; Liver; Male; Rats; Rats, Inbred Strains; Ubiquinone

The present study was undertaken to determine whether alpha-tocopherol pretreatment could modify cellular free radical metabolism during hepatic ischemia and subsequent reperfusion and prolong the viability of the liver. Although ischemia of the liver for 90 minutes did not permit survival of the animals, alpha-tocopherol administration (10 mg/kg of body weight) for 3 days increased the survival rate to 45.5%. The period of ischemia was accompanied by decreases in the hepatic adenosine triphosphate (ATP) level, endogenous alpha-tocopherol, and total glutathione (reduced and oxidized) without any significant increase in endogenous coenzyme Q (CoQ) homologs (CoQ9 and CoQ10) and lipid peroxide formation. The subsequent restoration of blood flow resulted in a low recovery of ATP and marked decreases in endogenous alpha-tocopherol, total glutathione, and CoQ homologs and, on the contrary, a marked increase in lipid peroxide levels. In alpha-tocopherol-treated animals, however, resynthesis of ATP was accelerated even after 90 minutes of ischemia, and there were no changes in the levels of total glutathione or CoQ homologs or in the level of the enhanced alpha-tocopherol during the reperfusion period. The pretreatment also completely suppressed the elevation of lipid peroxide levels. These results are compatible with the assumption that cellular damage caused by hepatic ischemia can be explained by free radical reaction processes during ischemia and especially reperfusion and suggest that administration of a free radical scavenger and antioxidant, alpha-tocopherol, is effective in ischemic liver cell injury.

Topics: Adenine Nucleotides; Animals; Free Radicals; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Ischemia; Lipid Peroxides; Liver; Male; Mitochondria, Liver; Rats; Rats, Inbred Strains; Ubiquinone; Vitamin E

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

The present study was undertaken to determine whether hepatic ischemia and the subsequent reflow of blood had any effect on the levels of endogenous coenzyme Q homologs, alpha-tocopherol, and glutathione, and whether coenzyme Q10 (6 mg/kg of body weight) altered these levels. Ischemia of the rat liver for 90 min resulted in decreases of 19.1 and 19.6% of endogenous alpha-tocopherol and total glutathione (GSH + GSSG) without significant changes in the levels of endogenous total coenzyme Q homologs (oxidized and reduced). Restoration of the blood flow resulted in marked decreases in endogenous coenzyme Q homologs, alpha-tocopherol, and total glutathione in the control group. In coenzyme Q10-treated animals, however, there were no changes in the levels of endogenous total coenzyme Q9, alpha-tocopherol, or total glutathione as well as in the level of the enhanced total coenzyme Q10 during the reperfusion period. On the other hand, decreases in alpha-tocopherol and total glutathione during the period of ischemia remained unchanged. These results are compatible with the assumption that cellular damage caused by hepatic ischemia can be explained by free radical reaction processes during ischemia and especially, reperfusion and suggest that exogenous coenzyme Q10 functions as an antioxidant with endogenous coenzyme Q homologs, alpha-tocopherol, and glutathione in lipid peroxidation during reperfusion.

Topics: Animals; Coenzymes; Glutathione; Ischemia; Liver; Male; Oxidation-Reduction; Rats; Rats, Inbred Strains; Ubiquinone; Vitamin E

A protective effect of coenzyme Q10 on the ischemic and reperfused myocardium was investigated in the isolated working rat heart preparation. Rats were treated intraperitoneally with 30 mg/kg coenzyme Q10, daily for 7 days. The controls were given the same dose of the vehicle. After 25 min of equilibration the hearts were made totally ischemic at 35.5 degrees C for 30 min, arrested with high potassium cardioplegic solution immediately after aortic cross clamping. The recovery of cardiac power in the coenzyme Q10 pretreated group was significantly (P less than 0.05) better than that in vehicle pretreated group. Creatine phosphokinase (CPK) release during reperfusion was significantly (P less than 0.05) reduced by the pretreatment of coenzyme Q10. Tissue analysis for high energy phosphate compounds revealed no significant difference between the two groups. Tissue lactate content at 30 min of ischemia was significantly (P less than 0.001) lower in the coenzyme Q10 pretreated group. These results suggest that pretreatment with coenzyme Q10 is effective for reducing ischemic injury caused by aortic cross clamping.

Topics: Animals; Aorta; Cardiac Surgical Procedures; Coenzymes; Constriction; Creatine Kinase; Heart Arrest, Induced; Hypothermia, Induced; Ischemia; Lactates; Myocardium; Rats; Rats, Inbred Strains; Ubiquinone

The present study was undertaken to determine whether CoQ10 administration to rats can protect hepatic mitochondrial functions, improve energy metabolism during hepatic ischemia and subsequent reperfusion, and prolong the viability of the organ. Although ischemia of the liver for 90 minutes did not permit survival of the animals, CoQ10 administration (6 mg/kg of body weight) increased the survival rate to 60%. The period of ischemia was accompanied by decreases in hepatic adenosine triphosphate (ATP) level and respiratory control index without significant increases in mitochondrial calcium content and lipid peroxide formation. The subsequent restoration of blood flow resulted in a low recovery of ATP level, recovery of respiratory control and ADP:O ratio to levels significantly lower than normal, and on the contrary, marked increases in mitochondrial calcium and lipid peroxide levels. However, in CoQ10-treated animals mitochondrial functions were all completely reversible, and resynthesis of ATP was accelerated even after 90 minutes of ischemia. The pretreatment also completely suppressed the elevation of mitochondrial calcium and lipid peroxide levels. These results suggest that preservation with CoQ10 of cellular damages caused by hepatic ischemia is probably due to protection of cellular and subcellular membranes from lipid peroxidation, so that mitochondrial functions are restored and cellular calcium homeostasis is maintained.

Topics: Adenosine Triphosphate; Animals; Calcium; Coenzymes; Ischemia; Liver; Male; Mitochondria, Liver; Premedication; Rats; Rats, Inbred Strains; Ubiquinone

Studies were done on the protective effects of alpha-tocopherol and coenzyme Q10 (CoQ10) on warm ischemic damage to the rat kidney. Administration of alpha-tocopherol (10 mg/kg body wt/day) for 7 days or a single i.p. injection of CoQ10 (6 mg/kg body wt) increased the survival rate from 0 to 46.7% of the rats subjected to warm ischemia for 120 min. The administration of alpha-tocopherol and CoQ10 increased adenosine triphosphate (ATP) in the renal tissue from 0.53 +/- 0.18 to 0.92 +/- 0.29, and from 0.64 +/- 0.26 to 1.00 +/- 0.54 mumol/g wet weight, respectively, 4-hr reperfusion after 120 min of warm ischemia. Serum creatinine levels of the surviving rats after 120 min of warm ischemia was 9.98 +/- 0.19 mg/100 ml in the control group and 5.84 +/- 0.95 and 7.27 +/- 1.62 mg/100 ml, respectively, in alpha-tocopherol and CoQ10 administered group, when determined 2 days after the operation. These results indicate that alpha-tocopherol and CoQ10 have a protective effect on warm ischemic damage to the rat kidney, demonstrated by an increase in ATP resynthesis after reflow following warm ischemia and by the maintenance of a lower serum creatinine level. This effect was accompanied by an increase in the survival rate of ischemic rats.

Topics: Adenosine Triphosphate; Animals; Creatinine; Dose-Response Relationship, Drug; Hot Temperature; Ischemia; Kidney; Male; Rats; Regional Blood Flow; Ubiquinone; Vitamin E