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

To elucidate the pathogenesis of acute acalculous cholecystitis, the gallbladder was subjected to ischemia-reperfusion by simultaneously occluding the middle hepatic artery and the superior mesenteric vein in dogs, and the degree of inflammation and biochemical changes in the gallbladder mucosa were studied by varying the duration of ischemia or reperfusion. Ischemia alone did not induce cholecystitis either macroscopically and histologically, although it increased phospholipase A2 (PLA2) activity, content of lipid peroxide, and superoxide dismutase (SOD) activity in the mucosa with prolongation of the ischemic time. Cholecystitis was produced in all animals by 45-min ischemia followed by 90-min reperfusion as the shortest ischemia and reperfusion times. In this model, prolongation of the ischemic time increased the area of mucosal inflammation horizontally with increases of the PLA2 activity, content of lipid peroxide, and SOD activity, whereas by prolonging the reperfusion time the inflammation area spread deeper vertically toward the serosal side with significant increase in the mucosal PLA2 activity, content of lipid peroxide, and SOD activity. These results revealed that ischemia-reperfusion plays an important role in the pathogenesis of acute acalculous cholecystitis, causing the generation of free radicals and the activation of membrane-bound PLA2.
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PMID:Experimental study on the pathogenesis of acute acalculous cholecystitis, with special reference to the roles of microcirculatory disturbances, free radicals and membrane-bound phospholipase A2. 175 95

Several feasible mechanisms have been proposed as sources of neuronal damage from ischemia and subsequent reperfusion. Included among these are oxidative damage caused by free radical production and lipid peroxidation and products derived from phospholipid breakdown. A series of 4-thiazolidinone compounds represented by LY178002 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene-4-thiazolidinon e) have been described as inhibitors of multiple enzymes in the arachidonic acid cascade, including fatty acid cyclooxygenase, 5-lipoxygenase, and phospholipase A2. Accordingly, we evaluated LY178002 in a four-vessel occlusion model of global forebrain ischemia with reperfusion. A 2-hour pretreatment of 11 male Wistar rats with 150 mg/kg LY178002 significantly protected against striatal (p = 0.0007) and hippocampal CA1 (p = 0.006) damage after 30 minutes of global ischemia. Similar protection was observed for the striatum (p = 0.005) and hippocampal CA1 layer (p = 0.025) after pretreatment of 13 rats with 50 mg/kg LY178002. We further evaluated LY178002 as a possible inhibitor of lipid peroxidation because part of its chemical structure incorporates the aromatic backbone of the known antioxidant butylated hydroxytoluene. We found LY178002 to be a potent inhibitor of iron-dependent lipid peroxidation. Few substances possessing a single pharmacological activity have been found to be of significant therapeutic benefit in global ischemia of 30 minutes' duration because the mechanisms that lead to cell death in response to ischemia are likely to be multifactorial. Thus, the efficacy of LY178002 in this model may be due to its ability to inhibit multiple sources of damage.
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PMID:LY178002 reduces rat brain damage after transient global forebrain ischemia. 186 52

Free radical species have been implicated as important agents in ischemia-reperfusion injury associated to transplantation procedures. This study was carried out to investigate the possible relationship between phospholipase A2 activity (PLA2), lipoperoxidation, and the changes in arachidonic acid metabolism during ischemia reperfusion injury in pancreas transplantation, as well as the effect of a free radical scavenger such as superoxide dismutase on these changes. For this purpose male Lewis rat groups (n = 7) were classified as follows: group I--control; group II--syngenic pancreas transplantation after 15 min preservation in Collins solution at 4 degrees C; group III--syngenic pancreas transplantation after 18 hr preservation in the same conditions; group IV--same as III but with administration of SOD (i.v.) immediately before revascularization in the recipient rat. The results indicate that significant increases in PLA2 activity and lipoperoxide levels occur concomitantly with an increase of thromboxane B2 (TXB2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) in pancreatic tissue after pancreas transplantation. The counteracting effect of a free radical scavenger such as SOD supports the role of oxygen free radicals (OFR) mediating activation of PLA2 and subsequent formation of eicosanoids in pancreas transplantation.
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PMID:Tissular prostanoid release, phospholipase A2 activity, and lipid peroxidation in pancreas transplantation. 190 24

The alpha 1-adrenergic receptor exists as at least two distinct subtypes, alpha 1a and alpha 1b. Based on hydrophobic exclusion studies and limited proteolysis of the cloned receptor, it appears to possess characteristics analogous to other membrane-bound receptors including seven membrane spanning domains, three extracellular, and three intracellular loops, with extensive glycosylation near the extracellular amino terminus. Although the receptor is coupled to phospholipase C in cardiac myocytes, with activation resulting in the production of inositol trisphosphate (IP3) and diacylglycerol, recent findings suggest that the receptor may also be linked to phospholipase A2, phospholipase D, and cyclic nucleotide phosphodiesterase. The alpha 1-adrenergic receptor has been shown to increase in response to myocardial ischemia in a number of different species and to mediate not only positive inotropic effects, but also to contribute substantially to arrhythmogenesis. The increase in alpha 1-adrenergic receptors can also occur in isolated adult ventricular myocytes in response to hypoxia, a mechanism which appears to be secondary to the sarcolemmal accumulation of long-chain acylcarnitines. This increase in alpha 1-adrenergic receptors in hypoxic myocytes is also linked to an enhanced increase in IP3 in response to receptor stimulation. These and other findings obtained in vivo during ischemia suggest that alpha 1-adrenergic mechanisms can become prominent in myocardium under pathophysiologic conditions in which a depressed contractile state exists and may therefore serve as a secondary inotropic system. However, the arrhythmogenic effects of stimulation of the alpha 1-adrenergic receptor in the ischemic heart in man may contribute substantially to arrhythmogenesis and, thereby, to the incidence of sudden cardiac death.
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PMID:Modulation of alpha-adrenergic receptors and their intracellular coupling in the ischemic heart. 196 2

The authors investigated the high affinity binding of [3H] muscimol to the receptor of synaptic plasma membranes (SPM) isolated from a normoxic and ischemic brain. Brain ischemia enhanced the [3H] muscimol binding to the receptor, located in native (Triton X-100 untreated) membranes. Scatchard's analysis showed that the total number of binding sites (BMAX) and the KD value increased by about 60%. The higher KD value persisted during 20 min of the reperfusion period. Concomitantly, ischemia stimulated the activity of phospholipase C and phospholipase A2, acting against phosphatidylinositol (PI). The degradation of PI and a transient accumulation of docosahexaenoic and arachidonic acids may be important factors involved in the modification of high affinity agonist binding to the GABAA receptor of SPM isolated from the brain submitted to ischemia.
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PMID:Brain ischemia increased high affinity binding of [3H]muscimol into synaptic plasma membrane receptor. 196 57

We investigated the role of phospholipase A2 (PLA2) and phospholipase C (PLC) in myocardial phosholipid degradation and cellular injury during reperfusion of ischemic myocardium. For this purpose, isolated rat hearts were perfused with isotopic arachidonic acid to label its membrane phospholipids. Hearts preperfused with antiphospholipase A2 (anti-PLA2) retained a significantly higher amount of radiolabel in phosphatidylcholine and phosphatidylinositol and a corresponding lower amount of radiolabel in lysophosphatidylcholine and nonesterified fatty acids (P less than 0.05) after 30 min of reperfusion following 30 min of normothermic global ischemia compared with hearts preperfused with nonimmune immunoglobulin G. In similar experiments, antiphospholipase C (anti-PLC)-treated hearts were associated with significantly (P less than 0.05) higher radiolabel in all phospholipids and lower radiolabel in diacyglycerol compared with nonimmune immunoglobulin G-treated hearts. Measurement of phospholipase activity in subcellular organelles of these hearts showed decreased PLA2 activity in cytosol, mitochondria, and microsomes of anti-PLA2-treated hearts and decreased PLC activity of microsomes in anti-PLC-treated hearts. Furthermore, both the antiphospholipases attenuated the release of creatine kinase and lactate dehydrogenase into perfusate and increased contractility as well as coronary flow in the reperfused hearts. Results of this study suggest that both PLA2 and PLC are involved in the degradation of phospholipids and cellular injury that occur during reperfusion of ischemic myocardium.
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PMID:Role of phospholipases A2 and C in myocardial ischemic reperfusion injury. 200 Sep 82

Lysophosphoglyceride accumulation in ischemic myocardium has been hypothesized to be a mechanism for altered sarcolemmal properties that underlie electrophysiological changes and Ca2+ accumulation in ischemia. We find that in vitro application of lysophosphatidylcholine to normal canine sarcolemmal vesicles at a concentration of 0.3 mumol/mg sarcolemmal protein inhibits Na(+)-Ca2+ exchange. Both maximum velocity (Vmax) for Ca2+ transport and Ca2+ affinity are reduced by lysophosphatidylcholine, whereas in ischemia only Vmax is reduced [M. M. Bersohn, K. D. Philipson, and J. Y. Fukushima. Am. J. Physiol. 242 (Cell Physiol. 11): C288-C295, 1982]. This amount of lysophosphatidylcholine does not affect sarcolemmal passive permeability to either Ca2+ or Na+. Treatment of sarcolemma with phospholipase A2 sufficient to inhibit Na(+)-Ca2+ exchange velocity by 50% causes large increases in sarcolemmal lysophosphatidylcholine and lysophosphatidylethanolamine. On the other hand, 1 h of ischemia in rabbit hearts does not affect sarcolemmal phospholipid composition. Thus, although in vitro treatment with lysophosphatidylcholine or phospholipase A2 has profound effects on sarcolemmal properties, sarcolemmal accumulation of lysophosphatidylcholine cannot account for the effects of ischemia as measured in highly purified sarcolemmal vesicles from ischemic hearts.
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PMID:Lysophosphatidylcholine and sodium-calcium exchange in cardiac sarcolemma: comparison with ischemia. 200 70

Recently, the prototype of a novel class of calcium-independent plasmalogen-selective phospholipase A2 activities was identified in the cytosolic fraction of canine myocardium (Wolf, R.A., and Gross, R.W. (1985) J. Biol. Chem. 260, 7295-7303) and subsequently purified and characterized (Hazen, S.L., Stuppy, R.J., and Gross, R.W. (1990) J. Biol. Chem. 265, 10622-10630). We now demonstrate that 15 min of myocardial ischemia utilizing a rabbit Langendorf perfused heart model results in a 10-fold increase in membrane-associated calcium-independent phospholipase A2 activity whose detection is entirely dependent upon utilization of plasmalogen substrate. Ischemia-induced phospholipase activity was identified as a membrane bound member of this class of phospholipases A2 by demonstration of: 1) concomitant production of lysoplasmenylcholine and sn-2 fatty acid from plasmenylcholine substrate; 2) maximal enzymatic activity in the absence of calcium ion; and 3) a 16-fold higher maximum reaction velocity utilizing plasmenylcholine compared to phosphatidylcholine substrate at multiple surface concentrations. Ischemia-induced phospholipase A2 activity was specifically localized to the microsomal fraction and could not be solubilized by sonication, salt treatment, exposure to chelators, or utilization of submicellar concentrations of detergent. The appearance of microsomal phospholipase A2 activity did not require ischemia-induced transcription or translation since identical increases in enzymic activity were obtained in hearts previously treated with actinomycin D and cycloheximide. Collectively, these results demonstrate that a membrane-associated calcium-independent phospholipase A2 that selectively hydrolyzes plasmalogen molecular species is the likely enzymic mediator of accelerated phospholipid catabolism during early myocardial ischemia.
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PMID:Activation of a membrane-associated phospholipase A2 during rabbit myocardial ischemia which is highly selective for plasmalogen substrate. 200 3

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. 203 71

Brain phospholipase A2 (PLA2) activity has not been well characterized. Given the importance of this enzymatic activity for a variety of cellular functions in the brain, we characterized the subcellular distribution of PLA2 activity in gerbil brain and evaluated how PLA2 activity was altered by ischemia and reperfusion. Cytosolic, mitochondrial, and microsomal fractions were prepared by differential centrifugation of forebrain homogenates. PLA2 activities of each fraction were assayed by measuring release of arachidonic acid (AA) from exogenous 14C-AA-phosphatidylcholine (PC), -phosphatidylethanolamine (PE), and -phosphatidylinositol (PI). Two forms of PLA2 were present in the cytosolic fraction: a high-molecular-weight form, active against PC and PE, and a smaller form with an Mr of approximately 14 kDa, active against PE. In the mitochondrial and microsomal fractions, a single form (Mr approximately 14 kDa) was dominant, active against both PC and PE. The role of PLA2 activation in ischemic brain injury remains controversial. PLA2 enzymatic activity was characterized in gerbil brain after 10 min of common carotid occlusion, followed by 10 min of reperfusion. Ischemic/reperfused brains had significantly higher PLA2 specific activities in each subcellular fraction. Ischemia and reperfusion did not change the gel-filtration elution patterns of PLA2 activity of the various forms of the enzyme. Cytosolic, mitochondrial, and microsomal activities were optimal at a pH of approximately 8.5. Cytosolic PLA2 activity was enhanced when Ca2+ concentration [( Ca2+]) was increased over the physiological range (10(-7) to 10(-6) M). Mitochondrial and microsomal PLA2 activities were also [Ca2+] dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of phospholipase A2 (PLA2) activity in gerbil brain: enhanced activities of cytosolic, mitochondrial, and microsomal forms after ischemia and reperfusion. 204 88


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