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)

Trimetazidine (TMZ) is an anti-ischemic compound whose precise mode of action is unknown, although several studies have suggested a metabolic effect, and there have been reports of protection of mitochondria against oxidative stress damage. Using a Langendorff rat heart model, we examined the effects of TMZ on the mitochondrial damage following 30 minutes of ischemia and 5 minutes of reperfusion. Mitochondrial respiration with succinate, glutamate-malate and ascorbate-N,N,N',N'-tetramethylphenylenediamine (TMPD) as substrates was significantly decreased following ischemia-reperfusion. Preperfusion with 10(-5) M TMZ had no effect on these rates in normoxic or ischemic hearts. However, 10(-3) M TMZ significantly decreased the glutamate-malate rate in mitochondria from normoxic hearts, and this rate was not further decreased following ischemia-reperfusion, and 10(-3) M TMZ also partially protected ascorbate-TMPD activity. The effect on glutamate-malate was probably due to an inhibition of complex I by TMZ, which specifically inhibited reduced nicotinamide-adenine-dinucleotide-cytochrome c reductase and complex I in lysed mitochondria. We also studied the effects of TMZ on the activity of pyruvate dehydrogenase (PDH) in normoxic and ischemic hearts perfused with 0.5 mM palmitate, which caused the enzyme to be almost completely inactivated. After short periods of ischemia (10-20 minutes) the PDH inactivation by palmitate was progressively lost. Preperfusion with 10(-5) M TMZ had a tendency to decrease lactate dehydrogenase release, accompanied by a maintenance of the inhibition of PDH by palmitate. This may allow the heart to oxidize fatty acids preferentially during reperfusion, hence removing possible toxic acyl esters.
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PMID:Trimetazidine effects on the damage to mitochondrial functions caused by ischemia and reperfusion. 764 24

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.
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PMID:alpha-Lipoic acid as a biological antioxidant. 764 94

Salicylate is widely used as a stable trap for the highly reactive hydroxyl radical. The purpose of this study was to determine whether the addition of salicylate to hearts subjected to ischemia and reperfusion was able to prevent some injury. Salicylate was able to inhibit mitochondrial damage, and preserved ascorbate and alpha-tocopherol depletion due to ischemia/reperfusion in rat hearts. It did not prevent the elevation of low molecular weight iron. We conclude that salicylate functions as an antioxidant and afforded protection against ischemia and reperfusion.
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PMID:Salicylate in the perfusate during ischemia/reperfusion prevented mitochondrial injury. 771 5

Four series of experiments were made on 82 rats which experienced 90-min renal ischemia. Animals from series 1 received no drugs. Animals of series 2 were injected i.v. emulsion (10 mg/kg alpha-tocopherol + 200 mg/kg dimethylsulphoxide) 10 min before ischemia termination. Animals of series 3 received i.v. verapamil (0.5 mg/kg) prior to reperfusion. Rats of series 4 were given alpha-tocopherol acetate emulsion simultaneously with verapamil. Introduction of alpha-tocopherol emulsion significantly inhibited lipid peroxidation (ascorbate-induced peroxidation activation) in intact kidneys blocking this activation in the reperfusion period. The ischemic kidney function proved much better on ischemia day 2 in the 2nd and 4th series. In series 3 the results were similar to control. On postischemia day 7 renal function did not differ much between the series. Mechanisms of the emulsion protective action and the causes of its absence in verapamil are covered in the discussion.
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PMID:[The effect of an emulsion containing alpha-tocopherol and dimethylsulfoxide and of verapamil on reperfusion injury to the rat kidneys]. 773 29

The polymorphonuclear neutrophilic granulocyte (PMN) has been implicated as one possible cause of the no-reflow phenomenon seen upon reperfusion after ischemia, by, for instance, the release of toxic substances and/or microvascular flow obstruction. In the present study we studied the effects of ascorbate (an antioxidant) and fucoidin (an inhibitor of leukocyte rolling in microvessels) on the rat gastric mucosal and submucosal PMN content and vascular patency (the latter assessed as the surface density of perfused vessels) in connection with hemorrhagic shock (15 min) and retransfusion (5 or 10 min). The effect of fucoidin on the leukocyte rolling in small venules was studied separately with vital microscopy in the rat mesentery. As found in earlier studies, shock and retransfusion led to a decrease in the surface density of perfused vessels, whereas the number of PMNs in the mucosa or the submucosa was not affected by shock and retransfusion. Ascorbate improved vascular patency without affecting the PMN content. In the mesentery, fucoidin caused a 76% reduction in the number of rolling PMNs and it reduced significantly the number of PMNs in the mucosa, but not in the submucosa, after 10 min of retransfusion. Fucoidin had no effect on the vascular patency at that or any other time point. On the basis of these experiments it is concluded that PMN accumulation cannot be singled out as the cause of no-reflow in the rat gastric mucosa after shock and retransfusion of the degree and duration analyzed in this investigation.
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PMID:Blocking of endothelial-leukocyte interaction (rolling) does not improve reflow in the rat gastric mucosa after hemorrhagic shock and retransfusion. 775 17

By using a recently developed ion-pairing high-performance liquid chromatographic method for the direct determination of malondialdehyde (MDA) and several other acid-soluble low-mol-wt compounds (ascorbate, oxypurines, nucleosides, nicotinic coenzymes, high-energy phosphates), the variations of tissue and plasma MDA as a function of ischemia and reperfusion were determined in the rat (isolated Langendorff-perfused hearts and short-term incomplete cerebral ischemia) and in human beings (patients suffering from acute myocardial infarction subjected to fibrinolysis). In the rat, the data obtained indicate that, contrary to what had been previously reported in literature, MDA is not present either in control heart or in control brain. Oxygen deprivation induces the production of a low, but detectable amount of MDA in both heart and brain, whereas reperfusion causes a marked increase of MDA in both tissues. In human beings, plasma MDA was deeply affected only in patients suffering from acute myocardial infarction with successful thrombolysis, thus indicating the occurrence of oxygen radical-mediated tissue injury also in humans. On the whole, these results suggest that MDA is a valid biochemical marker of lipid peroxidation of postischemic tissues, which however needs a reliable analytical technique for its determination.
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PMID:The relevance of malondialdehyde as a biochemical index of lipid peroxidation of postischemic tissues in the rat and human beings. 777 43

The in vivo measurement of the rapid changes in the extracellular concentrations of L-glutamic acid in the mammalian brain during normal neuronal activity or following excessive release due to episodes of anoxia or ischemia has not been possible to this date. Current techniques for the measurement of the release of endogenous glutamate into the extracellular space of the central nervous system are relatively slow and do not measure the actual concentration of free glutamate in the extracellular space. An enzyme-based electrode with rapid response times (about 1 s) and high degree of sensitivity (less than 2 microM) and selectivity for L-glutamic acid is described in this paper. This electrode has both L-glutamate and ascorbate oxidase immobilized on its surface. The latter enzyme removes almost completely any interferences produced by the high levels of extracellular ascorbate present in brain tissue. The response of the electrode to glutamate and other potentially interfering substances was fully characterized in vitro and its selectivity, sensitivity and rapidity in responding to a rise in extracellular glutamate concentrations was also demonstrated in vivo. Placement of the electrode in the dentate gyrus of the hippocampus led to the detection of both KCl-induced release of L-glutamic acid and the release induced by stimulation of the axons in the perforant pathway. The development of this selective, sensitive and rapidly responding glutamate sensor should make it now possible to measure the dynamic events associated with glutamate neurotransmission in the central nervous system.
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PMID:Direct measurement of glutamate release in the brain using a dual enzyme-based electrochemical sensor. 782 Jun 52

The effect of 32 mM ascorbate on the time courses of phosphocreatine (PCr), inorganic phosphate (Pi), adenosine triphosphate (ATP) and intracellular pH in rat skeletal muscle during ischemia and reperfusion was investigated in vivo using 31P nuclear magnetic resonance (NMR) spectroscopy. Ascorbate was administered intravenously prior to induction of ischemia and at the time of reperfusion. The changes in PCr/(PCr+Pi), ATP and pH were similar in the non-treated and in the treated groups during ischemia. PCr/(PCr+Pi) fell to < 10% and ATP to approximately 30% of the preischemic values after 4 hours of arrested circulation, and pH decreased considerably. Postischemic reperfusion was followed continuously for 150 minutes. At the time of reflow, treatment with ascorbate had an immediate, positive effect on the recovery of high energy phosphates and pH. The level of PCr/(PCr+Pi) was 86% higher (p < 0.001) and the ATP level was 40% higher (p < 0.001) in the treated group than in the control group by the end of the reperfusion period. The results provide in vivo evidence for a salvaging effect of ascorbate on ischemia-reperfusion injury in skeletal muscle, probably owing to its antioxidant function and other ancillary effects, mainly its provision of additional buffer capacity.
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PMID:In vivo 31P nuclear magnetic resonance evidence of the salvage effect of ascorbate on the postischemic reperfused rat skeletal muscle. 783 May

Free radicals have been implicated in the cause of ischemia-reperfusion injury. Various agents have been used in an attempt to reduce ischemia-reperfusion injury pharmacologically, including free radical scavengers. Vitamin C (ascorbic acid), a well-known free radical scavenger, has not, to the best of our knowledge, been evaluated in this respect. Previous work at our institution has shown that vitamin C decreases capillary permeability, thus significantly reducing fluid resuscitation requirements in postburn cases. Because this is due in part to the scavenging effect of vitamin C on free radicals, we investigated the role, if any, of vitamin C on ischemia-reperfusion injury in a rat epigastric island skin flap model. Twenty-four adult Sprague-Dawley rats were divided into control and vitamin C groups. Superficial epigastric island skin flaps measuring 6.0 x 3.5 cm were raised. Pedicles were isolated and occluded with microvascular clamps for 6 hours. The flaps were then sutured back to their beds over Steri-Drape barriers. Fifteen minutes before reperfusion, the control group flaps were perfused via femoral artery cannulation with normal saline (2.5 ml/kg). The vitamin C-treated group was perfused in a similar fashion with 2.5 ml/kg of a vitamin C/normal saline solution (27 mg/ml). The animals were observed for 7 days, and the percentage of flap survival was determined using a paper template technique. The vitamin C-treated group demonstrated a significantly higher percentage of flap survival than did the control group (25.8% mean vs. 7.5% mean, p < 0.025). In this animal model, vitamin C reduced or limited reperfusion injury after 6 hours of ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vitamin C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model. 788 53

A variety of events, including inhalation of atmospheric chemicals, trauma, and ischemia-reperfusion, may cause generation of reactive oxygen species in the lung and result in airways constriction. The specific metabolic mechanisms that translate oxygen radical production into airways constriction are yet to be identified. In the lung, calcium homeostasis is central to release of bronchoactive and vasoactive chemical mediators and to regulation of smooth muscle cell contractility, i.e., airway constriction. In the present work, we characterized Ca(2+)-transport in the microsomal fraction of mouse lungs, and determined how reactive oxygen species, generated by Fe2+/ascorbate and H2O2/hemoglobin, affected Ca2+ transport. The microsomal fraction of pulmonary tissue accumulated 90 +/- 5 nmol Ca2+/mg protein by an ATP-dependent process in the presence of 15 mM oxalate, and 16 +/- 2 nmol Ca2+ in its absence. In the presence of oxalate, the rate of Ca2+ uptake was 50 +/- 5 nmol Ca2+/min per mg protein at pCa 5.9 (37 degrees C). The Ca(2+)-ATPase activity was 50-60 nmol Pi/min per mg protein (pCa 5.9, 37 degrees C) in the presence of alamethicin. Inhibitors of mitochondrial H(+)-ATPase had no effect on the Ca2+ transport. Half-maximal activation of Ca2+ transport was produced by 0.4-0.5 microM Ca2+. Endoplasmic reticulum Ca(2+)-pump (SERC-ATPase) was found to be predominantly responsible for the Ca(2+)-accumulating capacity of the pulmonary microsomes. Incubation of the microsomes in the presence of either Fe2+/ascorbate or H2O2/hemoglobin resulted in a time-dependent accumulation of peroxidation products (TBARS) and in inhibition of the Ca2+ transport. The inhibitory effect of Fe2+/ascorbate on Ca2+ transport strictly correlated with the inhibition of the Ca(2+)-ATPase activity. These results are the first to indicate a highly active microsomal Ca2+ transport system in murine lungs which is sensitive to endogenous oxidation products. The importance of this system to pulmonary disorders exacerbated by oxidative chemicals remains to be studied.
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PMID:Pulmonary microsomes contain a Ca(2+)-transport system sensitive to oxidative stress. 789 26


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