Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

To gain insight into the mechanisms responsible for muscle dysfunction after ischemia-reperfusion, a rat spinotrapezius muscle preparation was developed which enabled sequential measurements of in vivo maximum tetanic force production and cell death assessed using digital microfluorographic determination of propidium iodide (PI) staining. After 60 min of no-flow ischemia, maximum tetanic force fell significantly during 90 min of reperfusion compared with control, nonischemic muscles. The most striking fall was evident within 30 min of reperfusion and occurred concomitant with an explosive increase in PI-positive myocyte nuclei. Treatment with the oxygen radical scavenger, dimethylthiourea, attenuated both the fall in force and increased PI staining. Indeed, the rise in PI-positive nuclei correlated closely (r= 0.728) with the reduction of maximum tetanic force developed following ischemia and reperfusion under all conditions. Superoxide dismutase also attenuated the rise in PI-positive nuclei. Assessment of mitochondrial inner membrane potential (deltapsi) using Rhodamine 123 fluorescence revealed that myocytes with the lowest initial mitochondrial membrane potential were subject to the greatest injury after 90 min of reperfusion (r= 0.828). These results support the hypothesis that myocyte injury, as visualized by PI-staining, reflects an impaired contractile function in fibers with a low oxidative potential which is likely mediated by oxygen radicals.
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PMID:Temporal correlation between maximum tetanic force and cell death in postischemic rat skeletal muscle. 867 60

We have determined the kinetics of the cellular viability ratio (CVR), defined as the number of living cells over the total cell count, in pig kidneys using propidium iodide and fluorescein diacetate staining, as a function of time and preservation conditions. The kidneys were preserved in warm or cold ischemia in order to mimic the conditions of transplantation from non-heart-beating donors or multiple removal with optimal preservation of the graft, respectively. To determine the CVR, the cells were obtained by a fine-needle aspiration biopsy, which minimizes the damage to the graft. A biometric analysis by regression enabled the determination of the time dependence for warm ischemia (CVR(t) = 80.0 x e(-0.733-t)(+2.7/-0.36)) and for cold ischemia (CVR(t) = 80.0 x e(-0.022-t)(+1.57/-0.64)) with a confidence interval of 95%. These master curves allow us to predict, under the described conditions, the CVR after a given ischemia time. The half-life of the cells can be deduced from the time-dependent CVR(t), and is 0.64 hr (38 min) for warm ischemia and 21.4 hr for cold ischemia. Further, the CVR for a given kidney can be used to assess its condition at removal: if the CVR is below 48% at 2 hr after removal, one can conclude that the organ has suffered a period of warm ischemia.
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PMID:Kinetics of cellular viability in warm versus cold ischemia conditions of kidney preservation. A biometric study. 877 93

In vitro combinations of MK-801, an NMDA receptor antagonist, and alpha-phenyl-tert-butyl-nitrone (PBN), a free radical scavenger, have been tested for possible additive neuroprotective effects against anoxia/hypoglycemia (Ax/Hg)-induced neuronal damage. Rat organotypic hippocampal slice cultures were exposed to Ax/Hg for different lengths of time to vary the severity of the insult. Cell death (CD) was assessed using propidium iodide fluorescence and expressed as a percentage of the total neuronal cells present. Pretreatment with PBN alone (500 microM) provided significant protection against moderate ischemic injury and reduced CD from 65% in controls to 2% in the treated group (P < 0.003). A longer ischemic exposure time caused more neuronal damage, which was only slightly reduced by PBN, but significantly reduced by MK-801 (30 microM) (4% CD with MK-801 vs 75% CD in controls; P < 0.0003). With a further increase in the time of ischemic exposure, MK-801 was still protective (33% CD with MK-801 vs 90% CD in controls; P < 0.002), although the combination MK-801 + PBN was more efficient (7% CD with combination, P < 0.01 compared to MK-801 alone). With yet a further increase in the ischemic exposure, PBN or MK-801 alone was not protective; however, a combination of the two still provided significant protection (64% CD with combination vs 100% CD with MK-801 alone; P < 0.01). PBN was protective when administered up to 2 h after Ax/Hg (66% CD in controls vs 36% CD with PBN 500 microM; P < 0.007). The combination MK-801 + PBN was able to increase the therapeutic window up to 3 h (61% CD in controls vs 41% with PBN alone vs 7% with MK-801 + PBN; P < 0.002 compared to PBN alone). In conclusion, the combination of MK-801 and PBN increases both the efficacy and the time window of protection against ischemia.
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PMID:Combination therapy with MK-801 and alpha-phenyl-tert-butyl-nitrone enhances protection against ischemic neuronal damage in organotypic hippocampal slice cultures. 881 69

We have investigated the neuroprotective actions of neurotrophins in a model of ischaemia using slice cultures. Ischaemia was induced in organotypic hippocampal cultures by simultaneous oxygen and glucose deprivation. Cell death was assessed 24 h later by propidium iodide fluorescence. Pre- but not post-ischaemic addition of brain-derived neurotrophic factor (BDNF) produced a concentration-dependent reduction in neuronal damage. Neurotrophin-3 was not neuroprotective. These data suggest that BDNF may form part of an endogenous neuroprotective mechanism.
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PMID:Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures. 881 76

A role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is increased in damaged neurons in models of ischemia and epilepsy. These findings were recently extended with the demonstration that mice deficient in p53 ("knock-out" mice) exhibit almost complete protection from seizure-induced brain injury, whereas wild-type mice display significant neuronal cell loss in the hippocampus and other brain regions. Because the p53 knock-out mice used in the latter study expressed a global p53 deficiency in all cell types, it was not possible to conclude that protection was conferred by the exclusive absence of p53 in neurons. Therefore, in the present study, we determined whether p53 expression in isolated neurons is directly coupled to a loss of viability associated with excitotoxic challenge. Primary cultures of hippocampal or cortical neurons were derived from animals containing p53 (+/+, +/-) or those deficient in p53 (-/-). p53-Deficient neurons appeared identical to wild-type neurons with respect to morphology, neurofilament expression, and resting levels of intracellular calcium. Neurons containing at least one copy of p53 were severely damaged by exposure to kainic acid or glutamate. Cell damage was assessed by direct cell counting and by nuclear morphology after propidium iodide staining of DNA. In contrast, neurons deficient in p53 (-/-) exhibited little or no damage in response to excitotoxin treatment. Despite their divergent outcomes, p53 (+/+) and p53 (-/-) neurons demonstrated similar sustained elevations in intracellular calcium levels triggered by glutamate exposure. Restoring p53 expression to p53-deficient neurons, using adenovirus-mediated transduction, was sufficient to promote neuronal cell death even in the absence of excitotoxin. These results demonstrate a direct relationship between p53 expression and loss of viability in CNS neurons.
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PMID:Evidence for p53-mediated modulation of neuronal viability. 882 16

Chronic hypoxia inhibits rat thyroid function in vivo. To determine possible mechanisms, we studied the effect of hypoxia on iodide uptake, the involvement of second messengers, and cell membrane permeability in rat thyroid FRTL-5 cells. Since sublethal heat stress protects tissues from ischemia, we also determined effects of heat stress. The initial rate of iodide uptake in untreated cells was between 12.98 and 15.28 pmol/micrograms DNA/min. Hypoxia (5% O2) increased the rate of uptake in a time-dependent manner. Heating cells at 45 degrees C for 15 min (heat shock) prior to exposure to hypoxia for 3 days inhibited the increase in the initial rate of I-uptake. Using fura-2, we found that the resting [Ca2+]i in suspended FRTL-5 cells was 65 +/- 7 nM (n = 16). [Ca2+]i was not increased in cells exposed to hypoxia for 1 day, while a 3-day exposure increased [Ca2+]i by 43 +/- 4% (p < 0.05); no additional increase occurred after 7 days of exposure. When cells were heated prior to hypoxia exposure for 3 days, the hypoxia-induced increase in [Ca2+]i did not occur. Similar observations were found with inositol trisphosphates (InsP3). Exposure of cells to hypoxia for 3 days increased InsP3 from 0.08 +/- 0.02 (n = 5) to 0.32 +/- 0.04% total cpm (n = 5, p < 0.05), but sublethal heating of cells prior to hypoxia exposure prevented the increase. Three-day hypoxia increased PKC activity in the membrane fraction (from 67 +/- 7 to 86 +/- 4% of total activity, p < 0.05), and heat shock inhibited these changes also. Immunoblots showed that hypoxia treatment alone and heat shock plus hypoxia resulted in the translocation of PKC-alpha, -delta, -epsilon, and -zeta isoforms, whereas heat shock alone translocated only PKC-beta I, -beta II, and -zeta. Cell membrane integrity was assayed by trypan blue exclusion. Hypoxia alone for 3 days did not affect membrane permeability, but only 49 +/- 3% of cells excluded trypan blue when a 3-day hypoxia exposure was followed by a 6 h reoxygenation. Heat shock prior to hypoxia and reoxygenation protected cell membrane function. Heat shock also induced heat shock protein 70 kDa (HSP-70) synthesis at the transcriptional level. Results suggest that heat shock protects FRTL-5 cells from hypoxic injury, perhaps by inhibiting the initial rate of iodide uptake and second messengers. It is likely that HSP-70 plays an essential role in the process of protection.
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PMID:Heat shock inhibits the hypoxia-induced effects on iodide uptake and signal transduction and enhances cell survival in rat thyroid FRTL-5 cells. 893 75

The extent of cardiac injury incurred during reperfusion as opposed to that occurring during ischemia is unclear. This study tested the hypothesis that simulated ischemia followed by simulated reperfusion causes significant "reperfusion injury" in isolated chick cardiomyocytes. Cells were exposed to hypoxia, hypercarbic acidosis, hyperkalemia, and substrate deprivation for 1 h followed by 3 h of reperfusion. Irreversible cell membrane injury, measured by propidium iodide uptake, increased from 4% of cells at the end of ischemia to 73% after reperfusion; death occurred in only 17% of cells kept ischemic for 4 h. Lactate dehydrogenase release was consistent with these changes. Lengthening ischemia from 30 to 90 min increased cell injury as expected, but of the total cell death, > 90% occurred during reperfusion. "Chemical hypoxia" composed of cyanide (2.5 mM) plus 2-deoxyglucose augmented injury before reperfusion compared with simulated ischemia. Inhibition of oxygen radical generation by use of metal chelator 1,10-phenanthroline reduced cell death from 73% to 40% after reperfusion (P = 0.001). We conclude that simulated reperfusion significantly augments the cellular membrane damage elicited by simulated ischemia in isolated cardiomyocytes devoid of other factors and suggest that reactive oxygen species, perhaps from the mitochondria, participate in this injury.
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PMID:Reperfusion injury on cardiac myocytes after simulated ischemia. 896 73

The purpose of this study was to examine the effect of varying durations of ischemia on several microvascular parameters in the awake hamster chamber model. The goal was to characterize the microvascular damage that occurs in skeletal muscle as a result of ischemia and reperfusion. The chamber tissues were subjected to 1-5 h of ischemia, and then the following parameters were measured: vessel diameter, endothelial thickness, macromolecular leakage, red blood cell velocity, adherent leukocytes, rolling leukocytes, freely flowing leukocytes, functional capillary density, and propidium iodide-positive cell nuclei. In control animals there was no significant difference in any parameters over the entire observation period. After 1 or 2 h of ischemia an increase in rolling and adherent leukocytes was measured. After 3 h of ischemia there was a significant increase in the mean endothelial thickness and in the number of nonviable cells. After 4 h of ischemia a significant difference in the extent of macromolecular leakage and the functional capillary density was additionally observed. After 5 h of ischemia this damage was more pronounced and often so severe that approximately 50% of the vessels demonstrated no reflow.
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PMID:Skeletal muscle microvascular and tissue injury after varying durations of ischemia. 899 97

The postsynaptic actions of glutamate are rapidly terminated by high affinity glutamate uptake into glial cells. In this study we demonstrate the stimulation of both glutamate uptake and Na,K-ATPase activity in rat astrocyte cultures in response to sublethal ischemia-like insults. Primary cultures of neonatal rat cortical astrocytes were subjected to hypoxia, or to serum- and glucose-free medium, or to both conditions (ischemia). Cell death was assessed by propidium iodide staining of cell nuclei. To measure sodium pump activity and glutamate uptake, 3H-glutamate and 86Rb were both simultaneously added to the cell culture in the presence or absence of 2 mM ouabain. Na,K-ATPase activity was defined as ouabain-sensitive 86Rb uptake. Concomitant transient increases (2-3 times above control levels) of both Na,K-ATPase and glutamate transporter activities were observed in astrocytes after 4-24 h of hypoxia, 4 h of glucose deprivation, and 2-4 h of ischemia. A 24 h ischemia caused a profound loss of both activities in parallel with significant cell death. The addition of 5 mM glucose to the cells after 4 h ischemia prevented the loss of both sodium pump activity and glutamate uptake and rescued astrocytes from death observed at the end of 24 h ischemia. Reoxygenation after the 4 h ischemic event caused the selective inhibition of Na,K-ATPase activity. The observed increases in Na,K-ATPase activity and glutamate uptake in cultured astrocytes subjected to sublethal ischemia-like insults may model an important functional response of astrocytes in vivo by which they attempt to maintain ion and glutamate homeostasis under restricted energy and oxygen supply.
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PMID:Stimulation of glutamate uptake and Na,K-ATPase activity in rat astrocytes exposed to ischemia-like insults. 903 29

The inhibition of the Na+/H+ exchanger during cardiac ischemia and reperfusion has been shown to be beneficial for the preservation of the cellular integrity and functional performance. The aim of the present investigation was to come up with potent and selective benzoylguanidines as NHE inhibitors for their use as an adjunctive therapy in the treatment of acute myocardial infarction. During the course of our investigations it became clear that the substitution ortho to the acylguanidine was of crucial importance for the potency of the compounds. 4-Chloro- and 4-fluoro-2-methylbenzoic acids 6 and 7 were prepared using the directed ortho metalation technique with the carboxylic acid as the directing group. With the LDA/methyl iodide system the 2-methyl group could be extended to an ethyl group. 4-Alkyl groups were inserted by the palladium-catalyzed cross-coupling reaction into the 4-bromo-2-methylbenzoic acid methyl ester (20). Starting with benzoic acids 6-19, the methylsulfonyl group was introduced by a sequence of standard reactions (sulfochlorination, reduction, and methylation). 4-Aryl derivatives 68-75 were synthesized by the palladium-catalyzed Suzuki reaction. A large number of nucleophilic displacement reactions in the 4-position were carried out with S-, O-, and N-nucleophiles as well as with the cyano and trifluoromethyl group. Using the ester method, acid chlorides, or Mukaiyama's procedure, the 5-(methylsulfonyl)benzoic acid derivatives were finally converted to the (5-(methylsulfonyl)benzoyl)guanidines 165-267 with excessive guanidine. In some cases nucleophilic substitutions with pyridinols and piperidine derivatives were carried out at the end of the reaction sequence with the 4-halo-N-(diaminomethylene)-5-(methylsulfonyl)-benzamides. Variations in the 4-position were most reasonable, but the volume of the substituents was of crucial importance. Substitution in the 3- and particularly in the 6-position led to considerable worsening of the inhibitory effects of the Na+/H+ exchanger. The 2-methyl compounds, however, showed without exception higher in vitro activities than their respective demethyl counterparts as they are exemplified by the reference compounds 266 and 267, obviously caused by a conformational restriction of the acylguanidine chain. The development compound (2-methyl-5-(methylsulfonyl)-4-pyrrolobenzoyl)guanidine, methanesulfonate (246) is a NHE-1 subtype specific NHE inhibitor, being 27-fold more potent toward the NHE-1 than the NHE-2 isoform. 246 was found to act cardioprotectively not only when given before an experimentally induced ischemia, but also curatively after the onset of symptoms of acute myocardial infarction when given prior to the induction of reperfusion.
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PMID:(2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. 920 43


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