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

The administration of multiple doses of cocaine on a single day during late gestation is teratogenic in rats in which hind limb ectrodactyly is a major finding (Webster and Brown-Woodman, '90). We have previously hypothesized that these limb malformations result from the generation of reactive oxygen species during the process of ischemia/reperfusion in vivo. In order to study the direct effects of cocaine versus the aberrant oxygenation it may induce, we have developed a system for culturing rat embryos between days 14 and 15 of gestation. Growth and development of cultured embryos are comparable to that of in vivo controls. Exposure to normoxia (95% O2) with or without cocaine failed to induce limb malformations and exposure to a single long period of hypoxia (20% O2) only reduced limb growth in the anterior-posterior axis. By contrast, embryos receiving multiple brief exposures to hypoxia developed a significant incidence of hind limb ectrodactyly that appeared indistinguishable from that induced by cocaine in vivo. By incubating day 14 embryos in a nitroblue tetrazolium derivative, 1-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), it was shown that superoxide anion radical appears in the digital rays following two episodes of reperfusion. Little reaction product was seen under the other conditions. Finally, mitochondrial electron transport particles prepared from teratogenically sensitive limb buds spontaneously "leak" electrons to form superoxide anion radical whereas those from insensitive heart fail to do so. We propose that cocaine and other exposures that can transiently reduce conceptual oxygenation during late gestation are teratogenic by virtue of their capacity to induce ischemia/reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine. 132 33

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.
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PMID:A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size. 199 25

To investigate the mechanisms responsible for the impairment of phospholipid metabolism observed in ischemic cells, we have studied the effect of conditions simulating ischemia on the metabolism of arachidonic acid (AA) by muscle (M-) and nonmuscle (F-) cells isolated from newborn rat hearts and cultured separately. In muscle cells, oxygen deprivation induces a significant stimulation of the release of [14C]AA from prelabeled cells associated with a preferential redistribution of [14C]AA into cell triglycerides but not formation of radioactive prostaglandins. Moreover, the fatty acid content of phospholipids, as measured by capillary gas chromatography, appears markedly reduced in ischemic myocardial cells. This fact may be related to phospholipase stimulation during ischemia as suggested by the antagonistic effect of mepacrine or p-bromophenacyl bromide. In contrast, oxygen deprivation failed to induce any significant alteration of AA metabolism in fibroblast-like heart cells. Our results indicate that these cultures of newborn rat heart cells, which exhibit many of the features observed in intact organ during ischemia, may represent a useful experimental model to investigate the pharmacological control of the membrane phospholipid turnover.
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PMID:Effect of oxygen deprivation on metabolism of arachidonic acid by cultures of rat heart cells. 250 57

Excitatory dicarboxylic amino acid neurotransmitters, particularly glutamate, have been implicated in mediating neuronal cell injury in brain ischemia-anoxia, epilepsy, and stroke. Glutamate neurotoxicity has been demonstrated in several in vitro models, as well as its prevention by a variety of agents, including several sialic acid-containing glycosphingolipid species, gangliosides. We have now examined ganglioside effects in anoxic exposed cultures of granule cells from Postnatal Day 8 rat cerebellum. Cells between 10 and 12 days in vitro were placed into an anoxic atmosphere or subjected to a chemical model of anoxia by a pulse exposure to rotenone. Widespread neuronal degeneration of neuronal cell bodies and their associated neurite network was seen the following day. These effects on cell vitality at the morphological level were quantitatively confirmed by measuring the photometric reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide to a blue formazan product. This neuronal injury was abolished by the specific N-methyl-D-aspartate receptor noncompetitive antagonists Mg2+, phencyclidine and MK-801, suggesting that this subtype of glutamate receptor is involved in the pathogenesis of anoxic granule cell injury. Pretreatment for 30 to 60 min or more or concurrent treatment with ganglioside GM1 largely prevented the ensuing neuronal death (ED50 = 25 microM), even 4 days later. Degeneration induced by exogenous glutamate was equally reduced. Asialo GM1 (lacking sialic acid) was ineffective. These results are consistent with the observed beneficial effects of the gangliosides in ischemic brain injury models in vivo.
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PMID:Monosialoganglioside GM1 protects against anoxia-induced neuronal death in vitro. 268 18

Brain pH changes during ischemia were observed by the newly established histochemical technique in Dr. Kogure's laboratory (Miami). The technique utilizes intravascular injection of neutral red as a pH indicator. Its use is based on the fact that neutral red is red in acid and yellow in alkaline pH. Thalamic infarction model in dogs was used in this experiment. The methods of producing this model by temporary occlusions of brain arteries have been published elsewhere. The animals were anesthetized with sodium thiopental, immobilized with pancronium bromide, and artificially ventilated with room air. Blood gases and blood pH were adjusted to normal. Before the experimental procedure, 3 ml/kg of a 5% saline suspension of neutral red was injected slowly into the femoral artery. After occlusions of cerebral arteries, the brain was frozen in situ by pouring liquid nitrogen into the bottomless cup. The frozen brain was mounted on a cryostat at -20 degrees C and sliced coronally in 10 micron thickness. Color differences in the serial sliced brain surface were observed. No change in the color was observed in the sham operated brains. Thirty minutes following occlusion, the color of the thalamus is reddish, and it was estimated that this area became acidotic. 1 hour following occlusion, too, the thalamus is acidotic. But 2 hour following occlusion, the color of the thalamus became yellowish, indicative of alkaline shift. From this experimental results, it is considered that the pH of ischemic brain changes dynamically, that is, ischemic brain becomes acidotic in the early stage of ischemia but with the lapse of time alkaline shift occurs.
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PMID:[Changes of tissue pH in dog brain during ischemia--alkaline shift (author's transl)]. 737 Jan 33

Intravital microscopy used with fluorescent vital stains provides the opportunity to measure the temporal and spatial extent of tissue injury following disease processes. However, this assumes that prolonged exposure to such dyes does not alter microvascular perfusion or cellular viability. To test this hypothesis, the extensor digitorum longus (EDL) muscle in 24 male Wistar rats, anesthetized with sodium pentobarbital (Somnotal, 65 mg/kg, ip), were prepared for microscopy. The EDL was either bathed continuously (n = 6) in Krebs solution containing bisbenzimide (5 micrograms/ml; labels nuclei of all cells) and ethidium bromide (5 micrograms/ml; labels nuclei of injured cells) or had dyes topically applied 1 hr (n = 4) and 4 hr (n = 4) following dissection of the muscle. Noxious stimuli (i.e., hypoxia:FiO2 of 8-10% (n = 3), 95% ethanol (n = 3), and 2 hr ischemia followed by 90 min reperfusion (n = 4) were used to test the ability of ethidium bromide, when used in conjunction with intravital microscopy, to differentiate injured tissue. Video recordings at the surface of the EDL muscle were made every 30 min for 5 hr from which the number of perfused capillaries was counted (NCper). The numbers of bisbenzimide- and ethidium bromide-labeled nuclei were counted at the surface of the muscle and at two to three additional locations within the muscle (to a maximum depth of approximately 120-160 microns). The average NCper (19.05 +/- 1.7) remained constant over 5 hr, while the number of nuclei stained by bisbenzimide increased linearly with time from an initial value of 1218 +/- 125.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Measurement of tissue viability using intravital microscopy and fluorescent nuclear dyes. 747 97

Damage to the cerebral endothelium from ischemia could exacerbate brain injury by altering vascular integrity, but little is known concerning the response of cerebral endothelial cells to hypoxia. To address this issue, cerebral capillary endothelial cells were isolated from 14-day-old rats, grown to confluence, and placed in hypoxic chambers for up to 62 h. Cells were undamaged by 24 hours of hypoxia as assessed by lactate dehydrogenase release and ethidium bromide staining, but 48 h resulted in marked damage. Hypoxia was probably exacerbated by hypoglycemia because glucose levels fell to < 1 mM by 24 h, at which point ATP levels began to fall in hypoxic cultures (3.25 +/- 1.48 nmol/mg protein; mean +/- S.D.) relative to normoxic cultures (9.52 +/- 1.41 nmol/mg protein). Cells treated with 4 mM fructose-1,6-bisphosphate (FBP) had significantly less damage at 48 h of hypoxia than controls. FBP had little effect on rate of glucose depletion from the media, but ATP depletion due to hypoxia was significantly less. Thus, the protective effect of FBP may be mediated by the ability of treated cells to maintain higher ATP levels. Unlike FBP, glutamate receptor antagonists including MK-801, NBQX, DNQX, and kynurenic acid were ineffective in ameliorating hypoxia-induced endothelial cell injury.
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PMID:Response of cerebral endothelial cells to hypoxia: modification by fructose-1,6-bisphosphate but not glutamate receptor antagonists. 752 60

Mitochondria are continually exposed to oxidative stress due to superoxide formation by the respiratory chain which increases in pathological situations such as ischemia reperfusion and neurodegeneration. During oxidative stress there are a number of changes in mitochondrial low-molecular-weight and protein thiols. In particular, the mitochondrial glutathione pool becomes oxidized and forms mixed disulfides with protein thiols. To investigate changes in the redox state and conjugation of mitochondrial glutathione, and other mitochondrial thiols, we designed and characterized a thiol probe specifically targeted to the mitochondrial matrix. This molecule, thiobutyltriphenylphosphonium bromide, contains a thiol group linked to a lipophilic triphenylphosphonium cation which causes it to accumulate in the negatively charged mitochondrial matrix. Using [14C]thiobutyltriphenylphosphonium bromide we confirmed that it was selectively accumulated by isolated mitochondria. In the mitochondrial matrix the thiol group equilibrated with endogenous thiols and during oxidative stress became disulfide-bonded to protein and nonprotein thiols. Therefore, this novel thiol probe can be used to label protein thiol groups and to investigate changes in conjugation and redox state of mitochondrial thiols during oxidative stress.
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PMID:Synthesis and characterization of thiobutyltriphenylphosphonium bromide, a novel thiol reagent targeted to the mitochondrial matrix. 757 95

We have previously proposed that cytokine-stimulated nitric oxide (NO) production is responsible for reversible myocardial depression in sepsis, trauma and ischemia. NO previously has been found to inhibit mitochondrial activity in other cell types. Accordingly, we sought to determine if cytokine-stimulated NO production inhibited cardiac myocyte mitochondrial activity. Treatment of neonatal rat cardiac myocytes with interleukin-beta (IL-1) resulted in the expression of mRNA for inducible NO synthase (iNOS) and stained positively for iNOS protein by immunohistochemistry. No iNOS staining was detected in untreated cells. IL-1 treatment resulted in significant nitrite levels vs control over 48 hrs (4.2 +/- 0.7 vs 0.3 +/- 0.2 nmol/1.25 x 10(5) cells, respectively) (n = 12) that was inhibited by 1mM NMA (0.3 +/- 0.2 nmoles; p < .01; n = 12). Mitochondrial activity was assessed by the MTT colorimetric assay using (3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and OD 570-630. Mitochondrial activity was significantly inhibited by IL-1 vs control cells (0.436 +/- 0.01 vs 0.608 +/- 0.03) and reversed by 1mM NMA (0.549 +/- 0.03) or removal of IL-1 (0.662 +/- 0.02) (p < .01; n = 12 for each). These data strongly suggest that cytokine-stimulated NO production by cardiac myocytes results in reversible inhibition of mitochondrial activity.
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PMID:Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. 765 17

Matrix proteins upregulate polymorphonuclear neutrophil (PMN) oxidative metabolism in a normoxic environment. We sought to investigate the relationship between matrix proteins and adherent PMN oxidative metabolism during acute ischemia. PMN adherent to buffer, fibronectin, Arg-Gly-Asp-Ser (RGDS), or laminin were placed in either normoxic or ischemic media. PMN adherence, superoxide anion production, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan production, and surface receptor expression (CD64, CD32w, CD16, CD35, and CD11b/CD18) using monoclonal antibodies directed against these receptors were assayed. Ischemia increased PMN adherence unless the PMN were adhered to fibronectin or RGDS. Ischemia reduced PMN superoxide anion, MTT formazan, and H2O2 production unless the PMN were adhered to fibronectin or RGDS. Fibronectin and RGDS prevented ischemic-induced suppression of FcR expression. Immunofluorescent studies demonstrated capping and clustering of PMN Fc and complement receptors during ischemia while adhered on matrix proteins. These results demonstrate that 1) ischemia suppresses matrix protein upregulation of PMN oxidative metabolism, which is restored by fibronectin; 2) fibronectin-mediated restoration of PMN oxidative metabolism involves the binding epitope of fibronectin; and 3) fibronectin maintains PMN oxidative metabolism during ischemia in part by maintaining PMN FcR on the cell surface and by recruiting a new population of PMN capable of undergoing oxidative metabolism.
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PMID:Matrix protein regulation of PMN oxidative metabolism during ischemia. 816 26


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