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

This investigation aimed to determine whether contractile dysfunction of the myocardium could be produced upon generation of free radicals in the anaesthetised rat. The enzyme xanthine oxidase, combined with its substrate purine and an iron source, was used to generate free radicals in the venous circulation. The suspended form of xanthine oxidase, with substrate, produced a transient, significant depression in the contractile indices dP dt-1 max and dP dt-1 P-1 and arterial blood pressure, 1146 +/- 87 mm Hg s-1, 9 +/- 1 s-1, and 18 +/- 1 mm Hg, respectively. This could not be attenuated by the enzymatic free radical scavengers superoxide dismutase and catalase. Furthermore, the suspended xanthine oxidase alone or its vehicle were able to produce a similar effect to that of the complete free-radical-generating system. The maximum soluble dose of the crystalline form of the enzyme when employed in the generating system had no effect upon administration despite its production of superoxide radicals in vitro. These results suggest that the haemodynamic effects of the free-radical-generating system containing the suspended form of xanthine oxidase were due to the effects of its vehicle and that the free-radical-generating system containing the crystalline form of the enzyme did not produce sufficient free radicals in vivo to modify myocardial contractility.
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PMID:Effects of the xanthine oxidase system on cardiac function in anaesthetised rats. 840 24

This study evaluated the contribution of O2 free radicals to changes in cardiac function after burn injury. Full-thickness scald burns comprising 42% of the total body surface area were produced in rats. Mean arterial pressure, heart rate, pH, cardiac transmembrane potential (Ling Gerard electrode, Em), myocardial ATP, creatine phosphate (CP), glucose 6-phosphate, and lactate were measured enzymatically 24 hr postburn in four groups: Group 1, sham burn controls, N = 12; Group 2, untreated burn injury, N = 14; Group 3, N = 10, burn injury resuscitated with Ringer's lactate (Parkland formula); Group 4, burns pretreated with oral allopurinol (10 mg/kg) for 5 days before burn injury, N = 11. In vitro cardiac contractile function was assessed 24 hr after burn injury in additional animals (N = 8) from each of the four experimental groups. Untreated burn injury caused hypotension, bradycardia, depolarization of the cardiac cell membrane (Em fell from 78.5 +/- 0.4 to 66.8 +/- 0.4, P < 0.05), and left ventricular contractile depression despite no significant fall in cardiac ATP content. In contrast, cardiac tissue CP fell and myocardial tissue lactate rose. Allopurinol pretreatment oblated burn-induced hypotension, bradycardia, and cardiac cell membrane depolarization and improved cardiac contractile function despite no fluid resuscitation from burn injury. In contrast, aggressive fluid resuscitation from burn injury (Group 3) repolarized cardiac cell membrane but did not reverse burn-induced cardiac contractile deficits. These data suggest that xanthine oxidase-mediated free radical production contributes, in part, to postburn alterations in cardiac function.
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PMID:Oxygen free radicals contribute to postburn cardiac cell membrane dysfunction. 876 49

Incubation of endothelium-denuded rings of rat aorta at 37 degrees C for 18 hours in Krebs solution led to a profound depression of the contractile actions of phenylephrine (1 nM-10 mu M). A major component of this depression of vasoconstriction was due to the relaxant actions of nitric oxide since it was reversed following inhibition of the synthesis of nitric oxide with N(G)-nitro-L-arginine methyl ester or its actions with haemoglobin (30 microM) or methylene blue (10 mu M). The depression was also reversed upon treatment with LY83583 (0.1-1 microM which generates superoxide anions, intracellularly and extracellularly, but was unaffected by hypoxanthine (100 microM)/ xanthine oxidase (16 mu/ml) which generates superoxide anion only extracellularly. The ability of polymixin B (30 microM) to inhibit the development of the depression of vasoconstriction suggests that it results from the expression of an inducible form of nitric oxide synthase, stimulated by bacterial lipopolysaccharide, contaminating the Krebs solution. In contrast to aortic rings, we found that lipopolysaccharide (10-10,000 ng/ml) alone from S. typhosa was unable to stimulate the expression of the inducible form of nitric oxide synthase in rat aortic smooth muscle cells grown in culture from explant, as assessed either by measuring the accumulation of nitrite into the culture medium during a 24 hour incubation period or by measuring the smooth muscle cyclic GMP content. Interferon-gamma (1-100 IU/ml) and interleukin-1 alpha (1-10 IU/ml) alone were, however, able to stimulate the accumulation of nitrite in a concentration-dependent manner. These inductions of nitrite accumulation were abolished following treatment with N(G)-nitro-(L)-arginine methyl ester (1 mM) and dexamethasone (1 microM). Further investigations are required to determine whether the ability of bacterial lipopolysaccharide to induce the inducible form of nitric oxide synthase in rat aortic rings, but not in rat aortic smooth muscle cells in culture, results from the presence of an endotoxin-sensitive, cytokine-secreting cell type in the vessel wall which is absent in culture, or from differences in smooth muscle phenotype in situ and in culture.
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PMID:Induction of nitric oxide synthase by endotoxin in rat isolated aorta but not in rat aortic smooth muscle cells grown in culture from explant. 886 13

Although in vitro studies have shown that oxygen free radicals depress the sarcolemmal Ca(2+)-pump activity and thereby may cause the occurrence of intracellular Ca2+ overload for the genesis of contractile failure, the exact relationship between changes in sarcolemmal Ca(2+)-pump activity and cardiac function due to these radicals is not clear. In this study we examined the effects of oxygen radicals on sarcolemmal Ca2+ uptake and Ca(2+)-stimulated ATPase activities as well as contractile force development by employing isolated rat heart preparations. When hearts were perfused with medium containing xanthine plus xanthine oxidase, the sarcolemmal Ca(2+)-stimulated ATPase activity and ATP-dependent Ca2+ accumulation were depressed within 1 min whereas the developed contractile force, rate of contraction and rate of relaxation were increased at 1 min and decreased over 3-20 min of perfusion. The resting tension started increasing at 2 min of perfusion with xanthine plus xanthine oxidase. Catalase showed protective effects against these alterations in heart function and sarcolemmal Ca(2+)-pump activities upon perfusion with xanthine plus xanthine oxidase whereas superoxide dismutase did not exert such effects. The combination of catalase and superoxide dismutase did not produce greater effects in comparison to catalase alone. These results are consistent with the view that the depression of heart sarcolemmal Ca2+ pump activities may result in myocardial dysfunction due to the formation of hydrogen peroxide and/or hydroxyl radicals upon perfusing the hearts with xanthine plus xanthine oxidase.
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PMID:Relationship between mechanical dysfunction and depression of sarcolemmal Ca(2+)-pump activity in hearts perfused with oxygen free radicals. 890 72

Sodium-hydrogen exchange (NHE) represents an important process mediating myocardial ischemic and reperfusion injury, and NHE inhibitors have been shown to be effective cardioprotective agents against this form of injury. The precise mechanisms by which NHE inhibition protect the heart are not known and we therefore postulated that attenuation of oxidative stress could contribute to such protection. Accordingly, we examined whether the potent and specific NHE inhibitor 4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate (HOE 642, 5 microM) can protect isolated rat hearts against mechanical and biochemical impairment produced by either hydrogen peroxide (150 or 200 microM) or a free radical generating system consisting of purine (4.6 or 9.2 mM) and xanthine oxidase (20 or 40 U/L). HOE 642 significantly delayed and attenuated both the depression in left ventricular developed pressure (LVDP) as well as the elevation in left ventricular end-diastolic pressure (LVEDP) produced by both concentrations of hydrogen peroxide, although greater protection was generally seen against the lower hydrogen peroxide concentration, particularly with respect to LVEDP. Hydrogen peroxide, at both concentrations, significantly reduced high energy phosphate and glycogen contents and elevated lactate levels, all of which were significantly attenuated by HOE 642. In contrast, HOE 642 had no effect on functional impairment produced by either concentration of the free radical generating system. At its lower concentration, the combination of purine plus xanthine oxidase had no effect on energy metabolites, although a significant reduction in high energy phosphate stores was seen with the higher concentration. However, this was unaffected by HOE 642. The protective effect of HOE 642 was mimicked by another NHE inhibitor, methylisobutylamiloride (MIA, 5 microM). Our study therefore shows that NHE inhibition selectively protects against functional and metabolic impairment produced by hydrogen peroxide. Since hydrogen peroxide formation has been implicated in the development of ischemic and reperfusion injury, it is possible that the protective effect of NHE inhibition against this form of oxidative stress may explain in part the basis for the well-established salutary actions of NHE inhibitors in the ischemic and reperfused myocardium. Since HOE 642 failed to modify the response to free radical generators, it is unlikely that the protective effects of NHE inhibitors can be explained by a free radical scavenging mechanism.
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PMID:Effect of sodium-hydrogen exchange inhibition on functional and metabolic impairment produced by oxidative stress in the isolated rat heart. 919 59

Acidosis during exercise has long been associated with skeletal muscle fatigue. Recent evidence also has linked reactive oxygen species (ROS) with fatigue in skeletal muscle, including the diaphragm. We hypothesized that acidosis (designed to mimic blood pH during maximal exercise) would worsen ROS-induced depression of diaphragm contractility. The xanthine oxidase (XO) reaction in solution (0.01 U/ml) allows direct assessment of the effects of oxidant stress by ROS. Costal diaphragm fiber bundles from 24 Sprague-Dawley rats (200-250 g) were divided into four treatment groups: 1) pH 7.4, no XO (H); 2) pH 7.4 + XO (HXO); 3) pH 7.0, no XO (L); and 4) pH 7.0 + XO (LXO). Baseline twitch mechanics and force-frequency relationships (Pre) were determined in control Krebs solution (pH 7.4, no XO) before treatment. Treatment solutions were introduced, and the diaphragm underwent 2 min of contractions at 25 Hz (250 ms) at a rate of 1/s. After 10 min of recovery, the control solution was reintroduced into the bath and postcontractile function (Post) was measured. Significant reductions in twitch tension and low-frequency tetanic tension were greater in HXO and LXO compared with H, without an effect on maximal tetanic tension. One-half relaxation time was prolonged only by the combination of acidosis and oxidative stress. Addition of superoxide dismutase (50 U/ml) worsened and catalase (1,800 U/ml) attenuated XO-induced depression of diaphragm contractility. We concluded that XO induced a reduction of low-frequency tension in the fatigued diaphragm, which was mediated directly or indirectly through hydrogen peroxide and was exacerbated to a modest extent with acidosis.
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PMID:Effect of oxidative stress and acidosis on diaphragm contractile function. 927 48

The aim of this study was to examine and compare the potential influence of cyclooxygenase or lipoxygenase derived metabolites of arachidonic acid on myocardial injury produced either by a free radical generating system consisting of purine plus xanthine oxidase or that produced by hydrogen peroxide. A free radical generating system consisting of purine (2.3 mM) and xanthine oxidase (10 U/L) as well as hydrogen peroxide (75 microM) produced significant functional changes in the absence of either significant deficits in high energy phosphates or ultrastructural damage. Prostaglandin F2 alpha (30 nM) significantly attenuated both the negative inotropic effect of purine plus xanthine oxidase as well as the ability of the free radical generator to elevate diastolic pressure. An identical concentration of prostaglandin 12 (prostacyclin) significantly reduced diastolic pressure elevation only and had no effect on contractile depression. The salutary effects of the two PGs occurred in the absence of any inhibitory influence on superoxide anion generation produced by the purine and xanthine oxidase reaction. None of prostaglandins modulated the response to hydrogen peroxide. In addition, neither prostaglandin E2 nor leukotrienes exerted any effect on changes produced by either type of oxidative stress. A 5 fold elevation in the concentrations of free radical generators or hydrogen peroxide produced extensive injury as characterized by a virtual total loss in contractility, 400% elevation in diastolic pressure, ultrastructural damage and significant depletions in high energy phosphate content. None of these effects were modulated by eicosanoid treatment. Our results therefore demonstrate a selective ability of both prostaglandin F2 alpha and to a lesser extent prostacyclin, to attenuate dysfunction produced by purine plus xanthine oxidase but not hydrogen peroxide. It is possible that these eicosanoids may represent endogenous protective factors under conditions of enhanced oxidative stress associated with superoxide anion generation.
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PMID:Prostaglandins attenuate cardiac contractile dysfunction produced by free radical generation but not by hydrogen peroxide. 940 59

Reactive free radical species appear to be involved in the ischemic injury of cardiac muscle, although the mechanisms by which oxygen-derived free radicals affect the heart cell function are not known. In the present study, cultured ventricular myocytes were exposed to an exogenous oxygen radical generating system. The myocyte-enriched, primary cultures were prepared from ventricles of new-born rat heart and exposed to a xanthine/xanthine oxidase (X+XO) system. The transmembrane potentials were recorded with glass microelectrodes. Cell contractions were monitored photometrically. The release of lactate dehydrogenase (LDH) in the medium was analysed. Quantitative measurement and the time course of the radical generation were performed by the electron paramagnetic resonance (EPR) spin trapping technique with the spin trap 5,5-dimethyl-1-pyroline-N-oxide (DMPO). We verified that X and XO alone had no significant functional and biochemical effects. The X+XO system produced a rapid decrease in the action potential amplitude. This effect was accompanied by a strong decrease in contractility and spontaneous rate. The time course of these functional defects were correlated with a progressive efflux of LDH from the cardiomyocytes. Prolonging the exposure to the X+XO system provoked the cessation of the spontaneous beatings and the progressive loss of the resting diastolic potential, together with a near total release of the cellular LDH. The LDH release and the functional depression were both efficiently prevented by catalase. On the contrary, superoxide dismutase (SOD) slowed down but did not protect against the functional and biochemical effects of the free radicals. In comparison, the EPR spectra obtained indicated that the X+XO system was associated with an important generation of superoxide anions but also with a small hydroxyl production. SOD scavenged the superoxide but a small .OH production persisted. Catalase (CAT) did not modify the superoxide generation but decreased the hydroxyl adduct formation. These results suggest that, although the generation of superoxide anions by the X+XO system was higher than the hydroxyl production, the functional injury and enzyme leakage seemed mainly mediated through a hydrogen peroxide-hydroxyl radical pathway. Cultured ventricular myocytes can be thus used as a valuable model to investigate the cellular mechanism of oxidant-induced damage in the heart.
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PMID:Correlation between direct ESR spectroscopic measurements and electromechanical and biochemical assessments of exogenous free radical injury in isolated rat cardiac myocytes. 943 21

Activation of ATP-sensitive (KATP) channels has been shown to exert protective effects on the ischemic and reperfused myocardium. Reactive oxygen species are thought to mediate, at least in part, this form of cardiac injury. Using isolated perfused rat hearts, we therefore studied whether KATP activation exerts any effect on the direct deleterious effects of either 200 microM hydrogen peroxide or a free radical generating system consisting of purine plus xanthine oxidase in terms of function and energy metabolite status. On their own, hydrogen peroxide or the combination of purine plus xanthine oxidase treatment resulted in a time-dependent depression of myocardial contractility, which reached over 90% after 30 min perfusion, an effect which was associated with approximately 1000% elevation in left ventricular end-diastolic pressure (LVEDP). The KATP channel opener cromakalim (0.5 microM) significantly attenuated the hydrogen peroxide-induced loss in systolic function throughout the treatment period, and reduced the elevation in LVEDP with significant attenuation 10, 15 and 20 min after hydrogen peroxide addition. Contractile dysfunction produced by hydrogen peroxide was associated with significantly reduced tissue ATP, creatine phosphate and glycogen content to approximately 70, 60 and 70% of control, respectively. The depletion of these metabolites was significantly attenuated to 35, 23 and 23% of control, respectively, in the presence of cromakalim. The protective effects of cromakalim against contractile dysfunction, as well as depletion in intermediary energy metabolites, was abolished in the presence of the KATP channel antagonist glibenclamide (1 microM). However, glibenclamide on its own failed to alter the cardiac response to hydrogen peroxide with respect to any parameter. The responses to the free radical generating system consisting of purine plus xanthine oxidase was unaffected by cromakalim. Our study shows that KATP channel activation selectively protects against the cardiotoxic influence of hydrogen peroxide, and may explain, in part, the salutary effects of KATP activators in myocardial ischemia.
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PMID:Protective effects against hydrogen peroxide-induced toxicity by activators of the ATP-sensitive potassium channel in isolated rat hearts. 950 Aug 62

To study the mechanism of the protective effect of gamma-glutamylcysteine ethyl ester, mitochondrial creatine kinase activity of rat heart was measured. Gamma-glutamylcysteine ethyl ester had a protective effect against the depression of creatine kinase activity induced by xanthine + xanthine oxidase or hydrogen peroxide. Gamma-glutamylcysteine ethyl ester also prevented the depression of creatine kinase activity induced by N-ethylmaleimide. It is suggested that the protective effect of gamma-glutamylcysteine ethyl ester is related to oxygen free radicals or to reduction of the sulfhydryl groups of the enzyme which were previously oxidized by oxygen free radicals.
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PMID:Effects of gamma-glutamylcysteine ethyl ester on heart mitochondrial creatine kinase activity: involvement of sulfhydryl groups. 966 7


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