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

Ischemia and reperfusion causes severe mitochondrial damage, including swelling and deposits of hydroxyapatite crystals in the mitochondrial matrix. These crystals are indicative of a massive influx of Ca2+ into the mitochondrial matrix occurring during reoxygenation. We have observed that mitochondria isolated from rat hearts after 90 minutes of anoxia followed by reoxygenation, show a specific inhibition in the electron transport chain between NADH dehydrogenase and ubiquinone in addition to becoming uncoupled (unable to generate ATP). This inhibition is associated with an increased H2O2 formation at the NADH dehydrogenase level in the presence of NADH dependent substrates. Control rat mitochondria exposed for 15 minutes to high Ca2+ (200 nmol/mg protein) also become uncoupled and electron transport inhibited between NADH dehydrogenase and ubiquinone, a lesion similar to that observed in post-ischemic mitochondria. This Ca(2+)-dependent effect is time dependent and may be partially prevented by albumin, suggesting that it may be due to phospholipase A2 activation, releasing fatty acids, leading to both inhibition of electron transport and uncoupling. Addition of arachidonic or linoleic acids to control rat heart mitochondria, inhibits electron transport between Complex I and III. These results are consistent with the following hypothesis: during ischemia, the intracellular energy content drops severely, affecting the cytoplasic concentration of ions such as Na+ and Ca2+. Upon reoxygenation, the mitochondrion is the only organelle capable of eliminating the excess cytoplasmic Ca2+ through an electrogenic process requiring oxygen (the low ATP concentration makes other ATP-dependent Ca2+ transport systems non-operational).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial generation of oxygen radicals during reoxygenation of ischemic tissues. 206 Aug 40

Although the specific cause(s) of inflammatory bowel diseases (IBD) has not been identified, one theory suggests ischemia as the early event that occurs in IBD and reperfusion causes sustained release of oxyradicals, leading to inflammation and ulceration. In this study, we have confirmed that H2O2 in the concentration seen during ischemia/reperfusion is primarily responsible for cellular membrane damage in the rat colonic fragments in vitro. Hydrogen peroxide caused a time and dose-dependent increase in 6-keto-PGF1 alpha and TXB2 release. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was blocked (50%) by phospholipase A2 (PLA2) inhibitors quinacrine and dimethyleicosadienoic acid at 5 min. Hydrogen peroxide-stimulated 6-keto-PGF1 alpha release was completely blocked by indomethacin, significantly blocked (69%) by nordihydroguiaretic acid, and completely blocked by catalase. Superoxide dismutase and uric acid failed to inhibit H2O2-stimulated 6-keto-PGF1 alpha release. Endogenous catalase inhibitors 3-aminotriazole and sodium azide further enhanced the release of 6-keto-PGF1 alpha stimulated by H2O2 by 29% and 73%, respectively. Xanthine-xanthine oxidase also increased 6-keto-PGF1 alpha release from the fragments by 110%. This release was not inhibited by superoxide dismutase and uric acid, but was completely inhibited by catalase. These studies suggest a direct effect of H2O2 on colonic fragments leading to submicroscopic cellular membrane damage and excess prostanoid production utilizing a PLA2/cyclooxygenase and catalase-sensitive pathway without the formation of toxic hydroxyl ions. The quick release of 6-keto-PGF1 alpha also suggests an early manifestation of H2O2-induced damage in rat colonic fragments.
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PMID:Hydrogen peroxide-induced alterations in prostaglandin secretion in the rat colon in vitro. 209 May 84

Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.
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PMID:Progress in understanding the pathophysiology of cerebral ischemia: the almitrine-raubasine approach. 209 21

Arachidonic acid is liberated from damaged cell membranes during ischemia and is the source of vasoactive prostanoids. In this study, specific drugs that influence AA metabolism were investigated for their effects on brain edema and energy metabolites during ischemia. The agents tested were: methylprednisolone (phospholipase A2 inhibition), indomethacin (cyclooxygenase inhibitor), trapidil (TXA2 synthetase inhibitor), and OP-41483 (prostacyclin derivative). Cerebral ischemia was produced using bilateral common carotid artery occlusion in spontaneously hypertensive rats. Brain water content and concentrations of ATP, pyruvate, and lactate were determined 3 hr after occlusion. Compared with its vehicle, methylprednisolone significantly reduced water content and lactate concentration and maintained high levels of ATP. Indomethacin had no effect on brain water content nor metabolite levels. Trapidil decreased water content and lactate levels and increased levels of ATP and pyruvate. OP-41483 had no effect on water content and lactate, but maintained ATP and pyruvate at high levels. These results indicate that some of the AA metabolites may play an important role in the development of brain edema and in the impairment of energy metabolism.
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PMID:Role of arachidonic acid metabolism on ischemic brain edema and metabolism. 211 11

Previous studies in our laboratory have demonstrated the peroxidation of myocardial phospholipid in a canine model of reversible global normothermic ischemia and reperfusion while on cardiopulmonary bypass. The present study examines the distribution of phospholipid peroxidation products in three major cellular organelle fractions of myocardium prepared by established centrifugal fractionation procedures (sarcolemma, sarcoplasmic reticulum, and mitochondria). These organelles were isolated from control (nonischemic) and ischemic-reperfused myocardium harvested during early reperfusion (5 min), when previous studies indicated maximal peroxidative injury in whole myocardial biopsies. Utilizing a more rapid analytic procedure for measuring phospholipid containing the conjugated diene chromophore in the polyunsaturated fatty acyl substituents, we were able to establish the fidelity of this procedure by comparing the results obtained with it to the previous more laborious analytic procedure (involving phospholipid hydrolysis with phospholipase A2 and subsequent derivatization for high-pressure liquid chromatography followed by gas chromatographic-mass spectrometric analysis). Analysis of phospholipid extracts from organelle fractions for evidence of peroxidative conjugated diene formation revealed that sarcolemmal membranes had the highest content of oxidized phospholipid containing the conjugated diene chromophore (mean 2.2 +/- 1.2 nmol phospholipid-conjugated diene/mumol phospholipid phosphorus, P less than 0.02 compared with control). Both sarcoplasmic reticulum and mitochondrial membranes were also peroxidized but to a much smaller extent (mean 0.4 +/- 0.2 and 0.3 +/- 0.25 nmol phospholipid conjugated diene/mumol phospholipid phosphorus).
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PMID:Subcellular distribution of peroxidized lipids in myocardial reperfusion injury. 216 62

Reperfusion of ischemic myocardium is associated with phospholipid degradation and corresponding changes in membrane fluidity. Dexamethasone (1.25 mg/kg i.v.) was evaluated in the pig, with pretreatment of the animal 1 1/2 hours before ischemic insult. The isolated perfused in vivo pig heart model was subjected to 60 minutes of regional ischemia of the left anterior descending coronary artery. The ischemic heart was then subjected to 60 minutes of global hypothermic cardioplegic arrest followed by 60 minutes of reperfusion, including reperfusion of the ischemic left anterior descending coronary artery region. Phospholipase A2, arachidonic acid, total free fatty acids, myocardial microviscosity, coronary blood flow, myocardial oxygen consumption, creatine kinase release, and regional and global myocardial function were measured. Dexamethasone pretreatment resulted in dramatic inhibition of phospholipase A2 activity accompanied by a reduction in arachidonic acid and total free fatty acid levels. Myocardial microviscosity (the inverse of membrane fluidity) was significantly increased only in untreated animals. Coronary blood flow and myocardial oxygen consumption were maintained at preischemic levels only in the dexamethasone-treated animals and were significantly reduced in the control group. Creatine kinase release increased nearly six times in control animals only while remaining stable in the dexamethasone-treated group, and regional and global myocardial contractility and compliance were improved dramatically in the dexamethasone-treated animals. These results indicate that dexamethasone enhances myocardial function by preserving membrane structure through inhibition of phospholipase activation, thereby preventing phospholipid degradation and maintaining membrane integrity and fluidity.
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PMID:Steroid-induced myocardial preservation is associated with decreased cell membrane microviscosity. 250 6

Using a Langendorff rat heart model, studies were performed on the effects of three drugs in protecting the heart against global ischemia. The drugs used were: (a) MR-256, a prostaglandin oligomeric derivative, which is a calcium chelating agent and at the same time, is an inhibitor of phospholipase A2 activity, (b) chlorpromazine which is not a calcium chelator, but is a calmodulin antagonist and is an inhibitor of phospholipase A2 activity, and (c) BAPTA/AM, a calcium chelating agent, but which is not an inhibitor of phospholipase A2 activity. The perfused heart was exposed to 15 minutes of global ischemia. In control experiments (no drug), the ventricular pressure recovered to 26.4 +/- 6.7% (n = 22) of the original level. With pretreatment of (a) MR-256 (b) chlorpromazine, and (c) BAPTA/AM, maximum recoveries were 0.5 +/- 6.7% (n = 5), 88.7 +/- 8.5% (n = 5), 45.3 +/- 26.6% (n = 5), respectively. MR-256 and chlorpromazine were found to react with free radicals. The modes of action of these three different types of drugs are discussed.
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PMID:Pharmacologic protection of perfused rat heart against global ischemia. 251 20

Transient cerebral ischemia results in selective neuronal cell death. The mechanisms underlying this selective vulnerability to ischemia are only beginning to be elucidated. We studied the effect of ischemia on alpha 1-adrenergic receptor binding by measuring [3H]prazosin binding in gerbil forebrain membranes after 10 min of bilateral carotid occlusion. Binding was reduced from 62 +/- 3 to 33 +/- 4 fmol/mg protein. Binding in the same membranes to beta 2-adrenergic receptors were also decreased, but not to the extent of that to alpha 1-adrenergic receptors. Binding to muscarinic cholinergic [( 3H]quinuclydil benzilate) and beta 1-adrenergic receptors were only slightly depressed. Surprisingly, the protein content was significantly increased in the membrane fraction studied from ischemic forebrain (68 +/- 4 mg/g wet weight) compared with sham operated controls (57 +/- 4). The dramatic decrease in alpha 1-adrenergic receptor binding during ischemia is consistent with receptor binding studies of membranes pretreated with phospholipase A2 in vitro. It is not clear what effect this change in alpha 1-adrenergic receptor binding has on subsequent selective neuronal death. The recent demonstration that catecholamines and locus ceruleus neurons influence the loss of CA1 neurons in the hippocampus suggests that it may play an important modulatory role.
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PMID:Rapid reduction in [3H]prazosin binding to gerbil forebrain membranes during bilateral common carotid artery occlusion. 254 Nov 47

The influence of quinacrine, a phospholipase A2 inhibitor, and enzymatic scavengers of active oxygen metabolites (superoxide dismutase and catalase) on ischemic small intestinal mucosal damage has been investigated. In the absence of an inhibitor, ischemia and reperfusion caused increased mucosal permeability to sodium fluorescein, increased N-acetyl-glucosaminidase release from the mucosa into the lumen, increased malondialdehyde content, and increased myeloperoxidase and phospholipase A2 (PLA2) activities in the mucosa. All these effects of ischemia were efficiently inhibited by the PLA2 inhibitor quinacrine. On the other hand, superoxide dismutase together with catalase, even if it totally prevented the increased formation of malondialdehyde, was only able to reduce 50 percent of the increases of the other parameters. These findings indicate that, in addition to free radicals, other factors are involved in the pathogenesis of small intestinal mucosal injury after ischemia and reperfusion. We suggest that one such factor is the activation of PLA2 and the generation of various PLA2-dependent compounds such as arachidonic acid metabolites, lysophosphatidyl choline, and platelet-activating factor.
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PMID:Role of phospholipase A2 and oxygenated free radicals in mucosal damage after small intestinal ischemia and reperfusion. 254 28

The effect of the mitochondrial membrane on the oxygen supply to the interior of mitochondria was analyzed with a cylinder model of diffusion. This estimation is based on the assumption that cytochrome a,a3 is distributed only on the inner surface of the mitochondrial inner membrane. The diffusion coefficient in the mitochondrial membrane was approximated from the fluorescently-determined viscosity of rat mitochondrial membrane. A pico-second time-resolved fluorometer at 37 degrees C gave values of 43.8 cp for intact mitochondria and 51.4 cp after phospholipase A2 treatment. Using the mean oxygen consumption rate of 10 ml O2/100 g tissue/sec in beating heart, oxygen gradients of 3.9 and 4.6 nmol was predicted across the intact and phospholipase-A2 treated mitochondrial membranes, respectively. The increased oxygen consumption during systole will yield oxygen gradients of 11.6 and 13.7 nmol. These gradients were much larger than the values estimated in a hypothetical case using the diffusion coefficient for the mitochondrial membrane of 1.5 x 10(-5) cm2/sec. The predicted oxygen gradient suggests a non-uniform distribution of oxygen in the myocardial cell and may be of importance in understanding the relationship between oxygen supply and myocardial function in hypoxia. Phospholipase A2, which is known to be activated in ischemia, destroys the microstructure of myocardial cells, seems deleterious to oxygen transport to cytochrome a,a3.
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PMID:Oxygen diffusion through mitochondrial membranes. 255 Nov 43


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