Nataly Strutynska - Academia.edu (original) (raw)
Papers by Nataly Strutynska
International Journal of Physiology, Pathophysiology and Pharmacology
In experiments on the mitochondria isolated from the heart tissue of adult rats, we studied the e... more In experiments on the mitochondria isolated from the heart tissue of adult rats, we studied the effects of NaHS, a hydrogen sulfide donor, on the respiratory chain of the organelles. We have found that NaHS (109 – 106 mol/l) causes a dose-dependent decrease in the rate of oxygen consumption both in the presence of succinate and ADP (state 3 by Chance), and in the absence of ADP (state 4). At that, a decrease in the oxygen consumption rate induced by NaHS in concentrations of 109 mol/l and 108 mol/l results in increased coupling of oxidation and phosphorylation, as evidenced by an increase in the respiratory control, while the efficiency of oxidative phosphorylation (ADP/O) remains unchanged. The study testifies to a protective effect of hydrogen sulfide donor on the functional state of the mitochondria. To elucidate other mechanisms of H2S protective action we also investigated the effect of hydrogen sulfide donor on the mitochondrial swelling. It has been found that NaHS in con...
FEBS letters
Hydrogen sulfide (H2S) is a biologically active gasotransmitter, which regulates a lot of importa... more Hydrogen sulfide (H2S) is a biologically active gasotransmitter, which regulates a lot of important physiological functions in the body. In the cardiovascular system H2S de novo synthesis in belongs to pyridoxal-5-phosphate-dependent enzymes – cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). The modulation of endogenous H2S generation in the cardiovascular system and other tissues and the functional consequence of this modulation are not clear. The formation of non-selective calcium-dependent cyclosporin-sensitive permeability transition pore (mPTP) between the outer and inner mitochondrial membranes is the basis for induction of the cell death by apoptosis. The aims of this study were to elucidate the mechanisms underlying the cardioprotective effects of H2S in aging rats. Exogenous hydrogen sulfide in physiological concentrations depressed Ca2+-induced mPTP opening in a dose-dependent fashion in adult and rat hearts. Prei...
The changes in functioning of isolated by Lanhendorf heart of old rats induced by an activation o... more The changes in functioning of isolated by Lanhendorf heart of old rats induced by an activation of ubiqinone -coenzyme Q (CoQ) endogenous synthesis via administration of its precursors – 4-hydroxybenzoic acid, methionine and a modulator of vitamin E were studied. An activation of ubiqinone biosynthesis contributed to cardioprotection against the development of the heart postreperfusion injures and also to a decrease in the sensitivity of mitochondrial permeability transition pore -opening to Са 2+ in the rat heart in aging
Introduction. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter, produced by de novo sy... more Introduction. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter, produced by de novo synthesis in mammalian tissues during cysteine metabolism. Three H2S synthesizing enzymes are known, namely: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). H2S and NO are key regulators of several cell processes and organ functions under both normal and pathological conditions. Mitochondrial permeability transition pore (mPTP) opening causes mitochondrial membrane potential collapse leading to mitochondrial dysfunction and apoptosis in aging heart. The role of H2S as a regulator of mitochondrial function is now receiving an increasing attention. The present study aims to elucidate the mechanisms underlying the cardioprotective effects of H2S in aging rats. Methods. H2S pools, uric acid, MDA and DK pools, generation of ROS (*O2- and *OH-radicals, H2O2), and RNS (NO2-, GSNO and protein nitrosothiol pools) as well as cNOS and iNOS ...
Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2009
ABSTRACT Aging is accompanied by changes in activity of electron-transport enzyme complexes in my... more ABSTRACT Aging is accompanied by changes in activity of electron-transport enzyme complexes in myocardial mitochondria of old rats and by increased sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of its opening (Ca2+ and phenylarsine oxide). We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (α-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) caused the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensity of lipid and protein free-radical peroxidation in the heart mitochondria and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be recommended for treatment of mitochondrial dysfunction in various pathologies of cardiovascular system, including in aging.
International Journal of Physiology and Pathophysiology, 2010
International Journal of Physiology and Pathophysiology, 2012
ABSTRACT In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat ... more ABSTRACT In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, we studied the effects of a donor of hydrogen sulfide (H2S), NaHS, and H2S biosynthesis substrate, L-cysteine, on the sensitivity of the mitochondrial permeability transition pore (mPTP) opening to its natural inductor, Ca(2+). We found that NaHS (10(-12) to 10(-4) mol/l) influenced mitochondrial swelling in a concentration-dependent manner. It was also demonstrated that the addition of NaHS (10(-12) to 10(-8) mol/l) to the calcium-free medium resulted in moderate a swelling of mitochondria from both adult and old rat hearts. At 10(-10) mol/l NaHS, the maximal values of the mitochondrial swelling observed in both adult and old hearts were 11 and 15 ,%, respectively. A specific inhibitor of KATP channels, 5-hydroxydecanoate (5-HD; 10(-4) mol/l) decreased the mitochondrial swelling in the presence of NaHS (10)-10) mol/l), which can be indicative of the contribution of these channels to the calcium-independent conductance of the mitochondrial membranes in the rat hearts. The H2S donor NaHS used in physiological concentrations (10(-6), 10(-5) and 5 10(-5) mol/l) exerted the inhibiting effect on the Ca(2+)-induced mPTP opening in adult hearts (corresponding values of such effect were 31, 76, and 77%, respectively), while in old hearts the protector effect of NaHS was observed only at its concentration of 10(-5) mol/l. Therefore, the donor of H2S used in the tested concentrations (10(-12) to 10(-4) mol/l) exerted ambiguous effect on the mitochondrial swelling: low concentrations of NaHS (10(-12) to 10(-8) mol/l) increased the mitochondrial swelling, while its physiological concentrations (10(-6) to 5 10(-5) mol/l) exerted the protective effect on Ca(2+)-induced mitochondrial swelling in adult and old hearts. Pre-incubation of isolated mitochondria with 5-HD (10(-4) mol/l) resulted in a decrease in the protective effect evoked by NaHS (10(-5) mol/l) on Ca(2+)-induced mPTP opening, which is indicative of the possible involvement of mitochondrial KATP-channels in the H2S-dependent inhibition of mPTP formation in both adult and old rat hearts. In experiments in vivo, single intraperitoneal injections of both NaHS (10(4) mol/kg) and L-cysteine ((10(-3) mol/kg) resulted in a decrease in the sensitivity of mPTP to its inductor Ca(2+) in adult and old rat hearts. The action of L-cysteine, as compared with that of NaHS, was more effective in prevention of Ca(2+)-induced mitochondrial swelling. We observed a rise in Ca(2+) concentration by one order of magnitude, which evoked the mitochondrial swelling in adult and old hearts. In experiments in vivo in which we used a specific blocker ofcystathionine-g-lyase, propargylglycine (10(-4) mol/kg) that is involved in the synthesis of H2S, we observed an increase in the sensitivity of mPTP opening in old hearts because of a decrease in the threshold Ca(2+) concentration required for mitochondrial swelling by two orders of magnitude. We demonstrate the involvement of endogenous H2S in the control of mPTP formation in adult and old hearts. Our studies are indicative of the involvement of H2S in modulation of changes in the permeability of mitochondrial membranes, which can be an important regulatory factor in the development of cardiovascular diseases
International Journal of Physiology and Pathophysiology, 2013
ABSTRACT At in vivo and in vitro experiments on the mitochondria isolated from the heart tissue o... more ABSTRACT At in vivo and in vitro experiments on the mitochondria isolated from the heart tissue of control and spontaneously hypertensive rats (SHR), we examined the effects of NaHS, hydrogen sulfide donor, as well as L-cysteine, a substrate for its biosynthesis, on the sensitivity of mitochondrial permeability transition pore (mPTP) opening to the action of Ca2+, its natural inducer. The concentration dependence of the NaHS-evoked effect (10 6 – 10 4 mol / l) and calcium-induced heart mitochondrial swelling in both groups of animals has been revealed. The hydrogen sulfide donor in concentrations 10 6, 10 5 and 10 4 mol / l inhibited calcium-induced mPTP opening by 31, 76 and 100%, respectively, indicating that its protective effect on pore formation in the heart of control rats, with the normal blood pressure. Inhibition of mPTP in the heart of SHR requires an order of magnitude higher concentration of NaHS (10–5 – 10–4 mol / l) on the background of increased organelle capacity to pore formation. At in vivo experiments, a single intraperitoneal administration L-cysteine (10 3 mol / kg) resulted in reduced sensitivity to Ca2+, an mPTP inducer, in both groups. Inhibition of hydrogen sulphide biosynthesis in vivo by propargyl glycine (10–4 mol / kg), a specific inhibitor of cystathionine-γ-lyase, prevented the effect of L-cysteine in the heart of control rats, unlike SHR, where we observed a reduction of increased mPTP sensitivity to Ca2+. Thus, under physiological conditions and in hypertension, both exogenous and endogenous hydrogen sulfide have stabilizing effect on the mitochondrial membranes by increasing organelle resistance to Ca2+, a natural mPTP inducer. KEY WORDS: hydrogen sulfide, L-cysteine, mitochondrial permeability transition pore, heart, hypertension, rats
International Journal of Physiology and Pathophysiology, 2013
ABSTRACT In vitro experiments on the mitochondria isolated from adult normotensive and spontaneou... more ABSTRACT In vitro experiments on the mitochondria isolated from adult normotensive and spontaneously hypertensive rat hearts, an increased sensitivity of mitochondrial permeability transition pore (mPTP) to Ca2+, its natural inducer, has been revealed. In spontaneously hypertensive rats, it is evoked by the reduction of active ion concentration by two orders, which causes organelle swelling. Calcium-induced swelling of the mitochondria isolated from the normotensive rats (control) is completely prevented by cyclosporin A (10 5 mol/l), a natural mPTP inhibitor, while in spontaneously hypertensive rats, it is prevented only partially (by 54%), indicating the presence of cyclosporin A-insensitive mPTP component. The results obtained give reason to conclude that hypertension is associated with mitochondrial dysfunction, characterized, in particular, by increased mPTP sensitivity to Ca2+, which may elicit widespread tissue damage, accompanying diseases of the cardiovascular system, especially hypertension. KEY WORDS: mitochondrial permeability transition pore, heart, hypertension, rats
Biokhimii͡a (Moscow, Russia), 1996
An in-depth study of the effects of Ca(2+)-precipitating anions (oxalate, phosphate), the Ca2+ io... more An in-depth study of the effects of Ca(2+)-precipitating anions (oxalate, phosphate), the Ca2+ ionophore A23187 and some highly effective selective inhibitors of the endo(sarco)plasmic reticulum Ca(2+)-pump (tapsigargin, cyclopiasonic acid) on ruthenium red (10 microM)-insensitive, Mg2+,ATP-dependent accumulation of Ca2+ in digitonin-permeabilized myometrium cells of nonpregnant estrogen-treated rats, has been carried out. Oxalate and phosphate stimulated Mg2+,ATP-dependent accumulation of Ca2+ in permeabilized smooth muscle cells. The Ca2+ ionophore A23187 (5 microM) added to the medium containing oxalate (10 mM) or phosphate (20 mM) prevented the energy-dependent accumulation of Ca2+. Tapsigargin (50 nM) and cyclopiasonic acid (10 microM) fully suppressed the Mg2+,ATP-dependent Ca2+ increase measured in the presence of the Ca(2+)-precipitating anions. The kinetic data indicate that the tapsigargin affinity for the energy-dependent Ca2+ transporting system is much higher than that ...
![Research paper thumbnail of [New fluorine-containing openers of ATP-sensitive potassium channels flokalin and tioflokalin inhibit calcium-induced mitochondrial pore opening in rat hearts]](https://attachments.academia-assets.com/72683448/thumbnails/1.jpg)
](Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2013
In experiments in vitro on the mitochondria isolated from the rat's heart we studied the effe... more In experiments in vitro on the mitochondria isolated from the rat's heart we studied the effects of the openers of ATP-sensitive potassium channels (K(ATP)-channels), flocalin and tioflocalin, on the calcium-induced mitochondrial pore (MPTP) opening. Flocalin and tioflocalin caused moderate Ca(2+)-independent mitochondria swelling, which was prevented by a specific inhibitor of 5-hydroxydecanoate. This allowed to identify these compounds as mitochondrial K(ATP)-channels openers. We found that concentration-dependent inhibitory effects (10(-7) to 10(-4) M) of flocalin (with IC50 = 50 microM) and tioflocalin (with IC50 = 2,7 microM) on Ca(2+)-induced mitochondrial swelling (MPTP opening) in the heart characterized more powerful cardioprotective action of the latter. It was shown that the administration of these compounds in experiments in vivo decreased the sensitivity of the MPTP opening to Ca2+. Thus, under physiological conditions the activators K(ATP)-channels probably provide...
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, 2013
In experiments on a model of ischemia-reperfusion in Langendorff isolated rat hearts and isolated... more In experiments on a model of ischemia-reperfusion in Langendorff isolated rat hearts and isolated mitochondria we studied the role of hydrogen sulfide donor - sodium hydrosulfide (NaHS, 7.4 mg/kg) in modulating the sensitivity ofmitochondrial permeability transition pore opening. It was shown that NaHS increased the reserves of rat myocardium and had cardioprotective effects from ischemia-reperfusion. In experiments on isolated mitochondria NaHS in concentrations of 10(-6), 10(-5) and 5 x 10(-5) mol/L inhibited Ca(2+)-induced swelling of mitochondria. Preincubation of isolated mitochondria with K+(ATphi)-channels inhibitor 5-hydroxydecanoate (10(-4) mol/L) reduced the protective effect of NaHS (10(-5) mol/L). Thus, we consider that NaHS protective effect from reperfusion disturbances of heart function was realized via inhibition of Ca(2+)-induced mitochondrial permeability transition pore opening.
![Research paper thumbnail of [Hydrogen sulfide inhibits Ca(2+)-induced mitochondrial permeability transition pore opening in adult and old rat heart]](https://attachments.academia-assets.com/72683437/thumbnails/1.jpg)
](Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2011
In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, w... more In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, we studied the effects of a donor of hydrogen sulfide (H2S), NaHS, and H2S biosynthesis substrate, L-cysteine, on the sensitivity of the mitochondrial permeability transition pore (mPTP) opening to its natural inductor, Ca(2+). We found that NaHS (10(-12) to 10(-4) mol/l) influenced mitochondrial swelling in a concentration-dependent manner. It was also demonstrated that the addition of NaHS (10(-12) to 10(-8) mol/l) to the calcium-free medium resulted in moderate a swelling of mitochondria from both adult and old rat hearts. At 10(-10) mol/l NaHS, the maximal values of the mitochondrial swelling observed in both adult and old hearts were 11 and 15 ,%, respectively. A specific inhibitor of KATP channels, 5-hydroxydecanoate (5-HD; 10(-4) mol/l) decreased the mitochondrial swelling in the presence of NaHS (10)-10) mol/l), which can be indicative of the contribution of these channels to the ...
Biomedit͡sinskai͡a khimii͡a
Our research demonstrate that ageing leads to changes in activity of electron-transporting enzyme... more Our research demonstrate that ageing leads to changes in activity of electron-transporting enzyme complexes in myocardial mitochondria of old rats and to increased sensitivity of mitochondrial permeability transition pore to inductors of its opening--Ca2+ and phenylarsine oxide. We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (alpha-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) we observed the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensivity of lipid and protein free-radical peroxidation in the heart and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be used to treat mitochondrial dysfunction under numerous pathologies of cardiovas...
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, 2009
The role of nitric oxide (NO) in modulation of sensitivity ofmitochondnal permeability transition... more The role of nitric oxide (NO) in modulation of sensitivity ofmitochondnal permeability transition pore (MPTP) opening under exposure to calcium as inductor was studied in experiments on the isolated heart (on Langendorff) and isolated mitochondria. The MPTP opening was studied on the hearts under ischemia-reperfusion and of the mitochondrial calcium loading. We investigated the degree ofreperfusional injury of the heart functional state after preliminary administration of the classic inhibitor of MPTP opening: cyclosporin A, the nitroprussid sodium salt as NO donor, NO-synthase (NOS) inhibitors such as L-NMMA and aminoguanidin to perfusional solution, and also the influence of Ca+ in the range of concentrations (10(-8)-10(-4) M) on the mitochondrial swelling under its preincubation with L-NMMA (10(-4) M). It is shown that the protective effect of nitric oxide on myocardium under reperfusion of ischemic heart will be realised by means of the inhibiting of Ca2+ -induced MPTP opening.
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2004
We studied the sensitivity of mitochondrial permeability transition pore (MPTP) opening to its in... more We studied the sensitivity of mitochondrial permeability transition pore (MPTP) opening to its inductor-phenylarsineoxide (PAO) in adult (6 months), old rat heart (24 months) and in old rat heart under conditions of intermittent hypoxic training (IHT). We defined the sensitivity of MPTP opening on two parameters: the alterations in mitochondrial swelling and the release ofmitochondrial substances (mitochondrial factor). It was shown that mitochondria of old rat heart are more sensitive to PAO which caused opening of cyclosporin-sensitive MPTP and MPTP-dependent factor release, in comparison with those of adult rat heart mitochondria. One of the causes of increased sensitivity of MPTP opening to PAO is development of an oxidative stress with age that was accompanied by increase of an active metabolite of oxygen IHT on PAO-induced MPTP-opening and MPTP-dependent factor release from old rat heart mitochondria. IHT also reduced the content of H2O2 and *OH in old rat hearts. IHT can be u...
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2004
An age-related increase in the sensitivity of the mitochondrial permeability transition pore (MPT... more An age-related increase in the sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of it's opening, Ca2+ ions and phenylarsineoxide (PAO) was studied in experiments in vitro on isolated heart mitochondria of adult and old rats. Two indices were measured spectrophotometrically (lambda = 520 nm) by a decrease in an optical density (OD), resulting from mitochondrial swelling and a release of mitochondrial unidentified substances (mitochondrial factor, MF) registered also spectrophotometrically in a range of waves lambda = 230-260 nm. Dose-dependent effect of Ca2+ (10(-7)-10(-4) mol/l) and PAO (10(-8)-10(-4) mol/l) on swelling of the mitochondria were observed in samples from both adult and old rats. Swelling of the mitochondria from the heart of old rats induced by application of the above inductors was more intensive than the respective effect in samples from adult rats. In samples from the heart of both adult and old rats Ca2+ ions within the tested ...
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2003
In experiments in vitro on isolated heart mitochondria of rats, an activation of mitochondrial pe... more In experiments in vitro on isolated heart mitochondria of rats, an activation of mitochondrial permeability transition pore (PTP) was induced by either modelling an oxidative stress with PTP-inductor phenylarsine oxide (PAO) or by calcium overload (CaCl2). PTP-opening was determined spectrophotometrically (lambda = 520 nm) by a decrease in an optical density (OD), resulting from mitochondrial swelling. We also observed a release of mitochondrial unidentified substances (mitochondrial factor, MF) registered spectrophotometrically in a range of waves lambda = 230-260 nm. Both correlation between mitochondrial swelling and a release of the mitochondrial factor have been found in experiments with PAO at concentrations 10(-7)-10(-4) mol/l, and in those with CaCl2 at concentrations 10(-6)-10(-4) mol/l. The classical inhibitor of mitochondrial PTP cyclosporin A (Cs A, 10(-5) mol/l) inhibited mitochondrial swelling and a release of that factor completely. Our experimental data give evidence...
Ukrainskiĭ biokhimicheskiĭ zhurnal
It is proved that at experimental diabetes the calcium content in hepatocytes is disturbed. This ... more It is proved that at experimental diabetes the calcium content in hepatocytes is disturbed. This disorder is mostly shown in increase of calcium content in hepatocytes and in decrease of accumulation of these ions in mitochondrias. One of the possible reasons of changes at this pathology is the change of lipid content of hepatocytes, mitochondrias and microsomes. It is proved that the in vitro model systems Ca ions inhibits the synthesis of 25-hydroxyvitamin D3 by hepatocytes.
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2003
The release of an unidentified substance (factor) induced by sulfhydryl group (SH) modifier and m... more The release of an unidentified substance (factor) induced by sulfhydryl group (SH) modifier and mitochondrial permeability transition pore (MPT) inductor phenylarsine oxide (PAO) has been found in vitro on isolated guinea-pig and rat heart mitochondria. The factor was also released at oxidative stress. The factor release induced by PAO was inhibited by cyclosporin A (CsA), the MPT inhibitor. Protective actions of antioxidants melatonin and trolox in vitro and in vivo, as well as dithiothreitol (DTT) and diethylmaleat (DEM) were studied. The influences of nitric oxide (NO) donor, sodium nitroprusside (SNP) on the mitochondrial factor release were also studied. We have shown the participation of this agent in the regulation of factor formation after inhibition of NO-synthase activity (NOS) by aminoguanidine. The data were obtained about MPT-opening after Ca2+ loading and under the influence of the MPT inductor PAO, inhibited by CsA. The results obtained on isolated mitochondria are in...
International Journal of Physiology, Pathophysiology and Pharmacology
In experiments on the mitochondria isolated from the heart tissue of adult rats, we studied the e... more In experiments on the mitochondria isolated from the heart tissue of adult rats, we studied the effects of NaHS, a hydrogen sulfide donor, on the respiratory chain of the organelles. We have found that NaHS (109 – 106 mol/l) causes a dose-dependent decrease in the rate of oxygen consumption both in the presence of succinate and ADP (state 3 by Chance), and in the absence of ADP (state 4). At that, a decrease in the oxygen consumption rate induced by NaHS in concentrations of 109 mol/l and 108 mol/l results in increased coupling of oxidation and phosphorylation, as evidenced by an increase in the respiratory control, while the efficiency of oxidative phosphorylation (ADP/O) remains unchanged. The study testifies to a protective effect of hydrogen sulfide donor on the functional state of the mitochondria. To elucidate other mechanisms of H2S protective action we also investigated the effect of hydrogen sulfide donor on the mitochondrial swelling. It has been found that NaHS in con...
FEBS letters
Hydrogen sulfide (H2S) is a biologically active gasotransmitter, which regulates a lot of importa... more Hydrogen sulfide (H2S) is a biologically active gasotransmitter, which regulates a lot of important physiological functions in the body. In the cardiovascular system H2S de novo synthesis in belongs to pyridoxal-5-phosphate-dependent enzymes – cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). The modulation of endogenous H2S generation in the cardiovascular system and other tissues and the functional consequence of this modulation are not clear. The formation of non-selective calcium-dependent cyclosporin-sensitive permeability transition pore (mPTP) between the outer and inner mitochondrial membranes is the basis for induction of the cell death by apoptosis. The aims of this study were to elucidate the mechanisms underlying the cardioprotective effects of H2S in aging rats. Exogenous hydrogen sulfide in physiological concentrations depressed Ca2+-induced mPTP opening in a dose-dependent fashion in adult and rat hearts. Prei...
The changes in functioning of isolated by Lanhendorf heart of old rats induced by an activation o... more The changes in functioning of isolated by Lanhendorf heart of old rats induced by an activation of ubiqinone -coenzyme Q (CoQ) endogenous synthesis via administration of its precursors – 4-hydroxybenzoic acid, methionine and a modulator of vitamin E were studied. An activation of ubiqinone biosynthesis contributed to cardioprotection against the development of the heart postreperfusion injures and also to a decrease in the sensitivity of mitochondrial permeability transition pore -opening to Са 2+ in the rat heart in aging
Introduction. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter, produced by de novo sy... more Introduction. Hydrogen sulfide (H2S) is an endogenous gaseous transmitter, produced by de novo synthesis in mammalian tissues during cysteine metabolism. Three H2S synthesizing enzymes are known, namely: cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). H2S and NO are key regulators of several cell processes and organ functions under both normal and pathological conditions. Mitochondrial permeability transition pore (mPTP) opening causes mitochondrial membrane potential collapse leading to mitochondrial dysfunction and apoptosis in aging heart. The role of H2S as a regulator of mitochondrial function is now receiving an increasing attention. The present study aims to elucidate the mechanisms underlying the cardioprotective effects of H2S in aging rats. Methods. H2S pools, uric acid, MDA and DK pools, generation of ROS (*O2- and *OH-radicals, H2O2), and RNS (NO2-, GSNO and protein nitrosothiol pools) as well as cNOS and iNOS ...
Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2009
ABSTRACT Aging is accompanied by changes in activity of electron-transport enzyme complexes in my... more ABSTRACT Aging is accompanied by changes in activity of electron-transport enzyme complexes in myocardial mitochondria of old rats and by increased sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of its opening (Ca2+ and phenylarsine oxide). We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (α-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) caused the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensity of lipid and protein free-radical peroxidation in the heart mitochondria and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be recommended for treatment of mitochondrial dysfunction in various pathologies of cardiovascular system, including in aging.
International Journal of Physiology and Pathophysiology, 2010
International Journal of Physiology and Pathophysiology, 2012
ABSTRACT In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat ... more ABSTRACT In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, we studied the effects of a donor of hydrogen sulfide (H2S), NaHS, and H2S biosynthesis substrate, L-cysteine, on the sensitivity of the mitochondrial permeability transition pore (mPTP) opening to its natural inductor, Ca(2+). We found that NaHS (10(-12) to 10(-4) mol/l) influenced mitochondrial swelling in a concentration-dependent manner. It was also demonstrated that the addition of NaHS (10(-12) to 10(-8) mol/l) to the calcium-free medium resulted in moderate a swelling of mitochondria from both adult and old rat hearts. At 10(-10) mol/l NaHS, the maximal values of the mitochondrial swelling observed in both adult and old hearts were 11 and 15 ,%, respectively. A specific inhibitor of KATP channels, 5-hydroxydecanoate (5-HD; 10(-4) mol/l) decreased the mitochondrial swelling in the presence of NaHS (10)-10) mol/l), which can be indicative of the contribution of these channels to the calcium-independent conductance of the mitochondrial membranes in the rat hearts. The H2S donor NaHS used in physiological concentrations (10(-6), 10(-5) and 5 10(-5) mol/l) exerted the inhibiting effect on the Ca(2+)-induced mPTP opening in adult hearts (corresponding values of such effect were 31, 76, and 77%, respectively), while in old hearts the protector effect of NaHS was observed only at its concentration of 10(-5) mol/l. Therefore, the donor of H2S used in the tested concentrations (10(-12) to 10(-4) mol/l) exerted ambiguous effect on the mitochondrial swelling: low concentrations of NaHS (10(-12) to 10(-8) mol/l) increased the mitochondrial swelling, while its physiological concentrations (10(-6) to 5 10(-5) mol/l) exerted the protective effect on Ca(2+)-induced mitochondrial swelling in adult and old hearts. Pre-incubation of isolated mitochondria with 5-HD (10(-4) mol/l) resulted in a decrease in the protective effect evoked by NaHS (10(-5) mol/l) on Ca(2+)-induced mPTP opening, which is indicative of the possible involvement of mitochondrial KATP-channels in the H2S-dependent inhibition of mPTP formation in both adult and old rat hearts. In experiments in vivo, single intraperitoneal injections of both NaHS (10(4) mol/kg) and L-cysteine ((10(-3) mol/kg) resulted in a decrease in the sensitivity of mPTP to its inductor Ca(2+) in adult and old rat hearts. The action of L-cysteine, as compared with that of NaHS, was more effective in prevention of Ca(2+)-induced mitochondrial swelling. We observed a rise in Ca(2+) concentration by one order of magnitude, which evoked the mitochondrial swelling in adult and old hearts. In experiments in vivo in which we used a specific blocker ofcystathionine-g-lyase, propargylglycine (10(-4) mol/kg) that is involved in the synthesis of H2S, we observed an increase in the sensitivity of mPTP opening in old hearts because of a decrease in the threshold Ca(2+) concentration required for mitochondrial swelling by two orders of magnitude. We demonstrate the involvement of endogenous H2S in the control of mPTP formation in adult and old hearts. Our studies are indicative of the involvement of H2S in modulation of changes in the permeability of mitochondrial membranes, which can be an important regulatory factor in the development of cardiovascular diseases
International Journal of Physiology and Pathophysiology, 2013
ABSTRACT At in vivo and in vitro experiments on the mitochondria isolated from the heart tissue o... more ABSTRACT At in vivo and in vitro experiments on the mitochondria isolated from the heart tissue of control and spontaneously hypertensive rats (SHR), we examined the effects of NaHS, hydrogen sulfide donor, as well as L-cysteine, a substrate for its biosynthesis, on the sensitivity of mitochondrial permeability transition pore (mPTP) opening to the action of Ca2+, its natural inducer. The concentration dependence of the NaHS-evoked effect (10 6 – 10 4 mol / l) and calcium-induced heart mitochondrial swelling in both groups of animals has been revealed. The hydrogen sulfide donor in concentrations 10 6, 10 5 and 10 4 mol / l inhibited calcium-induced mPTP opening by 31, 76 and 100%, respectively, indicating that its protective effect on pore formation in the heart of control rats, with the normal blood pressure. Inhibition of mPTP in the heart of SHR requires an order of magnitude higher concentration of NaHS (10–5 – 10–4 mol / l) on the background of increased organelle capacity to pore formation. At in vivo experiments, a single intraperitoneal administration L-cysteine (10 3 mol / kg) resulted in reduced sensitivity to Ca2+, an mPTP inducer, in both groups. Inhibition of hydrogen sulphide biosynthesis in vivo by propargyl glycine (10–4 mol / kg), a specific inhibitor of cystathionine-γ-lyase, prevented the effect of L-cysteine in the heart of control rats, unlike SHR, where we observed a reduction of increased mPTP sensitivity to Ca2+. Thus, under physiological conditions and in hypertension, both exogenous and endogenous hydrogen sulfide have stabilizing effect on the mitochondrial membranes by increasing organelle resistance to Ca2+, a natural mPTP inducer. KEY WORDS: hydrogen sulfide, L-cysteine, mitochondrial permeability transition pore, heart, hypertension, rats
International Journal of Physiology and Pathophysiology, 2013
ABSTRACT In vitro experiments on the mitochondria isolated from adult normotensive and spontaneou... more ABSTRACT In vitro experiments on the mitochondria isolated from adult normotensive and spontaneously hypertensive rat hearts, an increased sensitivity of mitochondrial permeability transition pore (mPTP) to Ca2+, its natural inducer, has been revealed. In spontaneously hypertensive rats, it is evoked by the reduction of active ion concentration by two orders, which causes organelle swelling. Calcium-induced swelling of the mitochondria isolated from the normotensive rats (control) is completely prevented by cyclosporin A (10 5 mol/l), a natural mPTP inhibitor, while in spontaneously hypertensive rats, it is prevented only partially (by 54%), indicating the presence of cyclosporin A-insensitive mPTP component. The results obtained give reason to conclude that hypertension is associated with mitochondrial dysfunction, characterized, in particular, by increased mPTP sensitivity to Ca2+, which may elicit widespread tissue damage, accompanying diseases of the cardiovascular system, especially hypertension. KEY WORDS: mitochondrial permeability transition pore, heart, hypertension, rats
Biokhimii͡a (Moscow, Russia), 1996
An in-depth study of the effects of Ca(2+)-precipitating anions (oxalate, phosphate), the Ca2+ io... more An in-depth study of the effects of Ca(2+)-precipitating anions (oxalate, phosphate), the Ca2+ ionophore A23187 and some highly effective selective inhibitors of the endo(sarco)plasmic reticulum Ca(2+)-pump (tapsigargin, cyclopiasonic acid) on ruthenium red (10 microM)-insensitive, Mg2+,ATP-dependent accumulation of Ca2+ in digitonin-permeabilized myometrium cells of nonpregnant estrogen-treated rats, has been carried out. Oxalate and phosphate stimulated Mg2+,ATP-dependent accumulation of Ca2+ in permeabilized smooth muscle cells. The Ca2+ ionophore A23187 (5 microM) added to the medium containing oxalate (10 mM) or phosphate (20 mM) prevented the energy-dependent accumulation of Ca2+. Tapsigargin (50 nM) and cyclopiasonic acid (10 microM) fully suppressed the Mg2+,ATP-dependent Ca2+ increase measured in the presence of the Ca(2+)-precipitating anions. The kinetic data indicate that the tapsigargin affinity for the energy-dependent Ca2+ transporting system is much higher than that ...
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2013
In experiments in vitro on the mitochondria isolated from the rat's heart we studied the effe... more In experiments in vitro on the mitochondria isolated from the rat's heart we studied the effects of the openers of ATP-sensitive potassium channels (K(ATP)-channels), flocalin and tioflocalin, on the calcium-induced mitochondrial pore (MPTP) opening. Flocalin and tioflocalin caused moderate Ca(2+)-independent mitochondria swelling, which was prevented by a specific inhibitor of 5-hydroxydecanoate. This allowed to identify these compounds as mitochondrial K(ATP)-channels openers. We found that concentration-dependent inhibitory effects (10(-7) to 10(-4) M) of flocalin (with IC50 = 50 microM) and tioflocalin (with IC50 = 2,7 microM) on Ca(2+)-induced mitochondrial swelling (MPTP opening) in the heart characterized more powerful cardioprotective action of the latter. It was shown that the administration of these compounds in experiments in vivo decreased the sensitivity of the MPTP opening to Ca2+. Thus, under physiological conditions the activators K(ATP)-channels probably provide...
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, 2013
In experiments on a model of ischemia-reperfusion in Langendorff isolated rat hearts and isolated... more In experiments on a model of ischemia-reperfusion in Langendorff isolated rat hearts and isolated mitochondria we studied the role of hydrogen sulfide donor - sodium hydrosulfide (NaHS, 7.4 mg/kg) in modulating the sensitivity ofmitochondrial permeability transition pore opening. It was shown that NaHS increased the reserves of rat myocardium and had cardioprotective effects from ischemia-reperfusion. In experiments on isolated mitochondria NaHS in concentrations of 10(-6), 10(-5) and 5 x 10(-5) mol/L inhibited Ca(2+)-induced swelling of mitochondria. Preincubation of isolated mitochondria with K+(ATphi)-channels inhibitor 5-hydroxydecanoate (10(-4) mol/L) reduced the protective effect of NaHS (10(-5) mol/L). Thus, we consider that NaHS protective effect from reperfusion disturbances of heart function was realized via inhibition of Ca(2+)-induced mitochondrial permeability transition pore opening.
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2011
In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, w... more In experiments in vivo and in vitro on the mitochondria isolated from adult and old rat hearts, we studied the effects of a donor of hydrogen sulfide (H2S), NaHS, and H2S biosynthesis substrate, L-cysteine, on the sensitivity of the mitochondrial permeability transition pore (mPTP) opening to its natural inductor, Ca(2+). We found that NaHS (10(-12) to 10(-4) mol/l) influenced mitochondrial swelling in a concentration-dependent manner. It was also demonstrated that the addition of NaHS (10(-12) to 10(-8) mol/l) to the calcium-free medium resulted in moderate a swelling of mitochondria from both adult and old rat hearts. At 10(-10) mol/l NaHS, the maximal values of the mitochondrial swelling observed in both adult and old hearts were 11 and 15 ,%, respectively. A specific inhibitor of KATP channels, 5-hydroxydecanoate (5-HD; 10(-4) mol/l) decreased the mitochondrial swelling in the presence of NaHS (10)-10) mol/l), which can be indicative of the contribution of these channels to the ...
Biomedit͡sinskai͡a khimii͡a
Our research demonstrate that ageing leads to changes in activity of electron-transporting enzyme... more Our research demonstrate that ageing leads to changes in activity of electron-transporting enzyme complexes in myocardial mitochondria of old rats and to increased sensitivity of mitochondrial permeability transition pore to inductors of its opening--Ca2+ and phenylarsine oxide. We also observed activation of lipid and protein free-radical peroxidation processes. Administration of a complex of biologically active substances that included precursors and modulators of coenzyme Q biosynthesis (alpha-tocopherol acetate, 4-hydroxybenzoic acid, and methionine) we observed the increase in coenzyme Q content, correction of functional activity of mitochondrial electron-transport chain enzyme complexes, the decrease in intensivity of lipid and protein free-radical peroxidation in the heart and the decrease in sensitivity of mitochondrial permeability transition pore to inductors of its opening. This complex may be used to treat mitochondrial dysfunction under numerous pathologies of cardiovas...
Rossiĭskii fiziologicheskiĭ zhurnal imeni I.M. Sechenova / Rossiĭskaia akademiia nauk, 2009
The role of nitric oxide (NO) in modulation of sensitivity ofmitochondnal permeability transition... more The role of nitric oxide (NO) in modulation of sensitivity ofmitochondnal permeability transition pore (MPTP) opening under exposure to calcium as inductor was studied in experiments on the isolated heart (on Langendorff) and isolated mitochondria. The MPTP opening was studied on the hearts under ischemia-reperfusion and of the mitochondrial calcium loading. We investigated the degree ofreperfusional injury of the heart functional state after preliminary administration of the classic inhibitor of MPTP opening: cyclosporin A, the nitroprussid sodium salt as NO donor, NO-synthase (NOS) inhibitors such as L-NMMA and aminoguanidin to perfusional solution, and also the influence of Ca+ in the range of concentrations (10(-8)-10(-4) M) on the mitochondrial swelling under its preincubation with L-NMMA (10(-4) M). It is shown that the protective effect of nitric oxide on myocardium under reperfusion of ischemic heart will be realised by means of the inhibiting of Ca2+ -induced MPTP opening.
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2004
We studied the sensitivity of mitochondrial permeability transition pore (MPTP) opening to its in... more We studied the sensitivity of mitochondrial permeability transition pore (MPTP) opening to its inductor-phenylarsineoxide (PAO) in adult (6 months), old rat heart (24 months) and in old rat heart under conditions of intermittent hypoxic training (IHT). We defined the sensitivity of MPTP opening on two parameters: the alterations in mitochondrial swelling and the release ofmitochondrial substances (mitochondrial factor). It was shown that mitochondria of old rat heart are more sensitive to PAO which caused opening of cyclosporin-sensitive MPTP and MPTP-dependent factor release, in comparison with those of adult rat heart mitochondria. One of the causes of increased sensitivity of MPTP opening to PAO is development of an oxidative stress with age that was accompanied by increase of an active metabolite of oxygen IHT on PAO-induced MPTP-opening and MPTP-dependent factor release from old rat heart mitochondria. IHT also reduced the content of H2O2 and *OH in old rat hearts. IHT can be u...
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2004
An age-related increase in the sensitivity of the mitochondrial permeability transition pore (MPT... more An age-related increase in the sensitivity of the mitochondrial permeability transition pore (MPTP) to inductors of it's opening, Ca2+ ions and phenylarsineoxide (PAO) was studied in experiments in vitro on isolated heart mitochondria of adult and old rats. Two indices were measured spectrophotometrically (lambda = 520 nm) by a decrease in an optical density (OD), resulting from mitochondrial swelling and a release of mitochondrial unidentified substances (mitochondrial factor, MF) registered also spectrophotometrically in a range of waves lambda = 230-260 nm. Dose-dependent effect of Ca2+ (10(-7)-10(-4) mol/l) and PAO (10(-8)-10(-4) mol/l) on swelling of the mitochondria were observed in samples from both adult and old rats. Swelling of the mitochondria from the heart of old rats induced by application of the above inductors was more intensive than the respective effect in samples from adult rats. In samples from the heart of both adult and old rats Ca2+ ions within the tested ...
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2003
In experiments in vitro on isolated heart mitochondria of rats, an activation of mitochondrial pe... more In experiments in vitro on isolated heart mitochondria of rats, an activation of mitochondrial permeability transition pore (PTP) was induced by either modelling an oxidative stress with PTP-inductor phenylarsine oxide (PAO) or by calcium overload (CaCl2). PTP-opening was determined spectrophotometrically (lambda = 520 nm) by a decrease in an optical density (OD), resulting from mitochondrial swelling. We also observed a release of mitochondrial unidentified substances (mitochondrial factor, MF) registered spectrophotometrically in a range of waves lambda = 230-260 nm. Both correlation between mitochondrial swelling and a release of the mitochondrial factor have been found in experiments with PAO at concentrations 10(-7)-10(-4) mol/l, and in those with CaCl2 at concentrations 10(-6)-10(-4) mol/l. The classical inhibitor of mitochondrial PTP cyclosporin A (Cs A, 10(-5) mol/l) inhibited mitochondrial swelling and a release of that factor completely. Our experimental data give evidence...
Ukrainskiĭ biokhimicheskiĭ zhurnal
It is proved that at experimental diabetes the calcium content in hepatocytes is disturbed. This ... more It is proved that at experimental diabetes the calcium content in hepatocytes is disturbed. This disorder is mostly shown in increase of calcium content in hepatocytes and in decrease of accumulation of these ions in mitochondrias. One of the possible reasons of changes at this pathology is the change of lipid content of hepatocytes, mitochondrias and microsomes. It is proved that the in vitro model systems Ca ions inhibits the synthesis of 25-hydroxyvitamin D3 by hepatocytes.
Fiziolohichnyĭ zhurnal (Kiev, Ukraine : 1994), 2003
The release of an unidentified substance (factor) induced by sulfhydryl group (SH) modifier and m... more The release of an unidentified substance (factor) induced by sulfhydryl group (SH) modifier and mitochondrial permeability transition pore (MPT) inductor phenylarsine oxide (PAO) has been found in vitro on isolated guinea-pig and rat heart mitochondria. The factor was also released at oxidative stress. The factor release induced by PAO was inhibited by cyclosporin A (CsA), the MPT inhibitor. Protective actions of antioxidants melatonin and trolox in vitro and in vivo, as well as dithiothreitol (DTT) and diethylmaleat (DEM) were studied. The influences of nitric oxide (NO) donor, sodium nitroprusside (SNP) on the mitochondrial factor release were also studied. We have shown the participation of this agent in the regulation of factor formation after inhibition of NO-synthase activity (NOS) by aminoguanidine. The data were obtained about MPT-opening after Ca2+ loading and under the influence of the MPT inductor PAO, inhibited by CsA. The results obtained on isolated mitochondria are in...