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)

The effects of ischemia on the canine myocardial (Na+ + K+)-ATPase complex were examined in terms of alterations in cardiac glycoside binding and enzymatic activity. Ability of the myocardial cell to bind tritiated ouabain in vivo was assessed after 1, 2, and 6 h of coronary occlusion followed by 45 min of reperfusion, and correlated with measurements of in vitro (Na+ + K+)-ATPase activity and in vitro [3H]ouabain binding after similar periods of ischemia. Regional blood flow alterations during occlusion and reperfusion were simultaneously determined utilizing 15 mum radioactive microspheres to determine the degree to which altered binding of ouabain might be flow related. Anterior wall infarction was produced in 34 dogs by snaring of confluent branches of the left coronary system. Epicardial electrograms delineated ischemic and border zone areas. Coronary reperfusion after 2 and 6 h of occlusion was associated with impaired reflow of blood and markedly impaired uptake of [3H]ouabain in ischemic myocardium. In both groups, in vivo [3H]ouabain binding by ischemic tissue was reduced out of proportion to the reduction in flow. Despite near-complete restoration of flow in seven dogs occluded for 1 h and reperfused, [3H]ouabain remained significantly reduced to 58 +/- 9% of nonischemic uptake in subendocardial layers of the central zone of ischemia. Thus, when coronary flow was restored to areas of myocardium rendered acutely ischemia for 1 or more hours, ischemic zones demonstrated progressively diminished ability to bind ouabain. To determine whether ischemia-induced alteration in myocardial (Na+ + K+)-ATPase might underlie these changes, (Na+ + K+)-ATPase activity and [3H]ouabain binding were measured in microsomal fractions from ischemic myocardium after 1, 2, and 6 h of coronary occlusion. In animals occluded for 6 h, (Na+ + K+)-ATPase activity was significantly reduced by 40% in epicardial and by 35% in endocardial layers compared with nonischemic myocardium. Comparable reductions in in vitro [3H]ouabain binding were also demonstrated. Reperfusion for 45 min after occlusion for 6 h resulted in no significant restoration of enzyme activity when compared to the nonreperfused animals. In six animals occluded for 2 h, a time at which myocardial creatine phosphokinase activity remains unchanged, (Na+ + K+)-ATPase activity was reduced by 25% compared with nonischemic enzyme activity. In five dogs occluded for 1 h, (Na+ + K+)-ATPase activity in ischemic myocardium was unchanged from control levels. We conclude that reduced regional myocardial blood flow, local alterations in cellular milieu, and altered glycoside-binding properties of (Na+ + K+)-ATPase all participate in the reduction of cardiac glycoside binding observed after reperfusion of ischemic myocardium. In addition, after 2 or more hours of severe ischemia, myocardial (Na+ + K+)-ATPase catalytic activity is significantly reduced despite incubation in the presence of optimal substrate concentrations.
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PMID:Ischemia-induced alterations in myocardial (Na+ + K+)-ATPase and cardiac glycoside binding. 13 Mar 83

Pieces of liver (in vitro ischemia) and isolated microsomes were subjected to incubation at 4 degrees C and 37 degrees C for various time intervals. The effects on microsomal protein, phospholipids, and cholesterol and on microsomal phosphatases and electron transport enzymes were followed as a functional of time and temperature. NADH-cytochrome c reductase was very labile and was completely inactivated by 1 h, whereas G6Pase lost 50% of its activity after 2 h at 37 degrees C. IDPase and NADPH-cyt. c red. were of intermediate susceptibility whereas cytochromes b5 and P-450 were the most stable enzymes assayed. After 24 h of incubation of isolated microsomes at 37 degrees C there was no significant detachment of membrane components (protein, PLP or cholesterol), indicating that the inactivation of the enzymes was not primarily attributable to their solubilization. Instead, experiments with 14C-leucine and 14C-glycerol prelabeled microsomes demonstrated that the proteins detached from microsomes during incubation originated mainly from the intravesicular space due to repture of the microsomal membranes. The addition of a lysosomal extract during incubation did not alter either the rate of inactivation of the enzymes or the proportion of solubilized membrane components indicating that attack from the outside by proteolytic enzymes is not the mechanism for enzyme inactivation. There was no apparent correlation between the rates of inactivation of enzymes in vitro and their calculated half-lives in vivo or their postulated intramembranous localization. Ultrastructurally, enzyme inactivation was initially associated with alterations of the microsomal membranes, such as vesicle aggregation, membrane rupture, loss of unit membrane structure, and subsequently, thickening of membranes and transformation of the microsomes into nonrecognizable amorphous material.
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PMID:Effect of storage and in vitro ischemia on the ultrasture of microsomal membranes and on microsomal enzymes. 18 24

We have used a new technique for extraction of myocardial membranes (0.25 M sucrose, 0.6 M KCl) to isolate particulate and soluble proteins and enzymatic activities in an effort to quantify changes characteristic of progressive ischemia. Myocardial blood flow (MBF) was measured with microspheres (15 micrometer diameter) in all samples of tissue used for assay of proteins and enzymatic activities; MBF to the moderately ischemic areas (M-ischemia) was 53% of control (H-control); MBF to the severely ischemic areas (L-ischemia) was 9% of control. Significant decreases (P less than 0.001) in content of protein were seen in all post 1,000 g pellets and supernatant fluids in the L-ischemia zones; particulate lysosomal enzymatic activity was significantly decreased (P less than 0.001) in all four post 1,000 g pellets (2,500 g to 140,000 g) of the L-ischemic areas (for N-acetyl-beta-glucosaminidase and beta-glucuronidase). The increase in percent free activity of lysosomal enzymes (index of loss of latency) also was highly significant (P less than 0.001) in all particulate fractions of the L-ischemic areas. In addition, about 45% of the total activity of the microsomal marker enzyme, rotenone-insensitive NADH cytochrome C reductase (RINCR), was found in the 140,000 g pellet of H-control tissue (9.9 micronmol/min per g); this activity fell to 8.1 micronmol/min per g in M-ischemic areas (P less than 0.001) and to 5.3 micronmol/min per g in L-ischemic areas (P less than 0.001). This study demonstrates that changes in myocardial proteins, lysosomes, and other membrane-bound enzymes (RINCR) may provide reproducible bichemical parameters for assessing ischemic myocardial injury.
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PMID:Effects of well-defined ischemia on myocardial lysosomal and microsomal enzymes in a canine model. 21 2

Myocardial ischemia was produced for 2 hours by coronary ligation in 11 dogs pretreated with methylprednisolone (MP, 30 mg/kg). Myocardial blood flow (MBF) was measured with microspheres (15 micrometer) in each tissue sample used for enzymatic analysis. Homogenates of these tissue samples were separated by ultracentrifugation into lysosome-rich and microsomal fractions and were analyzed for N-acetyl-beta-glusosaminidase (NAGA), beta-glucuronidase (beta-gluc), rotenone-insensitive-NADH-cytochrome c reductase (RINCR), and cytochrome oxidase. The enzymatic data from centrifugal fractions were grouped according to MBF values for statistical analysis of inter-group effects of ischemia. Significant losses (P less than 0.001) of NAGA and beta-gluc were seen in all MP-treated lysosome-rich particulate fractions that were isolated from zones demonstrating MBF values less than 25% of control (L-ischemia). Similar significant losses (P less than 0.001) of RINCR were seen in microsomal fractions from L-ischemia zones. Samples with MBF values greater than 25% but less than 75% of control (M-ischemia) also demonstrated significant decreases of lysosomal and microsomal enzymatic activity in specific fractions. When the data of the above MP-treated group were compared with the untreated control group, no significant intergroup effects of treatment with MP were observed. In addition, enzymatic data (NAGA, RINCR) were normalized prior to performing linear regression analyses; percent loss of particulate enzymatic activity was plotted against percent decrease in MBF. The effects of 2 hours of ischemia on the above biochemical parameters were comparable between untreated and MP-treated groups. Finally, when myocardial samples were grouped according to similar levels of MBF, statistical analysis using the general linear models procedure revealed no beneficial effect of MP treatment on changes in lysosomal hydrolases, microsomal RINCR, or latency of lysosomes.
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PMID:Lack of effect of methylprednisolone on lysosomal and microsomal enzymes after two hours of well-defined canine myocardial ischemia. 21 3

The effect of postdecapitative ischemia (5 min at 37 degrees) and hypoxia (5% O2, 95% N2, 30 min) on the distribution of protein radioactivity in the cellular fractions of guinea pig cerebral cortex was studied. Ischemic conditions resulted in the increase of total radioactivity level and protein content in the mitochondrial fraction. In the cytosol the opposite effect was observed; the radioactivity and protein content were decreased. The amino acid analysis of microsomal proteins and the distribution of glucose-6-phosphatase activity, differing from those in control animals, suggest structural disturbances in the microsomal fraction. The results indicate a different sedimentation of proteins in the given experimental conditions. After hypoxia such effects were not observed.
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PMID:Effect of hypoxia and ischemia on the distribution of protein in brain cellular fractions. 45 Jan 70

Ischemic rat liver tissue has been shown previously to exhibit a markedly accelerated rate of phospholipid degradation, producing a loss of almost one half the total cellular phospholipid with 3 hours of ischemia. Pretreatment of the rats with chlorpromazine completely prevented the disturbed phospholipid metabolism at the same time that it prevented the cell death associated with as much as 3 hours of ischemia. Lipid-depleted microsomal membranes were shown previously to manifest alterations in their structure and function. The present report documents that similar structural alterations are evident in ischemic liver cell plasma membranes. The technique of freeze-fracture electron microscopy was used to examine the morphology of ischemic liver cell plasma membranes. Freeze-fracture replicas of whole tissue fragments exhibited a diffuse aggregation of the intramembranous particles in the P face of the plasma membranes. The incidence of this change correlated with the duration of ischemia. Pretreatment of the rats with chlorpromazine (20 mg/kg) for 30 minutes before inducing ischemia prevented the aggregation of the membrane-associated particles. These findings establish the existence of plasma membrane alterations in ischemic liver cells. The time course of these changes, their prevention by chlorpromazine, and their similarity to the previously described structural alterations in the microsomal membranes suggest that they are related to the loss of liver cell phospholipid. The data in the present report support the hypothesis that an accelerated phospholipid degradation and its resultant membrane dysfunction are the critical alterations that produce irreversible liver cell injury and, ultimately, cell death in ischemia.
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PMID:Irreversible ischemic cell injury. Prevention by chlorpromazine of the aggregation of the intramembranous particles of rat liver plasma membranes. 68 54

Early changes in lysosomal enzymes must occur if their role is significant in irreversible myocardial injury. Therefore, we ligated the anterior descending coronary artery in 14 dogs and after 60 min excised epicardial and endocardial samples from the ischemic and adjacent normal heart. The collateral flow measured with radioactive microspheres in the endocardial samples averaged 19% of control. The muscle was disrupted and fractionated by ultracentrifugation into nuclear pellet (NP), heavy lysosomal pellet (HL), light lysosomal pellet (LL), microsomal pellet (M) and supernate (S). Electron microscopy demonstrated changes characteristic of sichemia in whole tissues and sedimented fractions. Acid phosphatase reaction product was present in residual bodies in the HL fraction and membrane-bound vesicles in the LL fraction and in the intact tissue. Significant decreases in the specific activity of N-acetyl-beta-glucosaminidase and beta-glucuronidase occurred in the endocardial LL fraction, while significant increases in both were found in the ts fraction (P less than 0.05). Losses of acid phosphatase occurred in both LL and S fractions. Moreover, decreases of total N-acetyl-beta-glucosaminidase in the HL fraction and of total beta-glucuronidase and acid phosphatase in the LL fraction were positively correlated (P less than 0.01) with the degree of ischemia measured with radioactive microspheres. Only insignificant enzymatic changes were found when the collateral flow was greater than 40%, and the differences were less significant in epicardial samples where the flow averaged 29%. The early loss of enzymes from the lysosomal fractions in severe ischemia suggests a role for lysosomal hydrolases in the necrosis that follows coronary occlusion.
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PMID:Effect of collateral flow on epicardial and endocardial lysosomal hydrolases in acute myocardial ischemia. 115 94

The intracellular accumulation of PAF following cell stimulation suggests an intracellular signal transduction pathway. High affinity binding sites for PAF in microsomal membranes and displacement of PAF from these sites by structurally distinct PAF antagonists suggests the existence of an intracellular receptor. Suppression of primary genomic responses by a PAF antagonist selective for the intracellular Ca2+ and arachidonic acid metabolites, is linking the intracellular generation of PAF to immediate-early transcription. Several of the metabolites that transiently accumulate after injury may elicit beneficial effects on regenerative processes. The membrane metabolite PAF, which accumulates after seizure and ischemia, may initiate reparative processes by promoting transcriptional activation of immediate-early transcription factors. The long-term effects of these immediate-early gene transcription factors may provide a synthetic mechanism to replenish and rebuild cells following traumatic events.
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PMID:Second messengers derived from excitable membranes are involved in ischemic and seizure-related brain damage. 130 97

It has been shown in vitro that dihydrolipoate (DL-6,8-dithioloctanoic acid) has antioxidant activity against microsomal lipid peroxidation. We tested dihydrolipoate for its neuroprotective activity using models of hypoxic and excitotoxic neuronal damage in vitro and rodent models of cerebral ischemia in vivo. In vitro, neuronal damage was induced in primary neuronal cultures derived form 7-day-old chick embryo telencephalon by adding either 1 mM cyanide or 1 mM glutamate to the cultures. Cyanide-exposed and dihydrolipoate-treated (10(-9)-10(-7) M) cultures showed an increased protein and ATP content compared with controls. The glutamate-exposed cultures treated with dihydrolipoate (10(-7)-10(-5) M) showed a decreased number of damaged neurons. In vivo, dihydrolipoate treatment (50 and 100 mg/kg) reduced brain infarction after permanent middle cerebral artery occlusion in mice and rats. Dihydrolipoate treatment (50 and 100 mg/kg) could not ameliorate neuronal damage in the rat hippocampus or cortex caused by 10 min of forebrain ischemia. A comparable neuroprotection was obtained by using dimethylthiourea, both in vitro (10(-7) and 10(-6) M) and at a dose of 750 mg/kg in the focal ischemia models. Lipoate, the oxidized form of dihydrolipoate, failed to reduce neuronal injury in any model tested. We conclude that dihydrolipoate, similarly to dimethylthiourea, is able to protect neurons against ischemic damage by diminishing the accumulation of reactive oxygen species within the cerebral tissue.
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PMID:Dihydrolipoate reduces neuronal injury after cerebral ischemia. 134 59

To determine whether heat shock proteins (HSPs) might be active in cellular recovery following transient ischemia, we examined rat kidneys for 70-kDa HSP (HSP-70) mRNA expression, protein elaboration, and intracellular localization after 45 min of renal ischemia and reflow of 15 min, 2, 6, and 24 h. Inducible HSP-70 mRNA is present at 15 min of reperfusion, peaks between 2 and 6 h, and falls by 24 h. Inducible 72-kDa HSP (HSP-72) protein accumulates progressively through 24 h and is found in both soluble and microsomal fractions following ischemia. Within proximal tubules, immunofluorescent localization of HSP-72 is restricted to the apical domain at 15 min, is dispersed through the cytoplasm in a vesicular pattern at 2 and 6 h, and has migrated away from the apical domain at 24 h. A portion of the vesicular HSP-72 is associated with lysosomes; no intranuclear HSP-72 is detected. The course of mRNA induction, protein elaboration, and HSP-72 localization coincides with previously described changes in proximal tubule morphology and polarity following sublethal ischemic injury. HSP-72 may be instrumental in cellular remodeling and restitution of epithelial polarity during recovery from ischemic renal injury.
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PMID:Induction and intracellular localization of HSP-72 after renal ischemia. 144 67


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