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

We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.
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PMID:Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. 1285 68

The aim of this study was to determine whether endothelium-derived mediators and the endocannabinoid system were involved in the cardioprotective effects induced by exogenous kinins, namely bradykinin and its active metabolites, des-Arg(9)-bradykinin. Isolated rat hearts were submitted to a 20-min stabilisation period, followed by 90 min of low-flow ischemia (flow rate, 0.6 ml min(-1)) before a 60-min reperfusion period. Perfusion of bradykinin (BK, 30 nM) or des-Arg(9)-bradykinin (DBK, 30 nM) was initiated 1 min before the ischemia and maintained during the entire ischemic period. Perfusion with BK reduced infarct size, when measured at the end of the 60-min reperfusion. This effect was blocked by the B2-receptor antagonist, HOE140 (30 nM). Likewise, DBK reduced infarct size, effect that was blocked by the B1-receptor antagonist (30 nM Lys(0)-Leu(8)-DBK). The cardioprotective effect of both BK and DBK was abolished by the cannabinoid CB1-receptor antagonist (1 microM SR141716A), but not by the CB2-receptor antagonist (1 microM SR144528). Neither the NO synthase inhibitor, N-nitro-L-arginine (NNLA, 30 microM), the COX inhibitor, indomethacin (2.8 microM), nor the CYP450 inhibitor, clotrimazole (1 microM), prevented the cardioprotective effect of the kinins. However, a combined treatment with those three inhibitors abolished completely the ability of BK and DBK to reduce infarct size. In conclusion, exogenously administered BK and DBK exert a protective effect against ischemia in an isolated heart model. Endothelium-derived mediators such as nitric oxide, prostanoids, and endothelium-derived hyperpolarizing factor, as well as an SR141716A-sensitive mediator, appear to be involved in this beneficial effect.
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PMID:A study of the mediators involved in the protection induced by exogenous kinins in the isolated rat heart. 1294 48

The peroxynitrite scavenging ability of Procyanidins from Vitis vinifera L. seeds was studied in homogeneous solution and in human umbilical endothelial cells (EA.hy926 cell line) using 3-morpholinosydnonimine (SIN-1) as peroxynitrite generator. In homogeneous phase procyanidins dose-dependently inhibited 2',7'-dichloro-dihydrofluorescein (DCFH) oxidation induced by SIN-1 with an IC50 value of 0.28 microM. When endothelial cells (EC) were exposed to 5 mM SIN-1, marked morphological alterations indicating a necrotic cell death (cell viability reduced to 16 +/- 2.5%) were observed. Cell damage was suppressed by procyanidins, with a minimal effective concentration of 1 microM (cell morphology and integrity completely recovered at 20 microM). Cellular localization of procyanidins in EC was confirmed using a new staining procedure and site-specific peroxyl radical inducers: AAPH and cumene hydroperoxide (CuOOH). Endothelial cells (EC) pre-incubated with procyanidins (20 microM) and exposed to FeCl3/K3Fe(CN)6 showed a characteristic blue staining, index of a site-specific binding of procyanidins to EC. Procyanidins dose-dependently inhibit the AAPH induced lipid oxidation and reverse the consequent loss of cell viability, but were ineffective when oxidation was driven at intracellular level (CuOOH). This demonstrates that the protective effect is due to their specific binding to the outer surface of EC thus to quench exogenous harmful radicals. Procyanidins dose-dependently relaxed human internal mammary aortic (IMA) rings (with intact endothelium) pre-contracted with norepinephrine (NE), showing a maximal vasorelaxant effect (85 +/- 9%) at 50 microM (catechin: 18 +/- 2% relaxation at 50 microM). This effect was completely abolished when IMA-rings were de-endothelized and when IMA-rings with intact endothelium were pretreated with L-NMMA or with the soluble guanylate cyclase inhibitor, ODQ. Pre-incubation with indomethacin reduces (by almost 50%) the vasodilating effect of procyanidins, indicating the involvement also of a COX-dependent mechanism. This was confirmed in another set of experiments, where procyanidins dose-dependently stimulate the prostacyclin (PGI2) release, reaching a plateau between 25 and 50 microM. Finally, pre-incubation of IMA-rings with procyanidins (from 6.25 to 25 microM) resulted in a dose-dependent prevention of the endothelin-1 (ET-1) vasoconstriction. The ability of procyanidins to prevent peroxynitrite attack to vascular cells, by layering on the surface of coronary EC, and to enhance endothelial NO-synthase-mediated relaxation in IMA rings provide further insight into the molecular mechanisms through which they exert cardioprotective activity in ischemia/reperfusion injury in vivo.
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PMID:Procyanidins from grape seeds protect endothelial cells from peroxynitrite damage and enhance endothelium-dependent relaxation in human artery: new evidences for cardio-protection. 1451 73

Cyclooxygenase (COX-2) inhibitors were developed with the hope that they will cause fewer gastrointestinal adverse effects. Ability of selective as well as nonselective COX inhibitors to alter ischemia-reperfusion induced damage of gastric mucosa and hapten-induced colitis in rats has been compared. Celecoxib (10, 20 and 40 mg/kg(-l)) was significantly more potent at aggravating ischemia-reperfusion injury as compared to nimesulide. Similarly, celecoxib was found to maximally potentiate TNBS-induced colitis, followed by nimesulide and indomethacin. Celecoxib at its highest dose produced maximum deep histological injury. This paradoxic ulcer and colitis aggravating effect of selective COX-2 inhibitors may be explained by suppression of protective prostaglandins generated as a consequence of COX-2 induction in inflammatory states.
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PMID:Comparative gastrointestinal toxicity of selective cyclooxygenase (COX-2) inhibitors. 1605 67

Cyclooxygenase-2 (COX-2) is up-regulated in stromal and inflammatory cells. The inducible COX-2 isoform is expressed during inflammation, in some cancers, and in brain tissue after global and focal ischemia. Tissue acidosis is a dominant factor in inflammation, and contributes to pain and hyperalgesia. Recently, compelling epidemiological and clinical evidence has documented the COX-independent effects of some COX-2 inhibitors (i.e., celecoxib, valdecoxib, and rofecoxib); among these effects are carbonic anhydrase (CA) inhibition. Carbonic anhydrases are zinc metalloenzymes expressed in various cell types, including those of the kidney, where they act as general acid-base catalysts. The kidneys are also known to express the highest concentration of COX-2 messenger ribonucleic acid. Celecoxib, like the prototypic CA inhibitor acetazolamide, is structurally characterized by an unsubstituted sulfonamide moiety. In the present study, we report that celecoxib exhibits the characteristics of a potent CA inhibitor, showing inhibitory human carbonic anhydrase II (hCAII) activity in the nanomolar range. Valdecoxib was relatively less potent. Rofecoxib, which lacks the unsubstituted sulfonamide moiety characteristic of CA inhibitors, showed no significant hCAII inhibitory activity. The current study corroborates our earlier report of structure-activity relationships as predictors of such metabolic events as hyperchloremia, acidosis, and changes in calcium and phosphate disposition; and clinical manifestations associated with CA inhibition reported with celecoxib. These data showing inhibition of hCAII by the unsubstituted sulfonamides celecoxib and valdecoxib, but not by rofecoxib, may have important implications for the elucidation of the mechanisms of action as well as the side effects associated with COX-2 inhibitors.
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PMID:The cyclooxygenase-2 inhibitor celecoxib is a potent inhibitor of human carbonic anhydrase II. 1613 2

The COX-inhibiting nitric oxide donors (CINODs) are a new class of agents designed for the treatment of pain and inflammation. CINODs have a multi-pathway mechanism of action that involves COX inhibition and nitric oxide donation. The anti-inflammatory and analgesic effects of COX inhibition are reinforced through inhibition of caspase-1 regulated cytokine production, while nitric oxide donation provides multiorgan protection. Whereas both conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2-selective NSAIDs are associated with a variety of adverse effects on the renal system, such as hypertension and edema, CINODs may offer an improved renal safety profile. These agents are devoid of hypertensive effects in animal models and their mechanism of action suggests that they may not cause edema. CINODs also have other renal-sparing effects, being better tolerated than NSAIDs in models of kidney failure. CINODs have been shown to prevent platelet activation in vitro and exhibit anti-thrombotic activity in vivo. In animal models of ischemia/reperfusion, CINODs treatment results in improved recovery of heart contractility and reduced left ventricular end-diastolic pressure, in contrast to the effects of aspirin. The combination of improved analgesia, reduced gastrointestinal toxicity and cardiorenal protection has been established in animal models, and early clinical results suggest a favourable gastrointestinal safety profile in humans. The potential for CINODs to provide cardiorenal protection in humans is currently being investigated.
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PMID:COX-inhibiting nitric oxide donors (CINODs): potential benefits on cardiovascular and renal function. 1661 Oct 49

In spite of opposing changes in rates of adenosine triphosphate turnover, hypertrophy and atrophy of the heart are accompanied by the same changes in gene expression, resembling a fetal genotype. Fetal hearts are characterized by increased ischemia tolerance. We assessed respiratory capacity of mitochondrial subpopulations from unloaded and pressure-overloaded hearts before and after 15 minutes of normothermic ischemia. Unloading was achieved by heterotopic rat heart transplantation and overloading by aortic banding. Respiratory chain gene expression (NADH dehydrogenase, cytochrome c oxidase [COX]) were analyzed by reverse transcriptase-polymerase chain reaction. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated by differential centrifugation. Citrate synthase was used as mitochondrial marker enzyme. Adenosine diphosphate-stimulated oxygen consumption (state 3) was measured with a Clark-type electrode. Unloading resulted in atrophy, overloading in hypertrophy. State 3 was reduced in atrophied hearts both in SSM and IFM (SSM: 204 +/- 79 vs 804 +/- 147 natoms oxygen min(-1) mL(-1), P < .001; IFM: 468 +/- 158 vs 1141 +/- 296 natoms oxygen min(-1) mL(-1), P < .05), but was unchanged in hypertrophied hearts. NADH dehydrogenase and COX expression was also decreased with atrophy and was unchanged with hypertrophy. Ischemia caused decreased recovery of citrate synthase in isolates of SSM (P < .05) but not of IFM. State 3 in control hearts was reduced in IFM (-41%, P < .01) and SSM (-19%, not significant). This ischemia-induced decrease was less pronounced in SSM (-2%) and IFM (-22%) of atrophied and IFM (-23%) of hypertrophied hearts. Subsarcolemmal mitochondria of hypertrophied hearts displayed the greatest ischemia-induced decrease of state 3 (-32%, P < .05). In conclusion, (1) long-term changes in workload differentially affect maximal respiratory capacity and ischemia tolerance of isolated mitochondria. The changes are not parallel to the changes in energy requirements. (2) Mitochondria of atrophied hearts appear to be more resistant against ischemia than controls.
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PMID:Differential changes in respiratory capacity and ischemia tolerance of isolated mitochondria from atrophied and hypertrophied hearts. 1683 47

Despite initial promising reports that anti-inflammatory properties of cycloxygenase-2 (COX-2) inhibitors may confer anti-atherosclerosis effects and stabilize the atherosclerotic plaque, subsequent data from long-term clinical trials have shown that selective COX-2 inhibitors are associated with increased risk of cardiovascular events. The commonly cited explanation is that selective inhibition of COX-2 leads to depletion of prostacyclin, whereas the production of pro-thrombotic thromboxane by means of cycloxygenase-1 (COX-1) is unopposed. This hypothesis seems unlikely as the overall explanation, because low-dose aspirin does not decrease the increased risk associated with COX-2 inhibitors. Moreover, the risk associated with nonselective COX inhibitors may be similar to selective COX-2 inhibitors. Alternative hypotheses include (1) elevated blood pressure, (2) abnormal vascular remodeling, (3) inhibition of protective mechanisms against ischemia-reperfusion injury, and (4) inhibition of 15-epi-lipoxin production. Varying results in different experimental models may be related to the fact that COX-2 is involved in numerous cellular functions. Inhibiting COX-2 in inflammatory cells may have favorable effects, whereas in organs such as the heart and brain and/or blood vessels may have deleterious effects. Currently, the "selective COX-2 inhibitors" are not selective in the sense that they inhibit COX-2 in all tissues without predilection to inflammatory cells and, as a result, may summate to increase the risk of cardiovascular events.
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PMID:The cycloxygenase 2 (COX-2) story: it's time to explain, not inflame. 1756 80

Ischaemia-reperfusion injury resulting from interruption and restoration of blood flow might be related to free radical mediated oxidative stress and inflammation, and subsequently to post-surgery related complications. We studied the impact of renal transplantation on oxidative stress and inflammation by measuring F(2)-isoprostanes and prostaglandin F(2alpha), respectively, during transplantation and post-surgery. Additionally, due to earlier observations, two dissimilar anaesthetic agents (thiopentone and propofol) were compared to determine their antioxidative capacity rather than their anaesthetic properties. Blood samples were collected before, post-intubation, immediately, 30, 60,120, 240 min, and 12 and 24 h after reperfusion. Oxidative stress and inflammatory response were detected by measuring 8-iso-PGF(2alpha) (a major F(2)-isoprostane and a biomarker of oxidative stress) and 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha) and a biomarker of COX-mediated inflammatory response), respectively. Reperfusion of the transplanted graft significantly increased plasma levels of 8-iso-PGF(2alpha). PGF(2alpha) metabolite levels, although elevated, did not reach statistical significance. In addition, significantly lower levels of 8-iso-PGF(2a) were observed in the propofol group compared to the thiopentone group. Together, these findings underline an augmented oxidative stress activity following an inflammatory response after human renal transplantation. Furthermore, propofol a well-known anaesthetic, counteracted oxidative stress by lowering the formation of a major F(2)-isoprostane.
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PMID:Time course and attenuation of ischaemia-reperfusion induced oxidative injury by propofol in human renal transplantation. 1770 90

Dysfunction of mitochondria induced by ischemia is considered to be a key event triggering neuronal cell death after brain ischemia. Here we report the effect of ischemia-reperfusion on mitochondrial protein synthesis and activity of cytochrome c oxidase (EC 1.9.3.1, COX). By performing 4-vessel occlusion model of global brain ischemia, we have observed that 15 min of global ischemia led to the inhibition of COX subunit I (COXI) synthesis to 56 % of control. After 1, 3 and 24 h of reperfusion, COXI synthesis was inhibited to 46, 50 and 72 % of control, respectively. Depressed synthesis of COXI was not a result of either diminished transcription of COXI gene or increased proteolytic degradation of COXI, since both Northern hybridization and Western blotting did not show significant changes in COXI mRNA and protein level. Thus, ischemia-reperfusion affects directly mitochondrial translation machinery. In addition, ischemia in duration of 15 min and consequent 1, 3 and 24 h of reperfusion led to the inhibition of COX activity to 90.3, 80.3, 81.9 and 83.5 % of control, respectively. Based on our data, we suggest that inhibition of COX activity is rather caused by ischemia-induced modification of COX polypeptides than by inhibition of mitochondrial translation.
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PMID:Ischemia-reperfusion induces inhibition of mitochondrial protein synthesis and cytochrome c oxidase activity in rat hippocampus. 1819 96


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