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)

Vasodepressor prostanoids have been suggested to regulate renal hemodynamics after nephrotoxic injury and thus protect the kidney against the effects of prolonged ischemia. This study assessed whether changes in two microvascular vasodilator prostanoids would correlate with changes seen in renal hemodynamics in rabbits with nephrotoxic renal injury produced by either uranyl nitrate or mercuric chloride. Rabbits were killed at 3, 24, and 72 h after the nephrotoxin injections and 6-ketoprostaglandin (PG) F1 alpha and PGE2 synthesis was measured in vitro in isolated renal microvessels. At the end of 24 h, synthesis of both prostanoids was significantly increased in all nephrotoxin-treated animals, an observation not noted at the end of 3 h. At 72 h, 6-keto-PGF1 alpha production remained elevated. Pretreatment with mepacrine blocked the increased prostanoid production seen in uranyl nitrate-treated animals. Thus, renal microvascular vasodilator prostanoid biosynthesis is increased 24-72 h after nephrotoxin administration. These data suggest that the biosynthesis of prostacyclin and PGE2 may contribute to the maintenance of renal blood flow in the first few days after acute renal injury and further suggest that a mechanism for this increase may be stimulation of phospholipase A2.
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PMID:Alterations in rabbit renal microvascular prostanoid synthesis in acute renal failure. 336 78

Amiodarone is used extensively for the chronic treatment of life-threatening arrhythmias caused by ischemic heart disease. However, chronic therapy with this agent results in phospholipidosis in various tissues and it has been suggested that the inhibition of lysosomal phospholipase A by this drug contributes to this abnormality. Exogenous amiodarone has been shown to inhibit purified rat liver lysosomal phospholipase A1, as well as acid phospholipase activities of alveolar macrophage homogenates and those of snake venom phospholipase A2 and bacterial phospholipase C. The effects of drug treatment on heart have not been explored. The results described here demonstrate that amiodarone also significantly increases (37%, p less than 0.001) phospholipid content in cat hearts. This increase is proportionately distributed to all major phospholipid classes, with the exception of sphingomyelin which appears to increase more than the others. In addition, the data also show that following amiodarone treatment, the endogenous drug levels in the heart were sufficient to reduce in vitro losses of membrane phospholipid at 37 degrees C by inhibiting a variety of endogenous phospholipases at physiological (7.4), ischemic (6.2) and acidic (5.0) pH values. This protection is more pronounced at acidic pH values than at physiological pH. Endogenous amiodarone also affects myocardial phospholipase activities towards exogenous phosphatidylcholine and again the extent of inhibition is more at acidic pH. These results suggest that amiodarone induces phospholipidosis in the heart by inhibiting phospholipid catabolism and that its antiarrhythmic properties may reside in its ability to modulate alkaline, neutral and acid phospholipase activities in ischemia. To what extent amiodarone metabolites (desethylamiodarone and bis-desethylamiodarone) are involved in these actions remains to be determined.
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PMID:Effects of chronic amiodarone treatment on cat myocardial phospholipid content and on in vitro phospholipid catabolism. 345 65

Pretreatment of the ischemic myocardium with verapamil protects against mitochondrial respiratory depression observed during ischemic arrest as well as during reperfusion. Since ischemic mitochondrial function appears not to be altered further by reperfusion, the purpose of this study is to identify a biochemical event affecting mitochondria that is specifically associated with reperfusion injury. It has been proposed that increased cellular Ca2+ influx and oxygen toxicity may result from reintroduction of coronary flow. Increased cytosolic Ca2+ is transmitted to the mitochondria with subsequent activation of Ca2+-dependent events, including phospholipase A2. Net production of lysophospholipids (and loss of total diacylphospholipids from the mitochondria) will proceed when reacylation mechanisms are inhibited. Since acyl-CoA:lysophospholipid acyltransferase is a sulfhydryl-sensitive enzyme and since increased activity of glutathione peroxidase shifts the levels of the mitochondrial sulfhydryl buffer, glutathione, towards oxidation, levels of glutathione and its oxidation state were measured during reperfusion in the absence or presence of verapamil pretreatment. Ischemia lowers total glutathione and reduces the redox ratio (reduced glutathione: oxidized glutathione) by 85%. Reperfusion partially returns the redox ratio to control by causing oxidized glutathione to disappear from the matrix. Verapamil maintains both the concentration and the redox potential of glutathione at control levels. Concomitant with alterations in reduced glutathione:oxidized glutathione is a decrease in ischemic mitochondrial phospholipid content. During reperfusion, phosphatidylethanolamine and its major constituent fatty acids (C 18:0 and C 20:4) are specifically lost from the mitochondrial membrane. Accompanying the significant loss of arachidonic acid during reperfusion is the decreased content of 11-OH, 12-OH, and 15-OH arachidonate. These lipid peroxidation products are not increased in ischemia. It is proposed that oxidation of matrix glutathione to glutathione disulfide during ischemia results in formation of glutathione-protein mixed disulfides and inhibition of sulfhydryl-sensitive proteins, including acyl-CoA lysophosphatide acyltransferase. Thus, metabolic events occurring within the ischemic period set the stage for prolonged dysfunction during reperfusion.
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PMID:Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium. 362 93

Oxygen free radicals and phospholipid degradation have been implicated in the pathogenesis of ischemia and reperfusion injury. The present study examines the involvement of such mechanisms in myocardial reperfusion injury in neonatal hearts. The isolated neonatal pig hearts from two different age groups, 0 to 2 days old (newborn) and 7 to 9 days old (week-old), were subjected to 60 min of normothermic global ischemia followed by 60 min of reperfusion. Although myocardial ischemia reduced superoxide dismutase, catalase, and glutathione peroxidase activities in both age groups, superoxide dismutase and catalase activities remained significantly lower in the newborn pig heart during ischemia and reperfusion. Oxidized glutathione release from the neonatal pig hearts was at minimum levels before ischemia, but it increased 10-fold at the onset of reperfusion and was significantly higher in the newborn heart. This indicates that generation of oxygen free radicals was enhanced in the newborn compared with that in the week-old heart. The increase in phospholipase A2 activity and decrease in acyl CoA synthetase and lysophosphatidylcholine acyl transferase activities during ischemia and reperfusion were associated with comparable loss of membrane phospholipids and accumulation of lysophosphatidylcholine and free fatty acids in both age groups, except that oleic acid content was significantly higher in the newborn heart during reperfusion. Myocardial damage appears to be potentiated in the newborn heart during reperfusion, as evidenced by higher release of creatine kinase and a lower content of high-energy phosphates. These results indicate that oxygen free radicals may play a crucial role in the occurrence of reperfusion injury in immature hearts.
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PMID:The mechanism of myocardial reperfusion injury in neonates. 366 15

Once brain ischemia was induced in the gerbil cerebral fronto-parietal cortex, serial changes occurred in energy metabolites and various lipids. The amounts of inositol-containing phospholipids began to decrease immediately after energy failure, followed by an increase in the amount of 1,2-diacylglycerol with a subsequent liberation of arachidonic acid and other free fatty acids. The fatty acid compositions of inositol-containing phospholipids, of 1,2-diacylglycerols produced by ischemia, and of free fatty acids liberated during ischemia were quite similar. The amount of stearic acid liberated was much larger than that of arachidonic acid between 30 s and 1 min of ischemia. On the other hand, there was no significant decrease in the amount of the other phospholipids except for phosphatidic acid. Furthermore, there was also no change in the fatty acid composition of phosphatidylcholine or phosphatidylethanolamine throughout 15 min of ischemia. The amount of cytidine-monophosphate reached a peak (36.7 nmol/g wet wt) at 2 min of ischemia. These results indicated that arachidonic acid was predominantly liberated from inositol-containing phospholipids by phospholipase C, and by the diglyceride lipase and monoglyceride lipase system rather than from phosphatidylcholine or phosphatidylethanolamine by phospholipase A2 or plasmalogenase or choline phosphotransferase during the early period of ischemia.
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PMID:Mechanism of arachidonic acid liberation during ischemia in gerbil cerebral cortex. 379 19

Gas liquid chromatography was used to study fatty acid (FA) composition of lysophosphatidylcholine (lyso-PC) and phosphatidylcholine in isolated rabbit heart mitochondria. In control, lyso-PC and PC were found to contain 95 and 66% of unsaturated FA, respectively. At 1 hour of ischemia (autolysis at 37 degrees C) the percentage of saturated FA in lyso-PC noticeably increased whereas FA composition remained unchanged. It is concluded that changes in FA composition of lyso-PC are caused by phospholipase A2 action.
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PMID:[Fatty acid composition of mitochondrial phospholipids of the ischemic heart]. 396 69

After periods of 5 and 30 min following decapitation, rat cerebral cortices were removed and subcellular fractions were prepared. Fractions P1A (large myelin), P1B (nuclei), P1C (cells and debris), P2A (small myelin), P2B (synaptosomes), P2C (mitochondria), and P3 (microsomes) were isolated. Free fatty acid levels of 1.0 and 1.4 mumol/g tissue were found in the homogenates at the early and late times of ischemia. In the 30-min samples, P1A, P1C, and P2A had relatively high specific contents of total free fatty acids in comparison with other subfractions. At this time P2C was relatively enriched in arachidonate, P1A and P2A were enriched in palmitate, and P2B and P3 were enriched in stearate in comparison with the homogenate. P2C had the highest ratio of polyunsaturates/saturates in its free fatty acid pool. Comparing the 5- and 30-min samples, a large increase in the quantity of free fatty acids was found in fractions P1A and P2A, so that at the later time P1A + P2A contained 60 mol% of the free fatty acid in the total subfractions derived from cerebral cortex. In comparison with the homogenate, the lack of accumulation of free fatty acids in certain membranes known to possess phospholipase activities (e.g., phospholipase A2 in P2C) and the buildup of free fatty acids in P1A and P2A led to the hypothesis that free fatty acids may be migrating outwards from intracellular sites of production and accumulating in the multilamellar structure of myelin.
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PMID:The subcellular distribution of free fatty acids released during post-decapitative ischemia in rat cerebral cortex. 408 56

Lysolecithin (lysoglycerophosphocholine, LPC) was isolated from rat cerebral cortex and quantitatively analyzed at various times after postdecapitative ischemic treatment. In addition, different procedures for extraction and analysis of the LPC in brain were evaluated. Results indicated that LPC can be quantitatively extracted into the organic phase using the conventional extraction procedure with chloroform-methanol (2:1, vol/vol). However, care should be taken to avoid using strong acids, which can hydrolyze the alkenylether side chain of the plasmalogens, resulting in the release of 2-acylphospholipids. Quantitative GLC analysis using myristoyl-LPC as internal standard revealed a level of 1.8 nmol LPC/mg protein in brain with acyl groups comprised mainly of 16:0, 18:0, and 18:1. The acyl group profile reflects that the LPC are derived mainly from phospholipase A2 action. An increase of 46% in the LPC level was observed at 1 min after ischemic treatment, but this was followed by a steady decline. Ischemia induced an increase in the LPC species that are enriched in 18:0 and 18:1 fatty acids. The transient appearance of LPC during ischemia further suggests that this phospholipid is undergoing active turnover, possibly hydrolysis by the lysophospholipase. This mechanism of action may account, at least in part, for the increase in both saturated and unsaturated fatty acids during the early phase of the ischemic treatment.
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PMID:On the status of lysolecithin in rat cerebral cortex during ischemia. 647 Jul 8

The purpose of the present study was to elucidate the effect of duodenal juice on development of gastric ulcer, in relation to changes of lipid composition and energy metabolism of the gastric mucosa in dogs. For regurgitation of duodenal juice and stagnation of gastric contents in the stomach, the duodenum was constricted below the papilla of Vater, accompanying with pyloroplasty and upper gastro-jejunostomy. Furthermore, to induce ischemia in the gastric mucosa, 0.5 ml of 1% formalin solution was injected into a descending branch of the left gastric artery. Three weeks later, U1 II-III gastric ulcer developed at the formalin injected area with severe gastritis but not with hyperacidity, and the histologic findings were similar to the one of a human gastric ulcer with hypoacidity. On assay of lipid composition in the gastric mucosa, lecithin decreased and both lysolecithin and NEFA increased, showing that lecithin of the gastric mucosa was decomposed by phospholipase A2 of the duodenal juice. In the gastric mucosa, ATP and energy charge decreased, and AMP and lactate increased, indicating that the energy metabolism was led to anaerobic glycolysis. These results revealed that the gastric mucosa becomes very fragile when duodenal juice regurgitates into the stomach and that gastric ulcer may develop even without hyperacidity when the microcirculation is disturbed in this condition.
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PMID:Effect of duodenal juice on pathogenesis of gastric ulcer. 683 47

Extracts of acetone-dried powders from ischemic gerbil brain were examined for phospholipase A1 and A2 activities with phosphatidylethanolamine at pH 7.2. Ischemia was induced by bilateral ligation, and the animals were killed by immersion into liquid nitrogen. Bilateral ligation with ketamine as general anesthetic resulted in a rapid, transient increase in phospholipase A2 activity. The activity increased from 0.46 nmol/h/mg protein at 0 time to 0.82 nmol/h/mg protein at 1 min of ligation. Phospholipase A1 activity also increased from 0.7 go 1.3 nmol/h/mg protein within the 1st min. When Nembutal was used as anesthetic, the phospholipase activation was earlier, within the first 30 s. Similar results were found for ischemia induced by decapitation of Wistar rats without anesthesia. Bilateral ligation of the carotid arteries of the gerbil is known to increase the concentration of free fatty acids, particularly arachidonate. This increase is, at least in part, due to phospholipase A activation. As ethanolamine phospholipase A2 in brain does not require Ca2+ for activity, these results suggest that phospholipase A2 activation in ischemic brain results from a covalent modification of the enzyme.
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PMID:Activation of ethanolamine phospholipase A2 in Brain during ischemia. 711 83


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