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

Alterations which occur during ischemia are reviewed. They modify the metabolic status in such a way they prepare the cell to an anomalous response to reoxygenation. The consequence of this disturbance is the generation of oxygen free radicals through several mechanisms, including the mitochondrial oxidative phosphorylation, the arachidonic acid cascade, the activation of xanthine oxidase, activation of phagocytes, iron mobilization, etc. Reduced glutathione is exhausted, proteins are inactivated. Lipid peroxidation induces membrane breakdown and cellular death.
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PMID:Ischemia, reperfusion and oxygen free radicals. 129 Jun 47

Brain damage initiated during global ischemia has been shown to be exacerbated by iron-dependent lipid peroxidation during early reperfusion. We hypothesized that other cellular components might be involved in similar free radical reactions. In this study we examined three brain protein fractions and ribosomal RNA for evidence of free radical damage during post-ischemic reperfusion. Global brain ischemia was induced by 20-min cardiac arrest. Dogs were divided into four groups: (1) non-ischemic controls; (2) 20-min cardiac arrest without reperfusion; (3) 20-min cardiac arrest and 2 h reperfusion; (4) 20-min cardiac arrest and 8 h reperfusion. Soluble proteins and proteins from ribosomes and synaptosomes were assayed by a dinitrophenylhydrazine method for carbonyl groups, which are characteristic products of protein peroxidation. The ribosomal RNA was also examined by electrophoresis. When proteins from each fraction were peroxidized in vitro by Fenton reagents, carbonyl content increased as [Fe2+] was increased from 0 to 100 microM. However, following reperfusion there was no significant accumulation of carbonyl content in either the soluble (ANOVA P = 0.92) or ribosome (P = 0.10) protein fractions. There was a significant decrease in the carbonyl content of the synaptosome protein fraction after 8 h of reperfusion (P = 0.03). Similarly, although ribosomal RNA fragmentation was observed in ethidium stained agarose gels following in vitro reaction with Fenton reagents, there was no evidence of ribosomal RNA fragmentation or cross-linking following reperfusion. These results suggest that reperfusion free radical reactions do not involve these cellular proteins or ribosomal RNA.
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PMID:Assessment of free radical-induced damage in brain proteins after ischemia and reperfusion. 131 70

The timely restoration of blood flow to severely ischemic myocardium limits myocardial infarct size. However, experimental studies demonstrate that the myocardial salvage achieved is suboptimal because of additional injury that occurs during reperfusion, due in part to the generation of reactive oxygen metabolites. Initially, superoxide (O2-) was considered to be the central mediator of reperfusion injury. While there are several potential pathways of O2- generation in reperfused myocardium, O2- is poorly reactive toward tissue biomolecules. However, O2-, in the presence of redox-active metals such as iron, generates .OH or hydroxyl-like species that are highly reactive with cell constituents. Thus, while O2- may initiate reaction sequences leading to myocardial injury, it may not be the actual injurious agent. In vitro studies suggest that oxygen metabolite injury occurs at intracellular sites and involves iron-catalyzed processes. Consistent with this mechanism, extracellular oxygen metabolite scavengers have not convincingly reduced infarct size. However, treatment around the time of reperfusion, after ischemia is well established, with cell-permeable scavengers of .OH reduce infarct size. Results with these cell-permeable agents suggest that in the intact animal during regional ischemia and reperfusion, oxygen metabolite injury also occurs at intracellular sites. Cell-permeable scavenger agents are a promising class of drugs for potential clinical use, though further experimental and toxicologic studies are required.
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PMID:Reduction of infarct size by cell-permeable oxygen metabolite scavengers. 838 Nov 8

To elucidate the pathophysiological role of the hydroxyl radical (.OH) during the postischemic reperfusion of the heart, we measured the .OH product in the coronary effluent from isolated perfused rat heart during a 30-minute reperfusion period after various ischemic intervals of 5, 10, 15, 20, 30, and 60 minutes. Salicylic acid was used as the probe for .OH, and its derivative, 2,5-dihydroxybenzoic acid (2,5-DHBA), was quantified using high-performance liquid chromatography with ultraviolet detection. 2,5-DHBA was negligible in the effluent from nonischemic hearts, but a significant amount was detected from the hearts rendered ischemic for 10 minutes or longer. The peak of 2,5-DHBA was seen within 90 seconds after the onset of reperfusion in every group. The accumulated amount of 2,5-DHBA was maximal in the group with 15-minute ischemia (6.73 +/- 1.04 nmol/g wet heart wt after 30 minutes of reperfusion); it decreased as the ischemic time was prolonged and was 2.38 +/- 0.84 nmol/g wet wt after 30 minutes of reperfusion in the group with 60-minute ischemia. In the model of 15-minute ischemia/30-minute reperfusion, there was no correlation between the accumulated amount of 2,5-DHBA and functional recovery (+/- dP/dt, heart rate, and coronary flow), lactate dehydrogenase release, and morphological damage. Although treatment with 0.5 mM deferoxamine, an iron chelator, significantly decreased 2,5-DHBA (from 6.73 +/- 1.04 to 2.29 +/- 0.80 nmol/g wet wt after 30 minutes of reperfusion, p less than 0.01), it failed to reduce the postischemic myocardial injury in the group with 15-minute ischemia. The results suggest that .OH production is influenced by the preceding ischemic interval and that .OH does not exert an immediate direct effect on postischemic damage during early reperfusion in the isolated perfused rat heart, although a possibility remains that the small portion of .OH trapped by salicylic acid may not be intimately associated with myocardial injury.
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PMID:Quantification of hydroxyl radical and its lack of relevance to myocardial injury during early reperfusion after graded ischemia in rat hearts. 131 98

The preservation of the heart and lung for transplantation remains a major concern in extended ischemic intervals. This experimental endeavor evaluates and compares the efficacy of iron chelating agents such as high molecular weight deferoxamine and 21-aminosteroid (U74006F) in a swine model of heart-lung transplantation. Heat-lung blocks were exposed to 4 h and 45 min of ischemia and 2 h of reperfusion. Animals were divided into three groups. Group A was a control without pharmacological intervention. In groups B and C, 21-aminosteroid (U74006F), 10 mg/kg, and high molecular weight deferoxamine, 50 mg/kg, were used, respectively. The results of functional parameters (cardiac index, stroke index, lung water, PO2, PCO2, alveolar-arterial gradient, and alveolar-arterial ratio) demonstrated superior heart and lung function for group C, where high molecular weight deferoxamine was used. Alterations of heart and lung function were significantly more (p less than .001) for control animals and for group B where U74006F was used. This study suggests that formation of hydroxyl radicals was affected by chelation of iron with high molecular weight deferoxamine, which reflects better heart and lung function and consequently less damage to this group of animals. The compound 21-aminosteroid U74006F failed to protect the heart and lung from ischemic-reperfusion injury in this model of heart-lung transplantation.
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PMID:Comparison of new iron chelating agents in the prevention of ischemia/reperfusion injury: a swine model of heart-lung transplantation. 131 95

L-Propionyl carnitine has been shown to improve the heart's mechanical recovery and other metabolic parameters after ischemia-reperfusion. However, the mechanism of protection is unknown. The two dominating hypotheses are: (i) L-propionyl carnitine can serve as an energy source for heart muscle cells by being enzymatically converted to propionyl-CoA and subsequently utilized in the Krebs cycle (a metabolic hypothesis), and (ii) it can act as an antiradical agent, protecting myocardial cells from oxidative damage (a free radical hypothesis). To test the two possible pathways, we compared the protection afforded to the ischemia-reperfused hearts by L-propionyl carnitine and its optical isomer, D-propionyl carnitine. The latter cannot be enzymatically utilized as an energy source. The Langendorff perfusion technique was used and the hearts were subjected to 40 min of ischemia and 20 min of reperfusion. In analysis of ischemia-reperfused hearts, a strong correlation was found between the recovery of mechanical function and the presence of protein oxidation products (protein carbonyls). Both propionyl carnitines efficiently prevented protein oxidation but L-propionyl carnitine-perfused hearts had two times greater left ventricular developed pressure. The results indicate that both metabolic and antiradical pathway are involved in the protective mechanism of L-propionyl carnitine. To obtain a better insight of the antiradical mechanism of L-propionyl carnitine, we compared the ability of L- and D-propionyl carnitines, L-carnitine, and deferoxamine to interact with: (i) peroxyl radicals, (ii) oxygen radicals, and (iii) iron. We found that none of the carnitine derivatives were able to scavenge peroxyl radicals or superoxide radicals. L- and D-propionyl carnitine and deferoxamine (not L-carnitine) suppressed hydroxyl radical production in the Fenton system, probably by chelating the iron required for the generation of hydroxyl radicals. We suggest that L-propionyl carnitine protects the heart by a dual mechanism: it is an efficient fuel source and an antiradical agent.
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PMID:Antiradical effects in L-propionyl carnitine protection of the heart against ischemia-reperfusion injury: the possible role of iron chelation. 132 84

Angiotensin converting enzyme inhibitors are utilized in the treatment of essential hypertension and of chronic cardiac failure. They are also employed in the treatment of the myocardial lesion of ischemia-reperfusion, which involves oxygen free radicals. In the present study we investigated the possibility of three angiotensin converting enzyme inhibitors (captopril, enalapril, lisinopril) to act as hydroxyl radical scavengers. The rate constants for reactions of those compounds with .OH were determined using the deoxyribose method. All there compounds proved to be good scavengers of .OH with rate constants of about 10(10)M-1s-1 and are iron chelators specially enalapril. The fact that captopril possesses a thiol group does not confer an higher antioxidative capacity. These results suggest that scavenging of oxygen free radicals may be a possible mechanism contributing to the therapeutic effect of angiotensin converting enzyme inhibitors.
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PMID:[Angiotensin-converting enzyme inhibitors as neutralizers of hydroxyl radical]. 132 14

Ischemia-reperfusion is observed in various diseases such as myocardium infarct. Different theories have been proposed to explain the reperfusion injury, among them that the free radical generation plays a crucial role. To study the mechanisms of the reperfusion injury, a hypoxia (H)-reoxygenation (R) model upon human umbilical vein endothelial cells in culture was developed in order to mimic the in vivo situation. Different parameters were quantified and compared under H or H/R, and we found that oxygen readmission led to damage amplification after a short hypoxia period. To estimate the importance of various causes of toxicity, the effects of various protective molecules were compared. Different antioxidant molecules, iron-chelating agent, xanthine oxidase inhibitors, and energy-supplying molecules were very efficient protectors. Synergy could also be observed between the antioxidants and the energy-supplying molecules or the xanthine oxidase inhibitors. The toxic effect of O2.(-) could be lowered by the presence of SOD or glutathione peroxidase in the culture medium, whereas glutathione peroxidase was the most efficient enzyme when injected into the cells. The production of O2.(-) and of H2O2 by endothelial cells was directly estimated to be, respectively, of 0.17 and 0.035 mumol/min/mg prot during the R period. O2.(-) production was completely inhibited when allopurinol was added during H and R. In addition, a xanthine oxidase activity of 21.5 10(-6) U/mg prot could be observed by a direct assay in cells after H but not in control cells, thus confirming the previous conclusions of xanthine oxidase as a potent source of free radicals in these conditions. Thanks to the use of cultured human endothelial cells, a clear picture was obtained of the overall process leading to cell degenerescence during the reoxygenation process. We particularly could stress the importance of the low energetic state of these cells, which is a critical factor acting synergistically with the oxidant molecules to injure the cells. These results also open new possibilities for the development of new therapeutics for ischemia.
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PMID:Human umbilical vein endothelial cells submitted to hypoxia-reoxygenation in vitro: implication of free radicals, xanthine oxidase, and energy deficiency. 132 79

It has been shown that multiple exposures of gravid rats to cocaine during late gestation result in significant incidences of severe malformations. Hind limb reduction defects were frequent findings in this study. Other studies have shown that comparable abnormalities can be induced in experimental animals by various procedures including vascular clamping, direct fetal exposure to epinephrine, uterine handling following laparotomy, as well as by exposure to hyperbaric oxygen. This paper reviews these and other studies, and presents a novel mechanistic hypothesis that explains their common findings. It is proposed that in each instance, conceptual hypoxia results from hypoperfusion caused by transient vasoconstriction. Following the resumption of normal perfusion, reactive oxygen species are generated by the ischemia/reperfusion mechanisms thought to underlie many pathobiologic lesions. It is proposed that the conceptus is particularly vulnerable to the toxicity of oxygen radicals because of its low antioxidant activities and the highly reduced state of its undifferentiated cells. Sensitivity to cocaine and uterine handling appears to be enhanced during late gestation and it is hypothesized that this results from changes in oxygenation and iron content that increase both the substrate and catalyst for generation of reactive oxygen species.
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PMID:Ischemia/reperfusion: a new hypothesis for the developmental toxicity of cocaine. 132 32

Superoxide production was measured as the superoxide dismutase (SOD)-inhibitable portion of nitro blue tetrazolium (NBT) reduction after cerebral ischemia-reperfusion in anesthetized cats equipped with cranial windows. Significant superoxide production was found in the early reperfusion period and continued for more than 1 h after ischemia. Superoxide was not detected in control animals not subjected to ischemia, during ischemia, and at 120 min of reperfusion. After ischemia, the vasoconstrictor response to arterial hypocapnia was reduced. This effect was prevented by pretreatment with SOD plus catalase or by deferoxamine. The response to topical acetylcholine was converted to vasoconstriction after ischemia. The normal vasodilator response reappeared spontaneously at 120 min of reperfusion. The vasodilator response to acetylcholine was preserved in animals pretreated with SOD plus catalase. Blood-brain barrier permeability to labeled albumin and horseradish peroxidase was increased after ischemia. These effects were minimized by pretreatment with SOD and catalase. We conclude that superoxide generation occurs during reperfusion after cerebral ischemia for a fairly long period and that superoxide and its derivatives are responsible at least in part for the vasodilation and the abnormal reactivity as well as for the increase in blood-brain barrier permeability to macromolecules seen after ischemia. Furthermore, the findings suggest that the agent responsible for the vascular abnormalities is hydroxyl radical generated via the iron-catalyzed Haber-Weiss reaction.
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PMID:Oxygen radicals in cerebral ischemia. 133 9


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