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

Pyruvate (PYR) improves cellular and organ function hypoxia and ischemia by stabilizing the reduced nicotinamide adenine dinucleotide redox state and cytosolic ATP phosphorylation potential. In this in vivo study, we evaluated the effects of intravenous pyruvate on neocortical function, indexes of the cytosolic redox state, cellular energy state, and ischemia during a prolonged (4 h) controlled arterial hemorrhage (40 mmHg) in swine. Thirty minutes after the onset of hemorrhagic shock, sodium PYR (n = 8) was infused (0.5 g x kg(-1) x h(-1)) to attain arterial levels of 5 mM. The volume and osmotic effects were matched with 10% NaCl [hypertonic saline (HTS)] (n = 8) or 0.9% NaCl [normal saline (NS)] (n = 8). During the hemorrhage protocol, the time to peak hemorrhage volume was significantly delayed in the PYR group compared with the HTS and NS groups (94 +/- 5 vs. 73 +/- 6 and 72 +/- 4 min, P < 0.05). In addition to the early onset of the decompensatory phase of hemorrhagic shock, the complete return of the hemorrhage volume during decompensatory shock resulted in the death of five and four animals, respectively, in the HTS and NS groups. In contrast, in the PYR group, reinfusion of the hemorrhage volume was slower and all animals survived the 4-h hemorrhage protocol. During hemorrhage, the PYR group also exhibited improved cerebral cortical metabolic and function status. PYR slowed and reduced the rise in neocortical microdialysis levels of adenosine, inosine, and hypoxanthine and delayed the loss of cerebral cortical biopsy ATP and phosphocreatine content. This improvement in energetic status was evident in the improved preservation of the electrocorticogram in the PYR group. PYR also prevented the eightfold increase in the excitotoxic amino acid glutamate observed in the HTS group. The findings show that PYR administered after the onset of hemorrhagic shock markedly improves cerebral metabolic and functional status for at least 4 h.
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PMID:Pyruvate improves cerebral metabolism during hemorrhagic shock. 1145 91

Pyruvate has a remarkable protective effect against zinc neurotoxicity. Because zinc neurotoxicity is likely one of the key mechanisms of ischemic brain injury, the neuroprotective effect of pyruvate was tested in a rat model of transient forebrain ischemia. Control experiments in mouse cortical culture showed that pyruvate almost completely blocked zinc toxicity but did not attenuate calcium-overload neuronal death. Adult rats subjected to 12 min forebrain ischemia exhibited widespread zinc accumulation and neuronal death throughout hippocampus and cortex 72 hr after reperfusion. However, rats injected intraperitoneally with sodium pyruvate (500-1000 mg/kg) within 1 hr after 12 min forebrain ischemia showed almost no neuronal death. In addition, the mortality was markedly decreased in the pyruvate-protected groups (3.8%) compared with the NaCl-injected control group (58.1%). The neuroprotective effect persisted even at 30 d after the insult. The spectacular protection without noticeable side effects makes pyruvate a promising neuroprotectant in human ischemic stroke.
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PMID:Protection by pyruvate against transient forebrain ischemia in rats. 1158 1

Pyruvate plays a central role in intermediary metabolism. Pyruvate, however, is also a potent antioxidant and free radical scavenger, and numerous studies have shown that treatment with this compound can be salutary in numerous pathologic conditions that are thought to be mediated, at least in part, by redox-dependent phenomena. Unfortunately, aqueous solutions of pyruvate rapidly undergo an aldol-like condensation reaction to form 2-hydroxy-2-methyl-4-ketoglutarate (parapyruvate), a compound that is a potent inhibitor of a critical step in the mitochondrial tricarboxylic acid cycle. To circumvent this issue, our laboratory formulated a derivative of pyruvic acid, ethyl pyruvate, in a calcium- and potassium-containing balanced salt solution. We showed that treatment with this fluid could ameliorate much of the structural and functional damage to the intestinal mucosa caused by mesenteric ischemia and reperfusion in rats. In subsequent studies, we showed that treatment with ethyl pyruvate solution could improve survival in rodent models of hemorrhagic shock and resuscitation and also down-regulate a number of proinflammatory genes. Recently, ethyl pyruvate was also shown to improve survival in murine models of acute endotoxemia and bacterial peritonitis. Although the biochemical basis for the anti-inflammatory actions of pyruvate remain to be elucidated, this simple compound warrants further evaluation as a treatment for a number of conditions commonly encountered in the practice of critical care medicine.
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PMID:Ethyl pyruvate: a novel anti-inflammatory agent. 1254 77

Pyruvate is an energy substrate with known cardioprotective activity. We know now that this is due not only to its antioxidant activity, but also to its reduction of intracellular acidosis, modulation of intracytosolic calcium and improvement of cardiomyocyte contractility. However, the role of cardiac mitochondria in such positive effects has only recently begun to be understood and the exact mechanisms of the effect of pyruvate on mitochondria are still largely unknown. Aiming to study the effect of pyruvate on cardiac mitochondrial function during acute ischemia, we used an ex-vivo animal model, perfused in a Langendorff system and then subjected to ischemia in the presence and absence of pyruvate. We evaluated the mitochondrial membrane electrical potential, the respiratory chain O2 consumption (and respiratory control ratio) and the energy charges generated with different energy substrates. We conclude that pyruvate has some effect on the mitochondrial oxidative system (by non-significantly improving the respiratory control ratio), but its main action is on the phosphorylation system, significantly decreasing the time taken to complete a phosphorylation cycle (lag phase) and improving ATP production (increase in energy charge), thus allowing better maintenance of mitochondrial membrane structure, with consequent improvement of the electrical potential after a phosphorylation cycle. These findings have enabled better understanding of the mechanisms behind pyruvate cytoprotection in ischemic cardiomyopathy, clearly highlighting the essential role of cardiac mitochondria in this process.
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PMID:Pyruvate improves mitochondrial bioenergetics in an ex-vivo animal model of myocardial ischemia. 1271 12

Reactive species of oxygen have been implicated as being important mediators in a variety of pathologic conditions, including burns, various forms of ischemia/reperfusion injury, and hemorrhagic shock. Pyruvate, an intermediate in the metabolism of glucose, is a potent reactive species of oxygen scavenger. Pyruvate, however, is unstable in aqueous solutions, and has not been developed as a therapeutic agent. Ethyl pyruvate, a simple derivative of the parent compound, is thought to be more stable in solution. Ringer's ethyl pyruvate solution (REPS) has been evaluated in a number of preclinical studies using animal models of mesenteric ischemia/reperfusion injury, hemorrhagic shock, and acute endotoxemia. Treatment with REPS, when compared with treatment with Ringer's lactate solution, has been shown to be able to improve survival and decrease expression of proinflammatory mediators. REPS warrants further evaluation for the resuscitation of patients with hemorrhagic shock.
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PMID:Ringer's ethyl pyruvate solution: a novel resuscitation fluid for the treatment of hemorrhagic shock and sepsis. 1276 16

The present study was aimed at characterizing alterations of the nucleotide content and morphological state of rat corticoencephalic cell cultures subjected to metabolic damage and treatment with modulators of mitochondrial ATP-dependent potassium channels (mitoK(ATP)). In a first series of experiments, in vitro ischemic changes of the contents of purine and pyrimidine nucleoside diphosphates and triphosphates were measured by high performance liquid chromatography (HPLC) and the corresponding histological alterations were determined by celestine blue/acid fuchsin staining. As an ischemic stimulus, incubation with a glucose-free medium saturated with argon was used. Ischemia decreased the levels of adenosine, guanine and uridine triphosphate (ATP, GTP, UTP) and increased the levels of the respective dinucleotides ADP and UDP, whereas the GDP content was not changed. Both 5-hydroxydecanoate (5-HD) and diazoxide failed to alter the contents of nucleoside diphosphates and triphosphates, when applied under normoxic conditions. 5-HD (30 microM) prevented the ischemia-induced changes of nucleotide and nucleoside levels. Diazoxide (300 microM), either alone or in combination with 5-hydroxydecanoate (30 microM) was ineffective. Pyruvate (5 mM) partially reversed the effects of ischemia or ischemia plus 2-deoxyglucose (20mM) in the incubation medium. Diazoxide (300 microM) and 5-HD (30 microM) had no effect in the presence of pyruvate (5mM) and 2-deoxyglucose (20mM). Staining the cells with celestine blue/acid fuchsin in order to classify them as intact, reversibly or profoundly injured, revealed a protective effect of 5-HD. When compared with 5-HD, diazoxide, pyruvate and 2-deoxyglucose had similar but less pronounced effects. In conclusion, these results suggest a protective role of 5-hydroxydecanoate on early corticoencephalic nucleotide and cell viability alterations during ischemia.
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PMID:Early biochemical and histological alterations in rat corticoencephalic cell cultures following metabolic damage and treatment with modulators of mitochondrial ATP-sensitive potassium channels. 1282 Sep 85

The beneficial effects of pyruvate in organ reperfusion injury have been documented, however the therapeutic use of pyruvate has been hindered by the lack of an appropriate delivery method. Pyruvic acid is unstable and high rates of sodium pyruvate infusion are toxic. Dipyruvyl-acetyl-glycerol (DPAG) ester was developed as a novel method for intravenous pyruvate delivery at a high rate without sodium overload. We tested the ability of DPAG to reduce myocardial infarct size when administered after severe myocardial ischemia in an anesthetized open-chest pig model of ischemia-reperfusion injury. Ischemia was induced by total occlusion of the distal 2/3 of the left anterior descending coronary artery for one hour, followed by two hours of reperfusion. Animals were either untreated (n = 7), or treated with intravenous DPAG (8.0 mg/kg(-1). min(-1), n = 8) during the two hours of reperfusion. Infarct size was measured on blinded samples using tetrazolium staining. The DPAG treated group had elevated pyruvate levels (0.82 +/- 0.07 mM) and reduced infarct size (20.1 +/- 4.2% of the volume at risk, compared to 30.8 +/- 4.6% in the untreated animals (p < 0.05)), with no difference in blood pressure or heart rate between groups. In conclusion, an intravenous infusion of DPAG safely increases arterial pyruvate concentration and reduces myocardial infarct size following myocardial ischemia.
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PMID:Post-ischemic treatment with dipyruvyl-acetyl-glycerol decreases myocardial infarct size in the pig. 1457 79

This in vitro study was designed to examine the efficacy of exogenous pyruvate and glucose as a fuel substrate to protect rat astrocytes from post-ischemic injury. Astrocytes were incubated in Kreb's buffer deprived of oxygen and glucose for 6 h (ischemia) followed by incubation with added pyruvate or glucose and normoxia for the next 6 h (reperfusion). The transformation of reactive astrocytes in response to various treatments was examined by immunostaining with glial fibrillary acidic protein. The extent of cell damage was evaluated in terms of lactate dehydrogenase leakage from the cells and altered intracellular redox status. The mechanism of cell death was determined by immunoblotting with cytochrome C, caspase-3 and PARP antibodies. The mechanism of the action of pyruvate was determined by measuring the activity of pyruvate dehydrogenase complex, and cellular metabolic status by measuring ATP levels. In comparison to glucose, supply of exogenous pyruvate restored the morphological integrity of post-ischemic astrocytes and prevented gliosis. Pyruvate prevented the cell death of post-ischemic astrocytes by inhibiting the leakage of lactate dehydrogenase, decreasing the redox ratio and restraining the activation of apoptotic events such as release of mitochondrial cytochrome c and fragmentation of caspase-3 and PARP. This study also suggests that pyruvate may accelerate its own metabolism by increasing the activity of pyruvate dehydrogenase and thus restores the cellular ATP levels in post-ischemic astrocytes. Use of pyruvate as an alternate fuel substrate may provide a possibility for the novel therapeutic approach to the treatment of cerebral ischemia.
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PMID:Pyruvate ameliorates post ischemic injury of rat astrocytes and protects them against PARP mediated cell death. 1460 78

Pyruvic acid is a simple 3 carbon a-keto-monocarboxylic acid. Recognition that pyruvate is an effective scavenger of reactive oxygen species (ROS) prompted investigators to use it as therapeutic agent for various pathological conditions that are thought to be mediated by redox dependent phenomena, like myocardial, intestinal or hepatic ischemia/reperfusion-induced injury. Ethyl Pyruvate showed to be more effective and safer than equimolar doses of sodium pyruvate. Ethyl Pyruvate showed to have anti-inflammatory effects. In animal models Ethyl Pyruvate improved hyperpermeability and bacterial translocation due to endotoxemia and improved the development of renal disfunction as well as some of the morphological findings of kidney injury. The pharmacological basis for the anti-inflammatory effects of EP remains to be explained. It is plausible that EP mediates suppression of NF-KB activation and secretion of NO and of pro-inflammatory cytokines.
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PMID:Ethyl pyruvate: a novel treatment for sepsis and shock. 1518 17

Cardioplegic arrest for bypass surgery imposes global ischemia on the myocardium, which generates oxyradicals and depletes myocardial high-energy phosphates. The glycolytic metabolite pyruvate, but not its reduced congener lactate, increases phosphorylation potential and detoxifies oxyradicals in ischemic and postischemic myocardium. This study tested the hypothesis that pyruvate mitigates oxidative stress and preserves the energy state in cardioplegically arrested myocardium. In situ swine hearts were arrested for 60 min with a 4:1 mixture of blood and crystalloid cardioplegia solution containing 188 mM glucose alone (control) or with additional 23.8 mM lactate or 23.8 mM pyruvate and then reperfused for 3 min with cardioplegia-free blood. Glutathione (GSH), glutathione disulfide (GSSG), and energy metabolites [phosphocreatine (PCr), creatine (Cr), P(i)] were measured in myocardium, which was snap frozen at 45 min arrest and 3 min reperfusion to determine antioxidant GSH redox state (GSH/GSSG) and PCr phosphorylation potential {[PCr]/([Cr][P(i)])}. Coronary sinus 8-isoprostane indexed oxidative stress. Pyruvate cardioplegia lowered 8-isoprostane release approximately 40% during arrest versus control and lactate cardioplegia. Lactate and pyruvate cardioplegia dampened (P < 0.05 vs. control) the surge of 8-isoprostane release following reperfusion. Pyruvate doubled GSH/GSSG versus lactate cardioplegia during arrest, but GSH/GSSG fell in all three groups after reperfusion. Myocardial [PCr]/([Cr][P(i)]) was maintained in all three groups during arrest. Pyruvate cardioplegia doubled [PCr]/([Cr][P(i)]) versus control and lactate cardioplegia after reperfusion. Pyruvate cardioplegia mitigates oxidative stress during cardioplegic arrest and enhances myocardial energy state on reperfusion.
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PMID:Pyruvate-fortified cardioplegia suppresses oxidative stress and enhances phosphorylation potential of arrested myocardium. 1590 64


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