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)

Axonal transport of acetylcholinesterase (AChE) and choline acetyltransferase (ChAc) and ultrastructural degenerative changes were compared in isolated nerve segments of rabbit peroneal nerves kept in vivo for 22 h, either with preserved blood supply (control segments) or under conditions of ischemia (ischemic segments). Ischemia abolished the proximo-distal and disto-proximal axonal transport of AChE and the proximo-distal transport of ChAc which, in control segments, were revealed by accumulations of the enzymes at corresponding ends of the segments. Total activities of AChE and ChAc recovered in isolated segments with intact blood supply corresponded to the activities in normal nerves; in ischemic segments, 50% of ChAc activity was lost in 22 h, whereas all AChE activity was preserved. Ultrastructural changes were found in few fibres in control segments and in many fibres in ischemic segments 22 h after nerve interruption. The early changes in control segments correspond to those described in the literature for peripheral stump of severed nerves. The microtubules, neurofilaments and mitochondria were not affected. In ischemic segments, various stages of axoplasmic disintegration occurred in the myelinated and unmyelinated axons:flocculation and clumping of axoplasmic material, decomposition of neurofilaments and microtubules, swelling, formation of amorphous densities and breakdown of mitochondrial cristae. Swelling, amorphous densities, clumping of nuclear chromatin and necrotic mitochondrial changes appeared also in Schwann cells. It is concluded that ischemia blocks axonal transport and brings about, within 22 h, ultrastructural changes both in nerve fibres and in Schwann cells. Cytoplasmic ChAc is affected earlier by necrotic degeneration of the axons than membrane-bound AChE.
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PMID:Effect of ischemia on axonal transport of choline acetyltransferase and acetylcholinesterase and on ultrastructural changes of isolated segments of rabbit nerves in situ. 7 11

The effect of ischemia on the integrity of myocardial lysosomes was observed 3 1/2 and 24 hours after the production of infarcts in 20 anesthetized closed-chest dogs by electrically induced thrombosis of the left anterior descending coronary artery. Biopsies from normal, marginal and infarcted areas were fixed and incubated to localize the lysosomal enzymes acid phosphatase and aryl sulphatase. Reaction product in normal cells was localized in small circular or oblong profiles between bundles of myofilaments and adjacent to mitochondria. In addition, curvilinear, membrane-bound profiles containing reaction product were found in close apposition to transverse tubules and near the free margins of the myocardial cells. Thus the distribution of elements of the sarcoplasmic reticulum. Additional reaction product was also seen in residual bodies, on myelin figures, and in the few conventional appearing spherical lysosomes. Little or no acid phosphatase or aryl sulphatase reaction product was seen in the sarcoplasmic reticulum of infarcted myocardium. The degree of cellular degeneration correlated with disappearance of enzyme activity from the sarcoplasmic reticulum and included disruption of membranes and loss of mitochondrial matrix and erosion of I but not A bands. Marginal areas showed variable amounts of cellular degeneration. Separation of myofilament bundles and loss of glycogen correlated with the localized disappearance of acid phosphatase and aryl sulphatase activity in marginal tissue. Disruption of mitochondrial and erosion of I bands correlated with extensive loss of these enzymes. The data suggest that degeneration of myocardial cells following ischemic injury is associated with release of endogenous lysosomal enzymes from the sarcoplasmic reticulum.
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PMID:Cytochemical localization of lysosomal enzyme activity in normal and ischemic dog myocardium. 16 85

Insulin accelerates the entry of glucose and amino acids into muscle cells by acting upon the 'carrier-facilitated' transport mechanism. For glucose this process is passive and leads to equilibration of intracellular and extracellular concentrations. In heart muscle, glucose transport is a rate-limiting step for glucose uptake. During hypoxia and ischemia the heart turns to anaerobic glycolysis for energy production and therefore, maximal glucose transport becomes important. Insulin is necessary to insure proper protein synthesis, probably at the level of membrane-bound polyribosomes. However, during myocardial hypoxia, insulin alone cannot restore the associated depression in protein synthesis. Although insulin hyperpolarizes the cell, a change in the ratio of intracellular to extracellular activities of potassium is not its primary mode of action. An insulin-induced configurational change in the plasma membrane could simultaneously account for the effects of insulin on sodium and potassium permeability and the action on facilitated transport. Intracellular levels of cyclic adenylate may be reduced by insulin in adipose tissue because of inhibition of adenyl cyclase or stimulation of phosphodiesterase. However, at this time there is little evidence that insulin alters cyclic AMP levels in the heart. Insulin secretion is depressed in patients with heart disease in proportion to the reduction of cardiac index sustained. Since the ischemic heart is dependent upon glucose as the major fuel, insulin lack may deprive the heart of adequate substrate.
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PMID:Insulin: fundamental mechanism of action and the heart. 18 67

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

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

Myocardial biochemical systems which are sensitive to hypoxic and ischemic insult were studied to determine the possible etiology of ventricular endocardial hemorrhage in miniature swine following +GZ stress. Unanesthetized animals were subjected to a single, 120-s +9 GZ acceleration. Approximately 1-2 h following +GZ exposure, the animals were anesthetized and the hearts removed for analyses. Acceleration exposure resulted in the loss of acid phosphatase enzyme activity from the membrane-bound lysosomal fraction with concomitant increased activity in the soluble fraction. This suggests that lysosomal membrane integrity had been disrupted. Mitochondrial preparations from +GZ-stressed hearts exhibited marked increases in active respiratory rate and rate of calcium transport while oxidative phosphorylation efficiency was unchanged. The results clearly indicate that +GZ acceleration is capable of altering myocardial biochemical systems. However, the results tend to suggest that these alterations in cellular processes may be mediated by influences other than hypoxia or ischemia.
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PMID:Heart biochemical responses in miniature swine subjected to +Gz acceleration. 121 43

The brain cyclic AMP generation was studied in rats subjected to 15 min of cardiac arrest. We have used a particulate, synaptoneurosomal fraction to demonstrate the effect of ischemia in vivo on the responsiveness of adenylate cyclase (AC) system. It has been shown that, although there is a slight decrease in AC activity after ischemia, the in vitro fractions produce more cAMP in response to a variety of stimuli, suggesting an indirect, nonadenylate cyclase activation mechanism. For elucidation of this mechanism we have probed phorbol-12,13-dibutyrate (PDBu) as a direct PKC activator, forskolin to activate the catalytic subunit of AC, and cholera toxin (CT) for stabilizing the active, GTP-bound form of stimulatory guanine nucleotide binding protein (Gs). All these postreceptor AC modulators as well as the receptor activators such as adenosine and alpha 1-adrenergic agonists markedly enhanced cAMP production in the rat brain particulate fraction, although the postischemic hyperactive response to these stimuli was still present. However, when AC was stimulated by the combination of CT and PDBu, cAMP responses were identical in both control and postischemic fractions. The data, taken together, support the hypothesis that ischemia increases cAMP accumulation by facilitating the postreceptor AC activation through a PKC-involving pathway and by promoting the stronger coupling of membrane AC receptors with G-protein. Protein kinase C (PKC) activity during cerebral ischemia was also investigated. In contradistinction to our expectation PKC decreased significantly in the ischemic brain to 85% of the control activity in the cytosol and 72% in the membranes. However, in the incubated post-ischemic brain particulate fraction a relative increase in the membrane-bound form of the enzyme, from 30% for control to 53% for ischemia, was observed. This may suggest that ischemia-induced membrane changes could promote the enzyme translocation/activation during recovery, resulting in the sensitization of cAMP producing system.
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PMID:Postreceptor modulation of cAMP accumulation in rat brain particulate fraction after ischemia--involvement of protein kinase C. 135 40

Covalent linkage of polyethylene glycol to superoxide dismutase prolongs the serum half-life of the enzyme and may facilitate intracellular access. We tested the myocardial protective effect of polyethylene glycol superoxide dismutase administered once, 24 hours before ischemia. Because hearts were studied ex vivo in a crystalloid perfused system, cardioprotection could be ascribed to intramyocardial or membrane-bound polyethylene glycol superoxide dismutase accumulation. Thirty isolated rabbit hearts from the four following groups were studied: (1) control: untreated rabbits (n = 7); (2) PEG-control: 24-hour intravenous preinfusion of methoxypolyethylene glycol 5000 (5 mg/kg) to examine the effect of polyethylene glycol alone, without conjugation to superoxide dismutase (n = 8); (3) PEG-SOD 10,000: 24-hour preinfusion of polyethylene glycol superoxide dismutase (10,000 U/kg) (n = 8); (4) PEG-SOD 30,000: 24-hour preinfusion of polyethylene glycol superoxide dismutase (30,000 U/kg) (n = 7). After measurement of baseline function with use of an intraventricular balloon, hearts were subjected to normothermic ischemia until a 4 mm Hg rise in intracavitary pressure was observed. Function was assessed at 15-minute intervals throughout reperfusion and expressed as percent return of developed pressure. After 60 minutes of reperfusion, recovery of function was greater for the PEG-SOD 30,000 group (85.6% +/- 2.6%) when compared with either the untreated or PEG-control group (68.9% +/- 2.3% and 71.4% +/- 2.0%, respectively). A similar difference was seen throughout reperfusion. Although an improved return of function was shown in the lower dose PEG-SOD 10,000 group, the margin of difference when compared with any of the control groups was determined to be insignificant at all times of reperfusion and at 60 minutes (75.9% +/- 3.2%). These data demonstrate that high, but not low, doses of polyethylene glycol superoxide dismutase significantly reduce reperfusion injury when administered 24 hours before initiation of global ischemia. Moreover, since the perfusate was superoxide dismutase free, this effect was most likely intramyocardial or membrane bound and therefore might be added to protection afforded by circulating superoxide dismutase.
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PMID:Polyethylene glycol-conjugated superoxide dismutase attenuates reperfusion injury when administered twenty-four hours before ischemia. 145 23

In renal preservation, the longer the organ is cold stored the greater the damage to the organ. The mechanism of hypothermic-induced kidney injury is not known. In this study the effects of long-term preservation (up to 120 h) of the dog kidney on mitochondrial functions in an homogenate of kidney cortex tissue was investigated. Kidneys were exposed to either warm ischemia (0 to 90 min) cold ischemia (0, 72, 96, and 120 h). The mitochondrial oxygen uptake was measured in an homogenate. In both warm and cold ischemia there were changes in the mitochondrial utilization of oxygen. The changes were characterized as a decrease in uncoupler stimulated oxygen uptake by up to 40%, an increase in oligomycin-sensitive respiration by up to about 150%, and a decrease in the respiratory control ratio (uncoupler control ratio) from about 3 to 1. These changes in mitochondrial utilization of oxygen were partially reversed by including albumin in the respiration medium. Albumin binds free fatty acids and these may originate, during ischemia, from the action of phospholipases during ischemia. The changes in mitochondrial oxygen uptake may result from both the loss of membrane-bound phospholipids and the accumulation of free fatty acids. The changes in mitochondrial activity between 72 h (viable kidneys on transplantation) and 96 to 120 h preservation (nonviable kidneys) were not significant. Furthermore, reperfusion of kidneys preserved for 72 to 120 h resulted in a restoration of mitochondrial oxygen uptake to near normal (control) values. Thus, it does not appear that the limitation of successful long-term renal preservation is due to mitochondrial injury caused by cold ischemia.
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PMID:Energy metabolism and renal ischemia. 150 57

We examined the influence of brain ischemia on the activity and subcellular distribution of protein kinase C (PKC). Two different models of ischemic brain injury were used: postdecapitative ischemia in rat forebrain and transient (6-min) cerebral ischemia in gerbil hippocampus. In the rat forebrain model, at 5 and 15 min postdecapitation there was a steady decrease of total PKC activity to 60% of control values. This decrease occurred without changes in the proportion of the particulate to the soluble enzyme pools. Isolated rat brain membranes also exhibited a concomitant decrease of [3H]phorbol 12,13-dibutyrate ([3H]PDBu) binding with an apparent increase of the ligand affinity to the postischemic membranes. On the other hand, the ischemic gerbil hippocampus model displayed a 40% decrease of total PKC activity, which was accompanied by a relative increase of PKC activity in its membrane-bound form. This resulted in an increase in the membrane/total activity ratio, indicating a possible enzyme translocation from cytosol to the membranes after ischemia. Moreover, after 1 day of recovery, a statistically significant enhancement of membrane-bound PKC activity resulted in a further increase of its relative activity up to 162% of control values. In vitro experiments using a synaptoneurosomal particulate fraction were performed to clarify the mechanism of the rapid PKC inhibition observed in cerebral tissue after ischemia. These experiments showed a progressive, Ca(2+)-dependent, antiprotease-insensitive down-regulation of PKC during incubation. This down-regulation was significantly enhanced by prior phorbol (PDBu) treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of brain ischemia on protein kinase C. 154 77


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