UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidants are known to mitigate the cardiac contractile dysfunction that follows brief periods of ischemia ("myocardial stunning"). Stunning decreases contractility at the level of the contractile proteins; therefore, we asked whether antioxidant treatment preserves myofilament Ca2+ responsiveness after global ischemia and reflow. Right ventricular trabeculae were dissected from rat hearts subjected either to 20 minutes ischemia and reperfusion in the absence of drugs (stunned group) or to the same protocol in the presence of allopurinol, an inhibitor of xanthine oxidase (XO), and mercaptopropionylglycine (MPG), a hydroxyl radical scavenger (antioxidant group). At 20 minutes of reflow, isovolumic developed pressure recovered completely in the antioxidant group, but in the stunned group it recovered by only 57%. [Ca2+]i and contractile force measurements in trabeculae revealed the expected depression of myofilament function in the stunned group, with no change in Ca2+ transients relative to nonischemic controls. In contrast, Ca2+ transients were smaller, but force was greater, in the antioxidant group relative to both the stunned group and to nonischemic controls. Steady-state [Ca2+]i-force relationships revealed a striking increase of maximal force and a modest shift of activation to a lower range of [Ca2+]i. The increase in maximal force was reproduced by allopurinol+MPG or by allopurinol alone under nonischemic conditions and also by oxypurinol (100 micromol/L), a potent inhibitor of XO. We conclude that allopurinol and oxypurinol sensitize the cardiac myofilaments to Ca2+. This Ca2+-sensitizing effect underlies the preservation of contractility observed with an allopurinol+MPG antioxidant cocktail in a model of stunned myocardium. These serendipitous findings identify allopurinol and oxypurinol as the lead compounds of a novel class of inotropic agents.
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PMID:Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. 972 99

Methotrexate (MTX) was investigated for possible effect on the metabolism of ethoxyresorufin, pentoxyresorufin and ethoxycoumarin, the model substrates of cytochrome P450. The investigation was carried out in liver microsomes of rats pretreated with classical inducers of cytochrome P450 as well as in microsomes of two human livers. Furthermore, we measured the conversion of MTX (100microM) to its main metabolite, 7-hydroxymethotrexate (7-OHMTX), in microsomes and cytosolic fractions of rat and human livers. The inhibition of 7-OHMTX formation by menadion (inhibitor of aldehyde oxidase) and allopurinol (inhibitor of xanthine oxidase) was studied in the cytosol of rat and human livers. In both species, MTX in the concentration range 0.5-500 microM exerted no inhibitory effect on enzymatic activities associated with cytochrome P450. Moreover, we did not observe any measurable formation of 7-OHMTX in liver microsomes. MTX was metabolized at a similar rate in the cytosol of rat and human liver. Allopurinol (100 microM) reduced the rate of MTX hydroxylation by 31.5% in the cytosol of human livers but had no effect in the rat. Menadion (100 microM) decreased the rate of 7-OHMTX formation in the cytosol of human and rat liver by 69% and 94%, respectively. Our results confirmed that MTX is oxidized by a soluble enzymatic system in both the rat and human liver. In human tissues, both aldehyde oxidase and xanthine oxidase may play an important role in the metabolism of MTX. Depression of cytochrome P450 and related enzymatic activities observed in vivo cannot be explained by a direct inhibitory action of MTX on cytochrome P450.
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PMID:An in vitro study on methotrexate hydroxylation in rat and human liver. 972 83

The roles of enzymatic antioxidant defenses in the natural tolerance of environmental stresses that impose changes in oxygen availability and oxygen consumption on animals is discussed with a particular focus on the biochemistry of estivation and metabolic depression in pulmonate land snails. Despite reduced oxygen consumption and PO2 during estivation, which should also mean reduced production of oxyradicals, the activities of antioxidant enzymes, such as superoxide dismutase and catalase, increased in 30 day-estivating snails. This appears to be an adaptation that allows the snails to deal with oxidative stress that takes place during arousal when PO2 and oxygen consumption rise rapidly. Indeed, oxidative stress was indicated by increased levels of lipid peroxidation damage products accumulating in hepatopancreas within minutes after arousal was initiated. The various metabolic sites responsible for free radical generation during arousal are still unknown but it seems unlikely that the enzyme xanthine oxidase plays any substantial role in this despite being implicated in oxidative stress in mammalian models of ischemia/reperfusion. We propose that the activation of antioxidant defenses in the organs of Otala lactea during estivation is a preparative mechanism against oxidative stress during arousal. Increased activities of antioxidant enzymes have also observed under other stress situations in which the actual production of oxyradicals should decrease. For example, antioxidant defenses are enhanced during anoxia exposure in garter snakes Thamnophis sirtalis parietalis (10 h at 5 degrees C) and leopard frogs Rana pipiens (30 h at 5 degrees C) and during freezing exposure (an ischemic condition due to plasma freezing) in T. sirtalis parietalis and wood frogs Rana sylvatica. It seems that enhancement of antioxidant enzymes during either anoxia or freezing is used as a preparatory mechanism to deal with a physiological oxidative stress that occurs rapidly within the early minutes of recovery during reoxygenation or thawing. Thus, a wide range of stress tolerant animals display coordinated changes in antioxidant defenses that allow them to deal with oxidative stress that occurs as part of natural cycles of stress/recovery that alter oxygen levels in tissues. The molecular mechanisms that trigger and regulate changes in antioxidant enzyme activities in these species are still unknown but could prove to have key relevance for the development of new intervention strategies in the treatment of cardiovascular ischemia/reperfusion injuries in humans.
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PMID:Antioxidant defenses and metabolic depression. The hypothesis of preparation for oxidative stress in land snails. 978 4

BACKGROUND: Although oxygen free radicals have been shown to induce myocardial cell damage and cardiac dysfunction, the exact mechanism by which these radicals affect the heart function is not clear. Since the occurrence of intracellular Ca(2+) overload is critical in the genesis of cellular damage and cardiac dysfunction, and since the sarcolemmal Na(+)-Ca(2+) exchange is intimately involved in Ca(2+) movements in myocardium, this study was undertaken to examine the effects of oxygen free radicals on the relationship between changes in cardiac contractile force development and sarcolemmal Na(+)-Ca(2+) exchange activity. METHODS AND RESULTS: Isolated rat hearts were perfused with a medium containing xanthine plus xanthine oxidase for different times, and changes in contractile force as well as sarcolemmal Na(+)-(2+) exchange activity were monitored. Perfusion of the heart with xanthine plus xanthine oxidase resulted in a transient increase followed by a marked decrease in contractile activity; the resting tension was markedly increased. The xanthine plus xanthine oxidase-induced depression in developed tension, rate of contraction, and rate of relaxation, except the transient increase in contractile activity, was prevented by the addition of catalase, but not by superoxide dismutase, in the perfusion medium. A time-dependent depression in sarcolemmal Na(+)-Ca(2+) was also evident upon perfusing the heart with xanthine plus xanthine oxidase. This depression in Na(+)-dependent Ca(2+) uptake was associated with a decrease in the maximal velocity of reaction without any changes in the affinity of Na(+)-Ca(2+) exchanger for Ca(2+). The presence of catalase, unlike superoxide dismutase, prevented the decrease in sarcolemmal Na(+)-Ca(2+) exchange activity in hearts perfused with xanthine plus xanthine oxidase. CONCLUSIONS: The results support the view that a depression in the sarcolemmal Na(+)-Ca(2+) exchange activity may contribute to the occurrence of intracellular Ca(2+) overload and subsequent decrease in contractile activity. Furthermore, these actions of xanthine plus xanthine oxidase in the whole heart appear to be a consequence of H(2)O(2) production rather than the generation of superoxide radicals.
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PMID:Effect of Oxygen Free Radicals on Cardiac Contractile Activity and Sarcolemmal Na(+)-Ca(2+) Exchange. 1068 19

We have used an enzyme-based, twin-barrelled sensor to measure adenosine release during hypoxia in the CA1 region of rat hippocampal slices in conjunction with simultaneous extracellular field recordings of excitatory synaptic transmission. When loaded with a combination of adenosine deaminase, nucleoside phosphorylase and xanthine oxidase, the sensor responded linearly to exogenous adenosine over the concentration range 10 nM to 20 microM. Without enzymes, the sensor when placed on the surface of hippocampal slices recorded a very small net signal during hypoxia of 40 +/- 43 pA (mean +/- s.e.m.; n = 7). Only when one barrel was loaded with the complete sequence of enzymes and the other with the last two in the cascade did the sensor record a large net difference signal during hypoxia (1226 +/- 423 pA; n = 7). This signal increased progressively during the hypoxic episode, scaled with the hypoxic depression of the simultaneously recorded field excitatory postsynaptic potential and was greatly reduced (67 +/- 6.5 %; n = 9) by coformycin (0.5-2 microM), a selective inhibitor of adenosine deaminase, the first enzyme in the enzymic cascade within the sensor. For 5 min hypoxic episodes, the sensor recorded a peak concentration of adenosine of 5.6 +/- 1.2 microM (n = 16) with an IC(50) for the depression of transmission of approximately 3 microM. In slices pre-incubated for 3-6 h in nominally Ca(2+)-free artificial cerebrospinal fluid, 5 min of hypoxia resulted in an approximately 9-fold greater release of adenosine (48.9 +/- 17.7 microM; n = 6). High extracellular Ca(2+) (4 mM) both reduced the adenosine signal recorded by the sensor during hypoxia (3.5 +/- 0.6 microM; n = 4) and delayed the hypoxic depression of excitatory synaptic transmission.
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PMID:Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice. 1087 7

Proinflammatory cytokines depress myocardial contractile function by enhancing the expression of inducible NO synthase (iNOS), yet the mechanism of iNOS-mediated myocardial injury is not clear. As the reaction of NO with superoxide to form peroxynitrite markedly enhances the toxicity of NO, we hypothesized that peroxynitrite itself is responsible for cytokine-induced cardiac depression. Isolated working rat hearts were perfused for 120 minutes with buffer containing interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha. Cardiac mechanical function and myocardial iNOS, xanthine oxidoreductase (XOR), and NAD(P)H oxidase activities (sources of superoxide) were measured during the perfusion. Cytokines induced a marked decline in myocardial contractile function accompanied by enhanced activity of myocardial XOR, NADH oxidase, and iNOS. Cardiac NO content, myocardial superoxide production, and perfusate nitrotyrosine and dityrosine levels, markers of peroxynitrite, were increased in cytokine-treated hearts. The peroxynitrite decomposition catalyst FeTPPS (5,10,15, 20-tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III]), the NO synthase inhibitor N(G)-nitro-L-arginine, and the superoxide scavenger tiron each inhibited the decline in myocardial function and decreased perfusate nitrotyrosine levels. Proinflammatory cytokines stimulate the concerted enhancement in superoxide and NO-generating activities in the heart, thereby enhancing peroxynitrite generation, which causes myocardial contractile failure.
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PMID:Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. 1092 63

Phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2) is the substrate for phosphoinositide-phospholipase C (PLC) and is required for the function of several cardiac cell plasma membrane (sarcolemma, SL) proteins. PtdIns 4,5-P2 is synthesized in the SL membrane by coordinated and successive actions of PtdIns 4-kinase and PtdIns 4-phosphate 5-kinase. These kinases and the generation of PtdIns 4,5-P2 may be a factor in the cardiac dysfunction during pathophysiological conditions of oxidative stress. Therefore, we examined the effects of different reactive oxygen species (ROS) on the kinases' activities and subsequent generation of PtdIns 4,5-P2. Exposure to the xanthine-xanthine oxidase-ROS generating system significantly reduced both SL kinase activities. Superoxide dismutase did not prevent this inhibition; however, catalase significantly prevented the xanthine-xanthine oxidase induced inhibition. Treatment of SL with hydrogen peroxide (H2O2) resulted in inhibition of both the kinases, which was prevented by catalase and dithiothreitol (DTT). Hypochlorous acid also inhibited both the kinases, which was prevented by DTT. Deferoxamine (an iron chelator) and mannitol (an *OH scavenger) did not modify the H2O2-induced depression of the kinases, eliminating any role of *OH. Furthermore, the IC50 of H2O2 on PtdIns 4-kinase and PtdIns 4-P 5-kinase was 27 and 81 microM, respectively. In addition, inclusion of reduced glutathione in the assay of the kinases in the absence of H2O2 did not affect the activities of the kinases; however, oxidized glutathione induced a significant depression. Also, a significant decline of the PtdIns 4-kinase and PtdIns 4-P 5-kinase activities due to changing of the redox ratio was observed. Thiol modifiers (N-ethylmaleimide, methyl methanethiosulfonate, or p-chloromercuriphenylsulfonic acid) were detected to depress the kinases' activities, which were substantially prevented by DTT. The results suggest that functionally critical thiol groups may be associated with PtdIns 4-kinase and PtdIns 4-P 5-kinase and that changes of their redox state by ROS can impair their activities, which may be an important factor in the oxidant-induced cardiac dysfunction.
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PMID:Oxidants depress the synthesis of phosphatidylinositol 4,5-bisphosphate in heart sarcolemma. 1105 Oct 96

Reactive oxygen species contribute to diaphragm dysfunction in certain pathophysiological conditions (i.e., sepsis and fatigue). However, the precise alterations induced by reactive oxygen species or the specific species that are responsible for the derangements in skeletal muscle function are incompletely understood. In this study, we evaluated the effect of the superoxide anion radical (O(2)(-).), hydroxyl radical (.OH), and hydrogen peroxide (H(2)O(2)) on maximum calcium-activated force (F(max)) and calcium sensitivity of the contractile apparatus in chemically skinned (Triton X-100) single rat diaphragm fibers. O(2)(-). was generated using the xanthine/xanthine oxidase system;.OH was generated using 1 mM FeCl(2), 1 mM ascorbate, and 1 mM H(2)O(2); and H(2)O(2) was added directly to the bathing medium. Exposure to O(2)(-). or.OH significantly decreased F(max) by 14.5% (P < 0.05) and 43.9% (P < 0. 005), respectively.OH had no effect on Ca(2+) sensitivity. Neither 10 nor 1,000 microM H(2)O(2) significantly altered F(max) or Ca(2+) sensitivity. We conclude that the diaphragm is susceptible to alterations induced by a direct effect of.OH and O(2)(-)., but not H(2)O(2), on the contractile proteins, which could, in part, be responsible for prolonged depression in contractility associated with respiratory muscle dysfunction in certain pathophysiological conditions.
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PMID:Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. 1113 92

St. John's wort (Hypericum perforatum) is an herbal compound used in the treatment of burns, bruises, swelling, anxiety, and most recently, mild to moderate depression. The present study was designed to evaluate the antioxidant properties of St. John's wort in both cell-free and human vascular tissue. The experiment was performed initially in a cell-free system using Krebs buffer and a combination of xanthine/xanthine oxidase to initiate the production of the superoxide radical. Additionally, human placental vein was incubated in Krebs buffer without xanthine or xanthine oxidase to study the effects of St. John's wort on human tissue in vitro. Commercially available formulations of St. John's wort, standardized to either hypericin or hyperforin, were dissolved in an alkaline solution, and the following dilutions were made: 1:1, 1:2.5, 1:5, 1:7.5, 1:10, and 1:20. Lucigenin chemiluminescence was used to measure free radical production in both systems. A pro-oxidant effect was seen at the highest concentration, 1:1. Lower concentrations revealed antioxidant properties of the compound. All dilutions below 1:1 in both systems showed a dose-related inverse relationship of superoxide inhibition. The largest suppression was seen at the most dilute concentration, 1:20. The addition of 10(-3) M tiron inhibited the chemiluminescence signal, thereby confirming the production of superoxide. The results of this study suggest that St. John's wort inhibits free radical production in both cell-free and human vascular tissue.
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PMID:Effect of St. John's wort on free radical production. 1144 8

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.
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PMID:Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. 1186 18

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