UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Species-related differences in the mechanisms of noradrenaline release during normoxia and myocardial ischemia emphasize the need for studies on human hearts. Therefore, the mechanisms of noradrenaline release were investigated during normoxia and energy depletion in incubated human atrial tissue and compared to the release characteristics in normoxic and ischemic rat heart. Potential differences of atrial versus ventricular myocardium were assessed by comparing catecholamine release during electrical stimulation and ischemia in isolated rat atrium with release characteristics in the intact perfused heart. The overflow of endogenous noradrenaline and its deaminated metabolite dihydroxyphenylethyleneglycol (DOPEG) were determined by high pressure liquid chromatography and electrochemical detection. During normoxia noradrenaline release was evoked by electrical field stimulation. Stimulation-induced noradrenaline release depended on the extracellular calcium concentration in both species and was almost completely suppressed under calcium-free conditions. The release was significantly inhibited by neuronal (N-type) calcium channel blockers such as omega-conotoxin (100 nmol/l) and cadmium chloride (100 mumol/l), indicating a predominant role of N-type calcium channels in exocytotic noradrenaline release from sympathetic neurons in human and rat heart. Desipramine (100 nmol/l) enhanced the overflow of noradrenaline evoked by electrical stimulation in both species by blocking neuronal catecholamine uptake (uptake1). Myocardial ischemia was caused by interruption of perfusion flow in rat heart and simulated by anoxic and glucose-free incubation in human and rat atrial tissue. Ischemia- and anoxia-induced noradrenaline release in rat heart and human atrial tissue was unaffected by varying extracellular calcium concentrations and occurred even after omission of calcium and addition of EGTA (1 mmol/l). In both species neither omega-conotoxin (100 nmol/l) nor cadmium chloride (100 mumol/l) affected ischemia-induced noradrenaline overflow in both rat heart and atrium as well as in human atrium. In human and rat atrial tissue, blockade of energy metabolism in the presence of oxygen (cyanide model) resulted in a desipramine-sensitive release of noradrenaline, which was accompanied by DOPEG overflow, indicating increased axoplasmic noradrenaline concentration. The data imply a dual mechanism of noradrenaline release in the human heart. During normoxia noradrenaline release is modulated by neuronal calcium influx indicating exocytotic release. Ischemia-induced noradrenaline release, however, is independent of calcium and inhibited by uptake1 blockade suggesting nonexocytotic release mechanism. The characteristics of noradrenaline release in human atrial tissue provide evidence for carrier-mediated release of noradrenaline from sympathetic neurons operative in the ischemic human myocardium.
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PMID:Two different mechanisms of noradrenaline release during normoxia and simulated ischemia in human cardiac tissue. 747 74

A sustained high voltage-activated (HVA), nifedipine- and cadmium-sensitive calcium current and a sustained calcium action potential (AP) were recorded from horizontal cells isolated from catfish retina. pH indicator dyes showed that superfusion with NH4Cl alkalinized these cells and that washout of NH4Cl or superfusion with Na-acetate acidified them. HVA current was slightly enhanced during superfusion of NH4Cl but was suppressed upon NH4Cl washout or application of Na-acetate. When 25 mM HEPES was added to the patch pipette to increase intracellular pH buffering, the effects of NH4Cl and Na-acetate on HVA current were reduced. These results indicated that intracellular acidification reduces HVA calcium current and alkalinization increases it. Sustained APs, recorded with high resistance, small diameter microelectrodes, were blocked by cobalt and cadmium and their magnitude varied with extracellular calcium concentration. These results provide confirmatory evidence that the HVA current is a major component of the AP and indicate that the AP can be used as a measure of how the HVA current can be modified in intact, undialyzed cells. The duration of APs was increased by superfusion with NH4Cl and reduced by washout of NH4Cl or superfusion with Na-acetate. The Na-acetate and NH4Cl washout-dependent shortening of the APs was observed in the presence of intracellular BAPTA, a calcium chelator, IBMX, a phosphodiesterase inhibitor, and in Na-free or TEA-enriched saline. These findings provide supportive evidence that intracellular acidification may directly suppress the HVA calcium current in intact cells. Intracellular pH changes would thereby be expected to modulate not only the resting membrane potential of these cells in darkness, but calcium-dependent release of neurotransmitter from these cells as well. Furthermore, this acidification-dependent suppression of calcium current could serve a protective role by reducing calcium entry during retinal ischemia, which is usually thought to be accompanied by intracellular acidosis.
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PMID:Modulation of a sustained calcium current by intracellular pH in horizontal cells of fish retina. 768 44

Gerbil cerebral cortical synaptosomes loaded with the fluorescent calcium probe FURA-2 were used to study depolarization-induced presynaptic cytosolic free calcium concentration, as an in vitro model of cerebral ischemia. The depolarization-induced increase in intrasynaptosomal cytosolic free calcium concentration is not sodium-dependent or sodium channel-dependent and may be due to an influx of extrasynaptosomal calcium resulting from a cadmium- and omega-conotoxin-sensitive, nickel-, nifedipine-, and nimodipine-insensitive voltage-regulated channel. The depolarization-induced increase in intrasynaptosomal free cytosolic calcium concentration is also inhibited by flunarizine, a calcium antagonist that has protective effects in animal models of cerebral anoxia and ischemia. Our results suggest that presynaptic calcium uptake following depolarization may be mediated in part by an N-type channel. Flunarizine may block presynaptic calcium accumulation, in part, by blocking this N-type channel; this blockade may be just one of several mechanisms by which flunarizine exerts protective effects following cerebral ischemia.
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PMID:Flunarizine blocks elevation of free cytosolic calcium in synaptosomes following sustained depolarization. 840 19

The effects of cadmium chloride on both incisor and molar teeth of ovariectomized female rats were studied histopathologically. The rats were injected intravenously with the compound at doses of 1.0 and 2.0 mg/kg, 5 days/wk. Six rats per group were sacrificed at 4, 8, and 13 wk. Discoloration of the incisors was observed in the rats of the 2.0-mg/kg group from 8 wk. Histopathologic examination of the incisor demonstrated decreased iron-containing pigment in ameloblasts and destruction of the enamel organ. These changes were accompanied with accumulation of cadmium and loss of iron in the teeth. Necrosis of the dental pulp occurred from the coronal end of both the incisor and molar teeth extended to the apical, deep portion of the teeth. The dental pulp of the molar teeth, which is shorter than that of the incisor, was mildly affected by cadmium intoxication. These findings suggested that intradental ischemia due to cadmium toxicity may have contributed to the development of the pulpal necrosis.
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PMID:Cadmium-induced dental lesions in ovariectomized rats. 886 86

Ischemia and simulated ischemic conditions induce enhanced release of norepinephrine (NE) in the brain and the heart. Although studies with neuronal preparations demonstrated a rise in [Ca2+]i under energy-depleted conditions, such release of NE in the heart appears to be predominantly Ca2+ independent. Since Ca2+ overload occurs in ischemia or energy depletion and since a rise in [Ca2+]i triggers exocytosis without membrane depolarization, we tested the possibility, using brain synaptosomes, that increased NE release could be, at least in part, a consequence of raised [Ca2+]i. Brain synaptosomes were incubated with Krebs-Henseleit medium, and ischemia was mimicked by treatment with metabolic inhibitors. NE content in incubation medium (supernatant) and synaptosomes was analyzed chromatographically. Treatment with metabolic inhibitors reduced ATP content by 75% and increased [Ca2+]i by more than fourfold within minutes. Metabolic inhibition elicited NE release, which started within 10 minutes and reached a maximum after 30 minutes, with a corresponding 55% reduction in synaptosomal NE content after 40 minutes. NE release, together with a marked increase in [Ca2+]i, was also induced in energy-depleted synaptosomes by Ca2+ repletion after incubation with the Ca(2+)-free medium. Effects on NE release of various interventions to prevent Ca2+ overload were tested. Omission of Ca2+ from the incubation medium or loading synaptosomes with the Ca2+ chelator BAPTA-AM (20 and 100 mumol/L) prevented NE release, indicating a Ca(2+)-dependent mechanism. Inhibition of Ca2+ channels with omega-conotoxin, cadmium, or nifedipine had no effect on NE release during energy depletion. In contrast, nickel and 3,4-dichlorobenzamil, Na(+)-Ca2+ exchange inhibitors, dose-dependently inhibited NE release. In conclusion, this study provides evidence that under energy-depleted conditions, Ca2+ overload in synaptosomes of noradrenergic neurons from the brain is an important mechanism for the enhanced release of NE and that a reversal of Na(+)-Ca2+ exchange may be the key pathway leading to intraneuronal Ca2+ overload.
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PMID:Role of Ca2+ in metabolic inhibition-induced norepinephrine release in rat brain synaptosomes. 901 40

Plasmalogen rather than diacyl phospholipids are the preferred substrate for the cardiac phospholipase A2 (PLA2) isoform activated during ischemia. The diacyl metabolite, lysophosphatidylcholine, is arrhythmogenic, but the effects of the plasmalogen metabolite, lysoplasmenylcholine (LPLC), are essentially unknown. We found that 2.5 and 5 micromol/L LPLC induced spontaneous contractions of intact isolated rabbit ventricular myocytes (median times, 27.4 and 16.4 minutes, respectively) significantly faster than lysophosphatidylcholine (>60 and 37.8 minutes, respectively). Whole-cell recordings revealed that LPLC depolarized the resting membrane potential from -83.5+/-0.2 to -21.5+/-1.0 mV. Depolarization was due to a guanidinium toxin-insensitive Na+ influx. The LPLC-induced current reversed at -18.5+/-0.9 mV and was shifted 26.7+/-4.2 mV negative by a 10-fold reduction of bath Na+ (Na+/K+ permeability ratio, approximately 0.12+/-0.06). In contrast, block of Ca2+ channels with Cd2+ and reducing bath Cl failed to affect the current. The actions of LPLC were opposed by lanthanides. Gd3+ and La3+ were equally effective inhibitors of the LPLC-induced current and equally delayed the onset of spontaneous contractions. However, the characteristics of lanthanide block imply that Gd3+-sensitive, poorly selective, stretch-activated channels were not involved. Instead, the data are consistent with the view that lanthanides increase phospholipid ordering and may thereby oppose membrane perturbations caused by LPLC. Plasmalogens constitute a significant fraction of cardiac sarcolemmal choline phospholipids. In light of their subclass-specific catabolism by phospholipase A2 and the present results, it is suggested that LPLC accumulation may contribute to ventricular dysrhythmias during ischemia.
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PMID:Plasmalogen-derived lysolipid induces a depolarizing cation current in rabbit ventricular myocytes. 973 76

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. In terms of its scavenging activity, melatonin has been shown to quench the hydroxyl radical, superoxide anion radical, singlet oxygen, peroxyl radical, and the peroxynitrite anion. Additionally, melatonin's antioxidant actions probably derive from its stimulatory effect on superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase and its inhibitory action on nitric oxide synthase. Finally, melatonin acts to stabilize cell membranes, thereby making them more resistant to oxidative attack. Melatonin is devoid of prooxidant actions. In models of oxidative stress, melatonin has been shown to resist lipid peroxidation induced by paraquat, lipopolysaccharide, ischemia-reperfusion, L-cysteine, potassium cyanide, cadmium chloride, glutathione depletion, alloxan, and alcohol ingestion. Likewise, free radical damage to DNA induced by ionizing radiation, the chemical carcinogen safrole, lipopolysaccharide, and kainic acid are inhibited by melatonin. These findings illustrate that melatonin, due to its high lipid solubility and modest aqueous solubility, is able to protect macromolecules in all parts of the cell from oxidative damage. Melatonin also prevents the inhibitory action of ruthenium red at the level of the mitochondria, thereby promoting ATP production. In humans, the total antioxidative capacity of serum is related to melatonin levels. Thus, the reduction in melatonin with age may be a factor in increased oxidative damage in the elderly.
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PMID:Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. 992 48

The mechanism of cadmium-mediated acute hepatotoxicity has been the subject of numerous investigations and although some uncertainties persist, sufficient evidence has emerged to provide a reasonable account of the toxic process. Acute hepatotoxicity involves two pathways, one for the initial injury produced by direct effects of cadmium and the other for the subsequent injury produced by inflammation. Primary injury appears to be caused by the binding of Cd2+ to sulfhydryl groups on critical molecules in mitochondria. Thiol group inactivation causes oxidative stress, the mitochondrial permeability transition, and mitochondrial dysfunction. Although cadmium may injure hepatocytes directly, there are compelling reasons to believe that hepatocellular injury is produced in vivo as the result of ischemia caused by damage to endothelial cells. Secondary injury from acute cadmium exposure is thought to occur from the activation of Kupffer cells and a cascade of events involving several types of liver cells and a large number of inflammatory and cytotoxic mediators. In this regard, it is clear that Kupffer cell activation and neutrophil infiltration are important events in the toxic process, and the involvement of proinflammatory cytokines and chemokines has also been implicated. The precise roles of the soluble mediators of inflammation warrant further investigation.
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PMID:Mechanisms of cadmium-mediated acute hepatotoxicity. 1063 Apr 25

We investigated the cardioprotective efficacy of a new compound, 3-[(1H-1-indolyl)methyl] -4-amino 4,5-dihydro-1H,1,2,4 triazole-5-thione (C6458). The effect of C6458 on the reduction of the infarct size and its protective ability against oxidative damage of the myocardium after ischemia-reperfusion was examined in rabbits that were subjected to 30 min regional ischemia and 2 h reperfusion. C6458 was administered by continuous infusion for 30 min starting at the 10th minute of sustained ischemia and ending at the 10th minute of reperfusion (two doses, 100 and 200 micromol/kg BW). Infarct and risk areas were delineated with Zn2+-Cd2+ particles and triphenyl tetrazolium chloride staining. Antioxidant activity was detected spectrophotometrically by the measurement of malondialdehyde formation. C6458 reduced significantly the level of malondialdehyde in rabbits under ischemia-reperfusion at both doses. Interestingly, at the dose of 200 micromol/kg, the compound decreased the malondialdehyde levels from the 1st minute of reperfusion and significantly reduced infarct size. The free radical scavenging properties of the compound were examined in vitro by determination of the interaction with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) stable free radical. The ability of the C6458 to scavenge HO* was established by its competition with dimethyl sulfoxide (DMSO) for HO radicals. The compound tested showed a significant effect in the above assays. We conclude that C6458 possesses a protective effect against both damaged myocardium and infarct size in anesthetized rabbits. This beneficial effect may be attributed, at least in part, to its antioxidant and free radical scavenging activity.
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PMID:Reduction of myocardial infarct size in rabbits by a novel indole derivative with antioxidant and free radical scavenging properties. 1239 15

Oxidative stress markedly alters protein function through redox modification of sulfhydryl groups present in cysteine residues. To explore the role of redox state in modulating cardiac K+ channels, this study examined the effects of sulfhydryl modifiers on the repolarizing transient outward current (Ito) in voltage-clamped myocytes from rat ventricle. Oxidized glutathione (GSSG; 5mM), an endogenous disulfide that specifically reacts with protein sulfhydryls, decreased maximum Ito amplitude from baseline by 49% when added to the external solution (P<0.05) and by 27% during internal dialysis (P<0.05). The membrane-impermeable disulfide, 5,5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) did not alter Ito when added to the external solution, but it decreased current amplitude by 31% during internal dialysis (P<0.05). GSSG-mediated Ito inhibition varied in a frequency- and voltage-dependent manner, consistent with a state-dependent blocking mechanism. This phenomenon was also observed in myocytes internally dialyzed with DTNB or Cd2+, which also covalently binds to free sulfhydryls. Inhibition of Ito by GSSG was not reversed by washout alone, consistent with the stable nature of covalently-modified sulfhydryl groups. However, when myocytes pretreated with GSSG were dialyzed with the reducing agent dithiothreitol, Ito amplitude increased significantly by 42% (P<0.05). These data suggest that alpha-subunits underlying Ito, or associated proteins, have one or more sulfhydryl groups within the cytoplasmic domain that directly modulate channel activity in response to changes in cell redox state. Redox modulation of Ito channels may be an important post-translational mechanism contributing to acute changes in cardiac repolarization under conditions of oxidative stress, such as ischemia and reperfusion.
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PMID:Sulfhydryl modulation of K+ channels in rat ventricular myocytes. 1262 95

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