E K Ruuge

Russian Cardiology Research and Production Complex, Moskva, Moscow, Russia

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Publications (180)190.09 Total impact

  • Article: PP.14.05
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    ABSTRACT: Objective: It is well known that dinitrosyl iron complexes (DNIC) play essential role, as physiological NO forms in mammalian organism. The injection of this substance exerts prolonged hypotensive action. The aim of the present research was study of DNIC with glutathione ligand (DNIC-GH) action in rat organism in different physiological states. Design and method: The experiments were carried out on normotensive and hypertensive rats. Standard doses of DNIC were injected into rats by intravenous, intraperitoneal, intramuscular, subcutaneous injections, and rectal introduction. Most experiments were carried out on the rats in native physiological conditions, while the others were performed on the model of regional cardiac ischemia, or during general endotoxic shock. In all experiments registration of mean aortic pressure and heart rate were carried out, and DNIC concentrations in whole blood and organs were obtained by EPR method. DNIC-GH effect on NO levels was studied using spin traps. Results: It has been shown that DNIC injection exerted substantial and prolonged hypotensive effect on normotensive and hypertensive rats. The hypotensive action of DNIC and its accumulation in whole blood and mammalian organs depended on the mode of introduction of this substance, and the most substantial and prolonged effects were registered after intravenous and subcutaneous injections. We have shown that DNIC-GH in organism operated mostly, as potent origin of NO physiological forms, such as DNIC with protein ligands and S-nitrosothiols, and its effect on free NO level was substantially slower. Meantime, DNIC-GH molecules also exerted protective action under the condition of NO hyperproduction. In particular, on the model of regional myocardial ischemia DNIC-GH injection resulted in cardioprotective action by suppression of free NO hyperproduction in ischemic area and effective scavenging of toxic oxygen active species. In the other experiments, DNIC-GH injection also exerted cytoprotective effect, causing the suppression of NO hyperproduction in rat lung and liver during endotoxing shock. Conclusions: DNIC-GH molecules in organism act generally, as the origin of NO physiological forms which cause prolonged hypotensive action. Meantime, this substance exerts regulating effect on NO level, suppressing its hyperproduction in organs. Copyright
    No preview · Article · Jun 2015 · Journal of Hypertension

  • No preview · Article · May 2015 · Doklady Biochemistry and Biophysics
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    ABSTRACT: Treatment of catechol, pyrogallol, DOPA, dopamine, norepinephrine, and natural polyhydroxy� 1,4�naphthoquinone echinochrome with solution of potassium superoxide (KO2) in the presence of CaCl2 leads to the formation of water�insoluble dark pigments with stable paramagnetic properties (“calcium mel� anins”). In control experiments in the same procedure without Ca2+, the pigments were not formed. EPR spectra of the calcium melanins had little difference from each other and from known melanins in shape, line width, and the g factor about 2.004. Addition of EDTA water solution to dried paramagnetic pigments leads to their fast dissolving and disappearing of EPR signal. Formation of similar polymers is also observed during autoxidation of o�diphenols in Ca2+�containing alkaline buffer solution, however, this process takes a few days instead of few seconds in the presence of KO2. Thus, calcium (and other divalent cation M2+) can be considered as a key structural element in formation of M2+�catecholate paramagnetic polymer. We assume the existence of two types of paramagnetic centers in melanin�like polymer: M2+�stabilized o�semiquinone radical or bi�radical complex containing o�semiquinone and superoxide anion radicals, stabilized by M2+.
    Full-text · Article · May 2013 · Biophysics
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    ABSTRACT: The objective of the present research was to study transformations of various physiological NO forms in an isolated rat heart, perfused with the medium containing dinitrosyl iron complexes with glutathione ligand (DNIC-GH). We showed that such aerobic perfusion resulted in accumulation of mostly diamagnetic NO physiological forms (S-nitrosothiols) in myocardial tissue. They were transformed into protein-bound mononuclear dinitrosyl iron complexes during subsequent total ischemia. Meantime, DNIC-GH injection on the onset of ischemia resulted in changes in the state of mitochondrial respiratory chain, characterized by the increase in myocardial concentration of flavosemiquinones.
    No preview · Article · Mar 2013 · Biophysics
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    ABSTRACT: It has been shown that interaction of cysteine dinitrosyl iron complexes with methylglyoxal leads to the formation of a new type of dinitrosyl iron complexes, EPR spectrum of these complexes essentially differs from spectra of dinitrosyl iron complexes containing unmodified thiol. The products of the cysteine reaction with methylglyoxal are hemithioacetals, Schiff bases and thiazolidines, which most likely serve as ligands for the new type of dinitrosyl iron complexes. It has been shown that the new type of dinitrosyl iron complexes as cysteine dinitrosyl iron complexes, which are physiological donors of nitric oxide, exert a vasodilator effect. It has also been found that the oxidative destruction of the new type of dinitrosyl iron complexes occurs at normal oxygen partial pressure, but these dinitrosyl iron complexes remain rather stable under hypoxia modeling. An assumption that the destruction of the new type of dinitrosyl iron complexes is caused by the formation of a bound peroxynitrite-containing intermediate is made.
    Full-text · Article · Mar 2013 · Biophysics
  • A A Timoshin · V L Lakomkin · É K Ruuge · A F Vanin
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    ABSTRACT: Protein-bound dinitrosyl-iron complexes (DNIC) in rat whole blood and organs were studied after intravenous injection of this substance with glutathione ligand (DNIC-GH). The effect of DNIC-GH injection on NO level (including NO physiological forms) in hydrophobic areas of rat tissues was also studied in normal physiological blood circulation condition. It has been shown, that after DNIC-GH injection the concentration of protein-bound DNICs in rat whole blood and organs rapidly reached maximum values, and then gradually decreased, that pointed to decomposition of DNIC molecules, coupled with NO release. At the beginning of the experiment the rates of DNIC decay in rat heart and lung were substantially higher, as compared with those in liver and kidney. By spin trappping it has been demonstrated that DNIC-GH, as a source of NO physiological forms (including S-nitrosothiols), in normal physiological blood circulation influence heart more selectively, as compared with the other organs.
    No preview · Article · Mar 2012 · Biofizika
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    ABSTRACT: Dinitrosyl iron complexes (DNICs) have been traced in rat blood and organs after intravenous infusion of Oxacom. It is shown that the active principle (DNIC with glutathione) is rapidly distributed through the organism and deposited in blood and organs as protein-bound DNICs. The specific levels of DNIC in the main body organs are comparable, whereas its apparent lifetimes relate as blood < heart = lung < liver < kidney. Spin trapping assays indicate that protein-bound DNICs are a major but not the only form of NO deposition; the next largest depot is most probably formed by S-nitrosothiols. The gradual release of NO from such pools ensures the smooth and prolonged hypotensive effect of Oxacom.
    No preview · Article · Mar 2012 · Biophysics
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    ABSTRACT: Injection of dinitrosyl iron complexes with glutathione at the onset of 40-min regional myocardial ischemia in rat was shown to exert a clear cardioprotective action by decreasing the infarct size and suppressing the cardiac rhythm disturbance. After introducing the preparation, its effective accumulation with protein thiol-containing ligands in the myocardial tissue was registered be the EPR method. It was also found that in postischemic reperfusion, the rate of decrease in the content of these complexes in the ischemic area increases, which reflects effective scavenging of short-lived reactive oxygen species by the dinitrosyl iron complexes. Keywordsrat heart–regional ischemia–dinitrosyl iron complexes–cardioprotective action–reactive oxygen species–EPR spectroscopy
    No preview · Article · Dec 2011 · Biophysics
  • A. V. Lebedev · M. V. Ivanova · E. K. Ruuge
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    ABSTRACT: The effect of calcium ions on the rate of pyrocatechol autoxidation at pH 9.0 has been studied by mathematical modeling. The effect of Ca2+ on the oxygen absorption rate has been studied, and a kinetic model has been suggested, which takes different stages of interaction of pyrocatechol and its radical form with oxygen into account. It has been shown that the prooxidant action of Ca2+ is related to an abrupt increase (approximately by three orders of magnitude) in the rate constant of comproportionation (reaction of chain branching and formation of o-semiquinonates) and a marked decrease (by two orders of magnitude, from 1.4 · 107 to 0.6 · 105 M−1 s−1) in the rate constant of disproportionation of o-semiquinones. The system can be used as a model for studying the prooxidant action of calcium ions.
    No preview · Article · Apr 2011 · Biofizika
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    ABSTRACT: The injection of dinitrosyliron iron complexes with glutathione at the onset of 40-min rat regional myocardial ischemia was shown to exert a clear cardioprotective action by decreasing the infarct size and suppressing the cardiac rhythm disturbance. After the introduction of the preparation, its effective accumulation with protein thiol-containing ligands in the myocardial tissue was registered be the EPR method. It was also found that, as a result of postischemic reperfusion, the rate of the decrease in the content of these complexes in the ischemic area increases, which demonstrates the effective scavenging of short-lived reactive oxygen species by molecules of dinitrosyl iron complexes.
    No preview · Article · Nov 2010 · Biofizika
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    Full-text · Article · Jun 2010 · Doklady Biochemistry and Biophysics

  • No preview · Article · Jun 2010 · Journal of Hypertension
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    ABSTRACT: It has been established that, in the presence of S-nitrosothiols, cysteine, and mitochondria, dinitrosyl iron complexes (DNIC) coupled to low-molecular-weight ligands and proteins are formed. The concentration of DNIC depended on oxygen partial pressure. It was shown that, under the conditions of hypoxia, the kinetics of the formation of low-molecular DNIC was biphasic. After the replacement of anaerobic conditions of incubation with aerobic ones, the level of DNIC came down; in this case, protein dinitrosyl complexes became more stable. We proposed that iron-and sulfur-containing proteins and low-molecular-weight iron complexes are the sources of iron for DNIC formation in mitochondrial suspensions. It was shown that a combination of DNIC and S-nitrosothiols inhibited effectively the respiration of cardiomyocytes. Key wordsdinitrosyl iron complexes-nitric oxide-superoxide-mitochondria-iron-sulfur proteins-cysteine-S-nitrosothiols
    Full-text · Article · Jun 2010 · Biophysics
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    ABSTRACT: The EPR signal recorded in reaction medium containing L-lysine and methylglyoxal is supposed to come from the anion radical (semidione) of methylglyoxal and cation radical of methylglyoxal dialkylimine. These free-radical intermediates might be formed as a result of electron transfer from dialkylimine to methylglyoxal. The EPR signal was observed in a nitrogen atmosphere, whereas only trace amounts of free radicals were registered under aerobic conditions. It has been established that the decay of methylglyoxal anion radical on aeration of the medium is inhibited by superoxide dismutase. Using the methods of EPR spectroscopy and lucigenin-dependent chemiluminescence, it has been shown that nonenzymatic generation of free radicals including superoxide anion radical takes place during the interaction of L-lysine with methylglyoxal--an intermediate of carbonyl stress--at different (including physiological) pH values. In the course of analogous reaction of L-lysine with malondialdehyde (the secondary product of the free radical derived oxidation of lipids), the formation of organic free radicals or superoxide radical was not observed.
    No preview · Article · May 2009 · Biochemistry (Moscow)
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    ABSTRACT: 110 Many authors consider the unstable compound nitric oxide (NO) as an important regulator of many metabolic and physiological processes in the body [1]. In the cardiovascular system, NO plays the role of an endogenous vasodilator, regulating the vascular tonus [2, 3]. For many years, the preparations of organic nitrates donating NO, such as nitroglycerin, its derivatives, and analogs, have been used in clinical practice. Along with intravenous and sublingual administration of the NO donors, an inhalation administration of NO has been recently used in the laboratory and clinical practice. Despite a comparatively wide use of this delivery route, its effect on the NO level in tissues of various organs is still vague as well as the on the animal or human blood. In many respects, this can be connected with the fact that the NO content in organs is assessed according to the concentration of nitrates and nitrites as NO metabolites [4]. In this case, the corresponding data cannot be considered adequate, because it is impossible under such conditions to discriminate between the nitrates and nitrites that were formed as a result of the NO metabolism or entered the mammalian body with food. In this work, we have studied the effect of a longterm inhalation of the air with increased NO content by narcotized rats on its levels in tissues of the organs corresponding to different circulation circles and on the animal blood. The NO level was detected with special selective spin traps (complexes of iron ions and diethyldithiocarbamate, Fe-DETC) [5‐7] using ESR analysis. EXPERIMENTAL
    No preview · Article · Apr 2009 · Doklady Biochemistry and Biophysics
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    ABSTRACT: We studied action of a nitric oxide donor, dinitrosyl complex of iron (DNIC) with glutathione as a ligand on the hemodynamics of normotensive Wistar rats, spontaneously hypertensive rats (SHR), and monkeys. Intravenous DNIC introduction (2-120 mg/kg) rendered fast (1-2 min) hypotensive effect combined with increased heart rate by 10-25%. Second phase of the effect in Wistar rats was characterized by slowed recovery of arterial pressure and heart rate up to initial level. A gradual DNIC breakdown in blood occurred during this period associated with increased NO accumulation in organs with intensive oxidative metabolism (liver, heart, and kidney). Duration of hypotensive effect in all animals depended on dose, this dependence was most expressed in SHR.
    No preview · Article · Feb 2009 · Kardiologiia
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    ABSTRACT: Antioxidants specifically addressed to mitochondria have been studied to determine if they can decelerate senescence of organisms. For this purpose, a project has been established with participation of several research groups from Russia and some other countries. This paper summarizes the first results of the project. A new type of compounds (SkQs) comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decyl-rhodamine 19 (SkQR1), and methylplastoquinonyldecyltriphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in aqueous solution, detergent micelles, liposomes, BLM, isolated mitochondria, and cell cultures. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (sub-micromolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1=SkQR1>SkQ3>MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Nanomolar SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H(2)O(2)-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. Moreover, the SkQ1 pretreatment of rats significantly decreased the H(2)O(2) or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in myocardial infarction or stroke and prevented the death of animals from kidney ischemia. In p53(-/-) mice, 5 nmol/kgxday SkQ1 decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant NAC. Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases.
    Full-text · Article · Dec 2008 · Biochimica et Biophysica Acta
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    ABSTRACT: It was found that microdialysis, i.e., passage of aqueous solutions of iron-N-methyl-D-glucamine dithiocarbamate complexes through dialysis fibers implanted into heart, kidney and liver tissues of narcotized rats, was accompanied by effective binding of the complexes to nitric oxide from interstitial fluid. The walls of dialysis fibers used in this study were permeable for compounds with molecular weight not exceeding 5 kDa. The dialyzate samples collected every 20 min and containing diamagnetic nitrosyl Fe3+-MGD adducts were reduced to the paramagnetic state with sodium dithionite; their concentration was measured by the EPR method. The basic level of the adducts, which represented mononitrosyl iron complexes with MGD (MNIC-MGD), in the dialyzate samples of all tested organs were similar (1 microM). Treatment of animals with the water-soluble nitroglycerine analog Isoket or a low-molecular dinitrosyl iron thiosulfate complex as a NO donor increased the concentration of MNIC-MGD with going out into a plateau. The novel approach allows determination of nitric oxide levels in tissue interstitial fluid from concentration of MNIC-MGD formed during microdialysis.
    No preview · Article · Aug 2008 · Nitric Oxide
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    ABSTRACT: EPR studies have shown that water-soluble mononitrosyl iron complexes with N-methyl-d-glucamine dithiocarbamate (MNIC-MGD) (3 micromol) injected to intact mice were decomposed virtually completely within 1h. The total content of MNIC-MGD in animal urine did not exceed 30 nmol/ml. In the liver, a small amount of MNIC-MGD were converted into dinitrosyl iron complexes (30 nmol/g of liver tissue). The same was observed in intact rabbits in which MNIC-MGD formation was induced by endogenous or exogenous NO binding to NO traps, viz., iron complexes with MGD. In mice, the content of MNIC-MGD in urine samples did not change after bacterial lipopolysaccharide-induced expression of iNOS. It was supposed that MNIC-MGD decomposition in intact animals was largely due to the release of NO from the complexes and its further transfer to other specific acceptors. In mice with iNOS expression, the main contribution to MNIC-MGD decomposition was made by superoxide ions whose destructive effect is mediated by an oxidative mechanism. This effect could fully compensate the augmented synthesis of MNIC-MGD involving endogenous NO whose production was supported by iNOS. Water-soluble dinitrosyl iron complexes (DNIC) with various thiol-containing ligands and thiosulfate injected to intact mice were also decomposed; however, in this case the effect was less pronounced than in the case of MNIC-MGD. It was concluded that DNIC decomposition was largely due to the oxidative effect of superoxide ions on these complexes.
    No preview · Article · Jun 2008 · Nitric Oxide
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    ABSTRACT: Destructive effect of superoxide anions O2- derived from KO(2) or xanthine-xanthine oxidase system on dinitrosyl-iron complexes bound with bovine albumin or methemoglobin (DNIC-BSA or DNIC-MetHb) was demonstrated. The sensitivity of DNIC-BSA synthesized by the addition of DNIC with cysteine, thiosulfate or phosphate (DNIC-BSA-1, DNIC-BSA-2 or DNIC-BSA-3, respectively) to destructive action of O2- decreased in row: DNIC-BSA-1>DNIC-BSA-3>DNIC-BSA-2. The estimated rate constant for the reaction between O2- and DNIC-BSA-3 was equal to approximately 10(7)M(-1)s(-1). However, hydrogen peroxide and tert-butyl hydrogenperoxide (t-BOOH) did not induce any noticeable degradation of DNIC-BSA-3 even when used at concentrations exceeding by one order of magnitude those of the complex. As to their action on DNIC-MetHb both hydrogen peroxide and t-BOOH-induced rapid degradation of the complex. Both agents could induce the process due to the effect of alkylperoxyl or protein-derived free radicals formed at the interaction of the agents with ferri-heme groups of MetHb. Peroxynitrite (ONOO(-)) could also initiate protein-bound DNIC degradation more efficiently in the reaction with DNIC-BSA-3. Higher resistance of DNIC-MetHb to peroxynitrite was most probably due to the protective action of heme groups on ONOO(-). However, the analysis allows to suggest that the interaction of protein-bound DNICs with O2- is the only factor responsible for the degradation of the complexes in cells and tissues.
    Full-text · Article · Feb 2008 · Nitric Oxide

Publication Stats

2k Citations
190.09 Total Impact Points


  • 1990-2013
    • Russian Cardiology Research and Production Complex
      Moskva, Moscow, Russia
  • 1988-2008
    • Kemerovo Cardiology Centre
      Shcheglovsk, Kemerovo, Russia
  • 1972-2005
    • Lomonosov Moscow State University
      • • Department of Biophysics at the Faculty of Physics
      • • Division of Physics
      Moskva, Moscow, Russia
  • 2001
    • Russian Academy of Sciences
      • N. N. Semenov Institute of Chemical Physics
      Moskva, Moscow, Russia
  • 1985-1994
    • Russian Academy of Medical Sciences
      Moskva, Moscow, Russia
  • 1992
    • Slovak Academy of Sciences
      • Institute of Experimental Physics
      Presburg, Bratislavský, Slovakia
  • 1987
    • Cardiology centre of Tyumen
      Tjumen, Tjumen, Russia
  • 1977-1984
    • Moscow State Forest University
      Mytishi, MO, Russia