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)

A myocardial membrane fraction enriched in sarcolemma was used to determine the susceptibility of the lipids to hydrolysis by a phospholipase A2 from granulocytes. After incubation (37 C, pH 7.0, 5 mM Ca2+) with the phospholipase A2 for 30 min, a more than 3-fold increase in unesterified fatty acids was found (up to 47 nmol/mg protein; P < 0.001) relative to a control incubated without phospholipase A2 or Ca2+. This included a 10-fold increase in the arachidonic acid content (up to 42 mol%) and at least a 7-fold increase in lysophosphatidylethanolamine (up to 7.4 mol% total phospholipid-P). However, the exogenous phospholipase did not augment the quantity of lysophosphatidylcholine produced by endogenous phospholipases in the presence of Ca2+ (5 mM). These results demonstrate the in vitro susceptibility of phospholipids of myocardial membranes, particularly phosphatidylethanolamine, to the neutral-active, Ca2+-dependent phospholipase A2 from granulocytes. This work may be relevant to myocardial inflammation and tissue damage during ischemia, where heterolytic injury of the myocardium may occur subsequent to the accumulation of granulocytes.
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PMID:Lipids of myocardial membranes: susceptibility of a fraction enriched in sarcolemma to hydrolysis by an exogenous mammalian phospholipase A2. 741 9

The involvement of phospholipase A2 (PLA2) products in ischemia-evoked release of excitatory neurotransmitter amino acids (EAAs) from the cerebral cortex was studied in a four vessel occlusion rat model of cerebral ischemia/reperfusion. In comparison with untreated animals, arachidonic acid (AA; 5 x 10(-7) M to 5 x 10(-5) M) significantly reduced the ischemia-evoked efflux of glutamate and aspartate into cortical superfusates. Direct application of lysophosphatidylcholine (LysoPC; 55.4 micrograms/ml) to the cerebral cortex of non-ischemic animals resulted in a significant increase in glutamate levels. These results indicate that the immediate products of PLA2 action on plasma membrane phospholipids can either enhance or inhibit excitotoxic amino acid release following cerebral ischemia. The effect of AA is likely to be a result of its ability to inhibit PLA2; that of LysoPC, a consequence of its detergent action.
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PMID:Arachidonic acid and lysophosphatidylcholine modulate excitatory transmitter amino acid release from the rat cerebral cortex. 747 65

There is widespread interest in the neurotoxicity of the endogenous excitatory amino acid neurotransmitter glutamate. Excessive glutamate release or accumulation leads to neuronal injury or death in a variety of experimental models of ischemia, anoxia and hypoglycemia. This injury appears to be caused by overactivation of the N-methyl-D-aspartate (NMDA) subclass of glutamate receptors since a variety of competitive and uncompetitive NMDA antagonists can attenuate this process, sometimes in a dramatic fashion. Given the clinical context in which this form of neuronal injury occurs, it would be desirable if we could identify agents that blocked NMDA toxicity, after initial receptor binding and ion channel fluxes had transpired. Because NMDA receptor activation initiates the arachidonic acid cascade, we have recently looked at whether the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) can reduce NMDA neurotoxicity in vitro. In the concentration range 1-30 microM, NDGA diminished the death of cultured rodent hippocampal neurons produced by 100 microM NMDA. When 30 microM NDGA was present both before and after NMDA exposure, death declined by over 50%. NDGA did not block NMDA-induced inward currents in voltage-clamped neurons, so the drug is not a direct NMDA receptor antagonist. It also had no effect on the elevation in intracellular calcium produced by NMDA exposure. It is likely that NDGA acts at a site(s) distal to the NMDA receptor and the neuronal membrane to limit NMDA toxicity. We are hopeful that strategies for limiting excitotoxicity, which halt destructive intracellular events, can be developed for use in human neurological diseases linked to excessive stimulation of glutamate receptors.
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PMID:Nordihydroguaiaretic acid attenuates NMDA neurotoxicity--action beyond the receptor. 750 52

Myocardial ischemia in vivo is associated with dramatic electrophysiologic alterations which occur within minutes of cessation of coronary flow and are rapidly reversible with reperfusion. This suggests that subtle and reversible biochemical and/or ionic alterations within or near the sarcolemma may contribute to the electrophysiologic derangements. Our studies have concentrated on 2 amphipathic metabolites, long-chain acylcarnitines and lysophosphatidylcholine (LPC) which have been shown to increase rapidly in ischemic tissue in vivo and to elicit electrophysiologic derangements in normoxic tissue in vitro. Incorporation of these amphiphiles into the sarcolemma at concentrations of 1 to 2 mol%, elicits profound electrophysiologic derangements analogous to those observed in ischemic myocardium in vivo. LPC is produced in endothelial cells and myocytes in response to thrombin. Thus, activation of the coagulation system during ischemia may result in extracellular production and accumulation of LPC. The pathophysiological effects of the accumulation of both amphiphiles are thought to be mediated by alterations in the biophysical properties of the sarcolemmal membrane, although there is a possibility of a direct effect on ion channels. Inhibition of carnitine acyltransferase I in the ischemic cat heart was found to prevent the increase in both long-chain acylcarnitines and LPC and to significantly reduce the incidence of malignant arrhythmias including ventricular tachycardia and fibrillation. This review focuses on the influence of these amphiphiles on cardiac ionic currents observed during early ischemia and presents data supporting the concept that accumulation of these amphiphiles within the sarcolemma contributes to changes in ionic conductances leading to electrophysiological derangements. The contribution and the accumulation of these amphiphiles to alterations in intracellular Ca2+ as related to changes in Na/K-ATPase activity and intracellular Na+ are examined. Other alterations occur during early myocardial ischemia in addition to the events reviewed here; however, the results of multiple studies over the past 2 decades indicate that accumulation of these amphiphiles contributes importantly to arrhythmogenesis and that development of specific inhibitors of carnitine acyltransferase I or phospholipase A2 may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease in man.
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PMID:Selected metabolic alterations in the ischemic heart and their contributions to arrhythmogenesis. 754 31

In this study the effect of an inhibitor of lipid peroxidation and of phospholipase A2 activity, EPC-K1, on spatial learning deficit and neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. EPC-K1 (10 mg/kg IP) was administered either a) 15 min before induction of ischemia, b) immediately after, or c) 30 min after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. EPC-K1 reduced the deficit in spatial learning when given immediately or 30 min after the onset of reperfusion but not when applied 15 min before ischemia. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was slightly, but not significantly attenuated by posttreatment. The present data demonstrate that posttreatment with EPC-K1 exerts a protective effect on deficits in spatial learning induced by 4VO. These results support the hypothesis that lipid peroxidation and activation of phospholipase A2 contribute to functional alterations of the brain during reperfusion following forebrain ischemia.
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PMID:Posttreatment with EPC-K1, an inhibitor of lipid peroxidation and of phospholipase A2 activity, reduces functional deficits after global ischemia in rats. 769 79

Mepacrine, a cell membrane stabilizer and inhibitor of phospholipase A2 (PLA2), exerts a protective effect on ischemia-reperfusion injury in heart; however, its effect in lungs has not been examined. This study aimed to determine whether mepacrine pretreatment attenuates ischemia-reperfusion lung injury simulated by hypoxia reoxygenation and to identify possible mechanisms for such protection. Acute lung injury was induced in Sprague-Dawley rats by ventilation with 5% CO2-95% N2 and 5% CO2-95% air. Pretreatment with 0.06 mM mepacrine significantly attenuated the acute lung injury. Capillary filtration coefficient, lung weight gain, and protein concentration of lung lavage fluid were significantly lower in mepacrine-treated rats than in rats exposed to hypoxia reoxygenation alone. Steroid dexamethasone, another potential PLA2 inhibitor, had almost no protective effect. Mepacrine but not dexamethasone caused dose-dependent attenuation of the increase in leukocyte chemiluminescence produced by exposure to phorbol myristate acetate. Mepacrine also dose-dependently inhibited production of tumor necrosis factor-alpha (TNF-alpha) by human monocytes; dexamethasone was much less effective in decreasing TNF-alpha production. We conclude that mepacrine but not dexamethasone can significantly attenuate a hypoxia-reoxygenation-induced injury of the lung. This protective effect of mepacrine may not be the result of its inhibition of PLA2 but rather of its downregulation of oxygen radical production by circulating or resident leukocytes or its attenuation of TNF-alpha production by macrophages.
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PMID:Protective effect of mepacrine on hypoxia-reoxygenation-induced acute lung injury in rats. 771 16

The involvement of phospholipases in ischemia-evoked release of aspartate, glutamate, glycine, and GABA from the cerebral cortex was studied in a four vessel occlusion rat model of cerebral ischemia/reperfusion. In comparison with the control group, the phospholipase A2 inhibitor mepacrine significantly decreased the ischemia-evoked efflux of transmitter amino acids into cortical superfusates. Direct application of phospholipases A2 or C to the cerebral cortex of non-ischemic animals resulted in a significant increase in amino acid levels. These results suggest that neurotransmitter release following cerebral ischemia may involve phospholipase induced plasma membrane disruption.
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PMID:A possible role for phospholipases in the release of neurotransmitter amino acids from ischemic rat cerebral cortex. 775 89

We induced cerebral complete ischemia (CCI) by "four-vessel" model. The changes of Na+,K(+)-ATPase, Ca2+, Mg(2+)-ATPase, phospholipase A2 (PLA2), total phospholipids on brain cellular membrane (BCM) at 30, 180, 360 min of reperfusion following 30 min CCI were observed. The effects of selective head cooling (SHC, 28C, surface cooling method), mannitol dehydration (MD), and selective head cooling-dehydration combined therapy (SHCDCT) on these changes were also investigated. Compared with non-ischemic, during reperfusion activities of Na+, K(+)-ATPase, Ca2+, Mg(2+)-ATPase decreased while PLA2 increased (P < 0.001), phospholipids decreased at 180 and 360 min of reperfusion (P < 0.01). SHC and SHCDCT blocked all above changes, MD had no effect. These results suggest that SHCDCT after starting reperfusion do promote recruitment of BCM function by blockade of the successive reperfusion damage on BCM.
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PMID:[Study of mechanism of selective head cooling-dehydration combined therapy for brain resuscitation: effect on function of brain cellular membrane]. 777 12

Our in vivo model of mesenteric ischemia/reperfusion (I/R) has shown that the gut serves as a priming bed for neutrophils (PMN). Activation of phospholipase A2 (PLA2) during ischemia temporally precedes PMN sequestration in the gut and the appearance of primed PMN in the portal circulation. Therefore, we hypothesized that reperfused gut secretes platelet activating factor (PAF) via PLA2 activation that is responsible for increased PMN chemotaxis and priming for superoxide (O2-) generation. Sprague-Dawley rats underwent gut ischemia/reperfusion (45 min SMA occlusion/2 hr reperfusion) or sham laparotomy. Distal ileum was harvested, rinsed with bacteriostatic saline/neomycin, and incubated for 1 hr at 37 degrees C in RPMI 1640 and the cell-free supernatant was collected. Normal human PMNs, isolated by plasma-Percoll gradients, were pretreated with or without a PAF receptor antagonist (WEB 2170). Chemotaxis toward gut supernatant was then measured by the agarose method. Additionally, PMNs were preincubated with or without WEB 2170 and their O2- release in response to 1 microM FMLP was measured by the Vmax of SOD-inhibitable cytochrome c reduction. Reperfused gut produced a chemotactic index of 2.1 +/- 0.1 compared to 0.2 +/- 0.9 following sham laparotomy (P < 0.05); this was reduced to 0.4 +/- 0.9 with PAF receptor blockade. Similarly, gut I/R supernatant primed PMNs for O2- (P < 0.05) compared to laparotomy, and this effect was abrogated by a PAF antagonist. These data suggest that reperfused gut can elaborate PAF which chemoattracts and primes PMNs for O2- generation.
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PMID:Reperfused gut elaborates PAF that chemoattracts and primes neutrophils. 779 40

Intestinal ischemia-reperfusion (I/R) provokes polymorphonuclear neutrophil (PMN)-mediated lung injury via a process characterized by circulating PMN priming, pulmonary PMN sequestration, and increased microvascular leak in the lung. We found in rats subjected to intestinal I/R (ischemia 45 min and reperfusion 6 h) that 1) intestinal phospholipase A2 (PLA2) was activated during ischemia, 2) circulating PMN priming (assessed by superoxide production with N-formyl-Met-Leu-Phe) occurred after 1 h reperfusion, and 3) exaggerated 125I-labeled albumin lung leak occurred after 2 h reperfusion, compared with sham-treated animals (P < 0.05). Treatment with a PLA2 inhibitor, quinacrine, within 15 min of reperfusion reversed the exaggerated gut PLA2 activity and abrogated subsequent PMN priming and lung leak (P < 0.05). However, when quinacrine was administered after 2 h of reperfusion, circulating PMN priming and lung leak continued to evolve despite suppression of intestinal PLA2 activity. We conclude that intestinal PLA2 activation may be a prerequisite for the sequelae of circulating PMN priming and pulmonary microvascular leak observed after intestinal I/R.
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PMID:Gut phospholipase A2 mediates neutrophil priming and lung injury after mesenteric ischemia-reperfusion. 790 Aug


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