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)

Oxygenated free-radicals appear to play a prominent role in mediating damage associated with gastrointestinal diseases. Production of reactive oxygen metabolites in ischemia-reperfusion involves oxidases found in resident phagocytic cells and microvascular and mucosal epithelial cells. Platelet activating factor (PAF), a phospholipid associated with inflammatory disorders, has been shown to both prime and amplify the release of superoxide anion and hydrogen peroxide from polymorphonuclear neutrophils and macrophages stimulated by FMLP or PMA. To further elucidate the involvement of free radicals in intestinal damage and the potential role of PAF in their production, we examined the effect of superoxide dismutase (SOD) and BN 52021 (ginkgolide B) on ischemia-reperfusion induced damage in the small intestine. The study involved 32 Sprague-Dawley rats (100-200 g) divided into four groups. Three of these groups were subjected to occlusion of the mesenteric artery 30 mins followed by 24 h reperfusion. On 2 groups SOD (15,000 U/kg/iv) and BN 52021 (20 mg/kg/po) were administered 45 mins before arterial occlusion. Following the 24 h reperfusion, the rats were sacrificed after overnight fasting. The jejunum and ileon were removed and fixed for morphological examination. Lesions in the small intestine were quantified. The results showed extensive necrosis, hemorrhage, oedema and neutrophil invasion in the jejunal and ileal mucosa. This injury was significantly reduced by SOD (15,000 U/kg/iv) and BN 52021 (20 mg/kg/po) pretreatment. In conclusion, free-oxygenated radicals appear to mediate reperfusion damage in the small intestine and PAF appears to be involved in the genesis of these toxic products. Thus, SOD and BN 52021 may be considered as protectors against ischemic disorders.
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PMID:Superoxide dismutase (SOD) and the PAF-antagonist (BN 52021) reduce small intestinal damage induced by ischemia-reperfusion. 206 Aug 44

Oxyradicals of neutrophils are supposed to play a role in the formation of gastric mucosal injury induced by ischemia-reinfusion (I-R). Recently, platelet-activating factor (PAF) is suggested to be involved in the I-R injury as one of chemical mediators since this substance may be produced in hypoxic tissue, stimulating oxyradical generation of neutrophils. In the present study, using CV-3988, a PAF antagonist, the severity of gastric mucosal damage and chemiluminescence (CL) activity of neutrophils of circulating blood were measured to evaluate the role of PAF in the I-R injury. SD rats fasted overnight were anesthetized and instilled 0.1N HCl into the stomach. Rats were then subjected to reduction of blood pressure to 20-30 mmHg for 20 min by bleeding followed by reinfusion of shed blood for 20 min. Two groups of rats each received 10 mg/kg CV-3988 (PAF-A grup) or saline (I-R group) i.v. 5 min prior to bleeding. After killing rats, the area of gross gastric lesions and the index of histologic damage were assessed. In separate PAF-A and I-R groups of rats, and control rats received saline i.v. and no hypotension, blood samples were collected from the portal vein and the abdominal aorta 45 min after acid instillation. Luminol-dependent CL stimulated by PMA of blood samples was measured using the photometer Monolight 401. CL activity was expressed as [peak CL/neutrophils number].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Role of PAF for the formation of gastric mucosal injury induced by ischemia-reinfusion in the rat]. 223

Oxygen-derived free radicals and their metabolites may contribute to the extension of irreversible cellular injury, which occurs on reperfusion of the previously ischemic myocardium. Therefore, therapy directed against the toxic effects of reactive oxygen species may provide protection to the ischemic myocardium, which undergoes subsequent reperfusion. We evaluated the effectiveness of N-2-mercaptopropionyl glycine (MPG), a free radical scavenger, to limit the extent of irreversible injury resulting from 90 min of ischemia followed by 6 h of reperfusion in a canine model of myocardial infarction. In three groups of dogs, MPG (20 mg/kg) was administered as a constant infusion into the left atrium. Group I received MPG for 2 h, starting 15 min before occlusion of the left circumflex coronary artery and ending 15 min after reperfusion. Group II received MPG for 1 h, starting 15 min before reperfusion. Group III received MPG for 1 h beginning 45 min after reperfusion. Each group was compared with its respective saline control group. Infarct size was reduced by 35% in Group I (32.2 +/- 5.1% vs. 47.7 +/- 3.4% of the area at risk, p less than 0.05) and Group II (31.4 +/- 3.6% vs. 47.5 +/- 5.1% of the area at risk, p less than 0.025) in comparison with the saline treated control animals. In contrast, in Group III infarct size did not differ significantly from the saline-treated control group (45.9 +/- 3.3% vs. 47.7 +/- 3.5% of the area at risk). The percent of left ventricle at risk did not differ among the groups. The beneficial effects of MPG could not be explained on the basis of hemodynamic differences. In addition, MPG did not influence regional myocardial blood flow. In vitro studies indicated that MPG effectively scavanges O2- generated by the hypoxanthine-xanthine oxidase reaction, as well as by PMA-activated polymorphonuclear leukocytes. Based on these observations, we propose that MPG exerts its beneficial effects by protecting against free radical-mediated damage during the early phase of reperfusion.
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PMID:Canine myocardial reperfusion injury: protection by a free radical scavenger, N-2-mercaptopropionyl glycine. 242

Polymorphonuclear neutrophils (PMNs) have been implicated in microvascular injury following ischemia and reperfusion (I/R) but the relative contribution of obstruction versus toxic mediators is not well defined. Therefore, the present study was performed to determine the contribution of exogenous or endogenous activation on PMN-induced microvascular and hepatocyte injury. Rat livers were isolated and perfused at constant pressure with Krebs buffer with red cells (Hct-10%) and monitored for perfused sinusoids (PS) and dead hepatocytes (propidium iodide-stained, DH) by intravital microscopy. PMNs isolated from the peritoneum after oyster glycogen injection were added to the perfusate either without or with activation by phorbol myristate acetate (PMA, 160 nM). Unactivated PMNs stuck in the liver but had no significant effect on either perfused sinusoids (11.1 +/- .4/field, unactivated PMNs versus 11.9 +/- .5/field, the time-matched control) or dead hepatocytes (1.2 +/- .4/field, unactivated PMNs versus 1 +/- .3/field, the time-matched control). Infusion of PMA-activated PMNs resulted in significant decrease in perfused sinusoids and increase in DH (9.5 +/- .3/field for PS and 3.2 +/- .6/field for DH, respectively). In contrast, when PMNs were "activated" by infusion into a liver previously made ischemic for 30 min, DH were significantly increased after 60 min (26.2 +/- 4.5/field, I/R plus PMNs versus 12.4 +/- 2/field, I/R only) but perfused sinusoids were not different from ischemia alone. These results demonstrate that oxidatively quiescent PMNs do not cause cellular or microvascular injury in spite of microvascular accumulation. Activated PMNs damage microcirculation or hepatocytes depending on the nature of the activation.
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PMID:Effect of activation on neutrophil-induced hepatic microvascular injury in isolated rat liver. 773 61

We examined the influence of transient myocardial ischemia on the number and function of neutrophils in patients with effort angina (EA). We tested fluorometrically the expression of neutrophil membrane molecules (CD11b, CD11c, CD18) and neutrophil oxidative burst using a chemiluminescence (CL) generation system. The estimations were conducted before, 1 min after and 20 min after percutaneous transluminal coronary angioplasty (PTCA) in 15 patients qualified for the treatment because of single-vessel disease. Eight EA patients subjected to coronary arteriography (CA) comprised a control group. We did not observe any marked changes in leucocytosis or lymphocyte number in peripheral blood (PB) or in coronary sinus blood (CSB) after the procedure. The percentage of granulocytes in coronary blood decreased significantly 20 min after reperfusion. No significant changes in white blood cell count were noted in peripheral blood of PTCA patients or in control CA subjects. Oxidative burst of nonstimulated and fMLP, PMA and zymosan stimulated sinus blood neutrophils was significantly depressed 1 min after inflation, and enhanced 20 min after reperfusion. We found a significant increase in the percentage of the CD11c+ neutrophils from 56.7 +/- 7.4% to 64 +/- 6.5% 20 min after inflation and postischemic decrease in the CD11c molecule expression on CSB neutrophils. Significant positive linear correlation (Rval = 0.71) between inflation time and the CD11c molecule expression on CSB immediately after reperfusion was also noted. The results may reflect local activation of neutrophils in ischemic myocardium as a response to ischemia induced increase of activating stimuli.
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PMID:The effect of short-term myocardial ischemia on the expression of adhesion molecules and the oxidative burst of coronary sinus blood neutrophils. 791 25

In order to study the possible role of C kinase (PKC) on sodium pump of cerebral vessels, we used diacylglycerol (diC8: sn-1,2-dioctanoylglycerol) and phorbol esters (PMA: phorbol 12-myristate 13-acetate; PDA: phorbol 12,13-diacetate; 4 alpha-P: 4-alpha phorbol) as PKC activators, and examined their effects on Na,K-ATPase activity in rat brain microvessels (MVs). Rats were divided into non-treated (control; n = 9), four-vessel occlusion (4VO; 30-30 minutes ischemia and recirculation, n = 5), and middle cerebral artery occlusion (MCAO, n = 3) groups. MVs were passed through nylon meshes and were obtained by ultracentrifuge at 58000 g. Na,K-ATPase activity in MVs was determined by the phosphomolybdate method. DiC8 enhanced Na,K-ATPase activity at 10(-4) M in the control group, the 4VO group and the contralateral hemispheres of the MCAO group (139% +/- 0.06, 135% +/- 0.2, 133% +/- 0.18, mean +/- SE, p < 0.05, p < 0.01, Wilcoxon rank sum) respectively, but had no effects on MVs in the ipsilateral hemispheres of MCAO group (74% +/- 0.04). This activation by diC8 was inhibited by PKC inhibitors, staurosporine (3 x 10(8) M) and H7 (10(-6) M) in the control MVs. By contrast, PMA suppressed Na, K-ATPase at 10(-5) M in the control group (-25% +/- 0.07), but it tended to activate Na,K-ATPase activity in the ipsilateral hemispheres of the MCAO groups (33% +/- 0.09). PDA and 4 alpha-P did not have any consistent effects at the concentration examined. The cause of difference between the effects of diC8 and PMA is unclear at present, but it may stem from the mode of lipid-membrane interaction in these agents and the difference in the condition of cells as well.
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PMID:Effects of protein kinase C activators on Na, K-ATPase activity in rat brain microvessels. 797 18

The 21-aminosteroids are potent inhibitors of iron-dependent lipid peroxidation and more protective than methylprednisolone in models of trauma and reperfusion, but without glucocorticosteroid side effects. Histologically, animals treated with 21-aminosteroids have decreased neutrophil (PMN) infiltrates and diminished tissue destruction associated with trauma or reperfusion. Since PMN contribute to organ failure following ischemia-reperfusion, we assessed the effect of U-74389F (U7), on normal PMN function. Neutrophils from normal volunteers were incubated for 90 min with either vehicle, 15 microM U7 or 80 microM methylprednisolone (MP), in DMSO. Lactoferrin released and generation of leukotrienes to calcium ionophore A23187, also oxygen consumed to PMA and leukotriene B4 (LTB4) and chemotaxis to FMLP and LTB4, were determined for each group of PMN. Lactoferrin released to A23187 was significantly decreased in both steroid groups (7.29 +/- 0.82 micrograms vs 3.06 +/- 0.57 micrograms U7 and 2.88 +/- 0.62 micrograms MP, P < 0.01). PMN incubated with U7 or MP generated significantly less LTB4 (60.6 +/- 4.3 ng vs 47.7 +/- 2.4 ng U7 and 43.3 +/- 5.6 ng MP, P < 0.05). There were no differences noted in the ability of PMN incubated with either compound to consume oxygen or to respond to chemotactic stimuli. We conclude that the proven protective action of the 21-aminosteroids in models of ischemia-reperfusion is related to the ability of "steroids" to inhibit leukotriene generation and degranulation and may be related to the prevention of tissue lipid peroxidation by scavenging oxygen radicals.
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PMID:Inhibition of neutrophil leukotriene generation by the 21-aminosteroid, U-74389F. 802 30

We used three interventions to test critically the theory that ischemic preconditioning is the result of translocation of cytosolic protein kinase C (PKC) into the membranes where it can be activated. If that theory were true then kinase activity should not be necessary during the preconditioning ischemia and thus blocking kinase activity at this time should not block protection. Secondly, since most translocation processes in the cell are accomplished by cytoskeletal microtubules, disrupting them with colchicine should also block protection from preconditioning. Finally, translocating PKC by transient exposure to PMA, should still require adenosine receptor activation to reactivate the PKC pathway during the subsequent ischemia. Blocking kinase activity with staurosporine during a 30 min insult completely blocks protection in preconditioned hearts but when staurosporine treatment was confined to the preconditioning episode protection was not blocked in five of the eight hearts studied. Microtubule disruption with colchincine did block the protective effect of preconditioning (38.3 +/- 1.9% infarction v 40.6 +/- 4.1% in non-preconditioned). Colchicine had no effect on infarct size in the non-preconditioned group. Five min PMA treatment plus 10 min washout significantly limited infarct size in isolated rabbit hearts subjected to 30 min regional ischemia (5.9 +/- 1.1% v 31 +/- 3.5% infarction in control). PMA's protection was blocked by adding the adenosine receptor blocker, SPT, during the sustained ischemia (38.1 +/- 6.1% infarction). All three of these experiments strongly support the translocation theory of ischemic preconditioning.
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PMID:Evidence that translocation of protein kinase C is a key event during ischemic preconditioning of rabbit myocardium. 807 20

The median and left lateral lobes of rat liver in situ were rendered ischemic for 30 min, then blood flow reinstituted. After 1, 3, 6, 24, or 48 h, livers were removed and set up for isolated perfused organ study. Luminol enhanced chemiluminescence (LEC) was recorded from the surface of the median and left lateral lobes before and for 90 min following phorbol myristate acetate (PMA, 1.6 x 10(-8) M) perfusion. An increase in PMA induced LEC was evident at 1 h and continued to increase up to 6 h. By 24 h the magnitude of the PMA response had returned to within control values. This indicates that a large influx of inflammatory cells had occurred in the liver following the in vivo ischemia-reperfusion insult and that these cells were well fixed in the tissue and capable of mounting a very large and sustained burst of radical production on stimulation with PMA. This combined in vivo/in vitro technique is ideally suited for the assessment of interventions designed to ameliorate damage following oxidative stress.
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PMID:Chemiluminescent response to PMA in isolated rat liver after in situ ischemia-reperfusion. 813 82

Multiple processes lead to neuronal death after ischemia, but the generation of nitric oxide (NO) is a key component in this cascade of events. The mechanisms that regulate the extent of neuronal degeneration during anoxia and NO toxicity are multifactorial. Neuronal death may be modulated by the activity of signal transduction systems that influence the toxicity of NO or its metabolic products such as cGMP. The enzyme responsible for the production of NO, nitric oxide synthase (NOS), is phosphorylated by protein kinase C (PKC), the cAMP-dependent protein kinase (PKA), and the calcium/calmodulin-dependent protein kinase II (CaM-II). We examined in primary cultured hippocampal neurons whether the protein kinases PKC, PKA, CaM-II, and cGMP-dependent protein kinase modified the toxic effects of anoxia and NO. Down-regulation of PKC activity with PMA (1 microM) increased hippocampal neuronal survival during anoxia and NO exposure from approximately 22% to 88%. Inhibitors of PKC activity (H-7, H-8, sphingosine, and staurosporine) also were neuroprotective. Down-regulation of PKC activity increased survival during anoxia even in the presence of the NOS inhibitor, N omega-methyl-L-arginine. Thus, although down-regulation of PKC activity may increase neuronal survival by decreasing NOS activity, it also is likely that PKC contributes to ischemic neuronal death by mechanisms that are independent of NOS. Inhibition of the cGMP-dependent protein kinase activity, but not the activity of the CaM-II also was neuroprotective during NO administration. In contrast to the protective effects of inhibition of PKC and the cGMP-dependent protein kinase, activation rather than inhibition of PKA increased hippocampal neuronal survival during NO exposure. These results indicate that neuronal survival during anoxia and NO exposure is linked to the modulation of PKC, PKA, and cGMP-dependent protein kinase activity but is not dependent on the CaM-II pathway. Understanding the involvement of PKC, PKA, and the cGMP-dependent protein kinase in modulating the effect of neuronal death during ischemia and NO toxicity may help in directing future therapeutic modalities for cerebrovascular disease.
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PMID:Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. 823 Mar 23


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