Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen radicals produced by activated neutrophils have been involved in brain injury during ischemia-reperfusion. Platelet-activating factor (PAF) is a candidate as one of the mediators of neutrophil activation during cerebral ischemia-reperfusion. Recent evidence indicates that PAF-induced neutrophil activation is mediated by thromboxane A2 (TXA2). To study the role of PAF and TXA2 in radical production during cerebral ischemia-reperfusion, we evaluated the effects of a PAF antagonist, Y-24180, and a TXA2 antagonist, S-1452, on radical formation in rats with 1 h middle cerebral artery (MCA) occlusion. In the present study, we employed a new electron spin resonance (ESR) method coupled with brain microdialysis. The method uses the endogenous ascorbyl radical (AR) concentration as a marker of oxygen radicals and requires no spin-trapping agents. In the vehicle controls, extracellular AR from the ischemic brain cortex decreased during MCA occlusion. Following reperfusion, AR significantly increased at 30 mm and 1 h, returned to near the basal levels at 2 h, and increased again at 24 h after reperfusion. In the rats treated with S-1452 or Y-24180, AR decreased during MCA occlusion to the same extent as in the vehicle control. However, pretreatment with Y-24180 or S-1452 significantly attenuated the increase in extracellular AR after reperfusion, while it exerted no effect on the changes in extracellular ascorbate or tissue pO2 throughout the experimental period. In conclusion, PAF and TXA2 might contribute to cerebral ischemia-reperfusion injury by increasing the generation of oxygen radicals.
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PMID:Role of platelet-activating factor and thromboxane A2 in radical production during ischemia and reperfusion of the rat brain. 883 66

We evaluated experimentally (80 Lewis-rats) possible pharmacological strategies in the treatment of intestinal reperfusion injury in hypo- and normothermia. We used a specific perfusion solution containing PGI2 or radical scavengers (superoxide dismutase, oxypurinol, tocopherol, ascorbate). Decreased malondialdehyde (MDA) plasma release after reperfusion proved the antioxidative efficiency of the administered radical scavengers (normothermia-control group: MDA increase after 15 min of reperfusion to 160 +/- 30% compared to level at the end of ischemia, oxypurinol: 110 +/- 23%, tocopherol: 112 +/- 12%, ascorbate: 104 +/- 20%; p < 0.05). The ATP/ADP-ratio of the therapy groups was stable in contrast to the control group. Alkaline phosphatase release was significantly diminished under radical scavenger administration (normothermia/15 min reperfusion-control group: 7.7 +/- 0.9 mumol/ls, oxypurinol: 4.4 +/- 0.4 mumol/ls, tocopherol: 3.5 +/- 0.1 mumol/ls, ascorbate: 5.9 +/- 0.3 mumol/ls; p < 0.05). Histologically we observed a mucosa protective effect particularly in the ascorbate group. Other pharmacological strategies are discussed.
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PMID:[Pharmacologic modification of intestinal reperfusion injury in the animal experiment]. 885 45

Oxidative stress, assessed by tissue ascorbate loss following ischemia, is greater in male than female rat brain. The factors mediating this gender difference are unclear. The goal of the present studies was to determine the influence of gonadal sex hormones on this difference. Three weeks prior to experiment, adult Long-Evans male and female rats were gonadectomized for comparison with controls. Ascorbate and glutathione levels were determined in brain and plasma under basal conditions and in brain after one-hour decapitation ischemia, using liquid chromatography with electrochemical detection. Basal ascorbate levels in brain were 6-9% higher in males than in females, whereas plasma levels were 100% higher in males. After gonadectomy, the gender difference in plasma ascorbate levels was lost, while the effect on basal brain levels depended upon region. Ischemia-induced losses in brain ascorbate were three-fold greater in control males compared to control females. Significant losses occurred in frontal cortex, hippocampus, and cerebellum in males during ischemia, whereas loss in females was significant in cerebellum only. After gonadectomy, increased ascorbate loss was seen in all female brain regions, indicating enhanced oxidative stress. This increase eliminated the gender difference in loss; male ascorbate loss was comparatively unaffected by gonadectomy. Glutathione levels and loss were unaffected by either gender or gonadectomy, indicating differences in regulation from that of ascorbate. These findings provide evidence for the hypothesis that protection against oxidative stress is afforded by ovarian sex hormones, thus decreasing the potential for oxidative cell damage in females compared to males.
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PMID:Enhanced oxidative stress in female rat brain after gonadectomy. 894 21

We describe real-time measurement of myocardial oxygen consumption during ischemia in the intact heart. Measurement of extracellular oxygen concentration during myocardial ischemia by spin label oximetry has been limited by ischemia-induced reduction of the neutral, water-soluble nitroxide TEMPONE. We have overcome this problem by encapsulating the nitroxides. Isolated immature (7-10 d old) rabbit hearts (n = 8) were perfused aerobically within the cavity of a loop gap resonator with bicarbonate buffer containing an oxygen-sensitive, lipid-soluble nitroxide (14N-TEMPO laurate in FC-43 perfluorocarbon micelles) and a much less oxygen-sensitive and positively charged nitroxide (15N-TEMPO choline in multilamellar vesicles) as an internal standard. The ratio of the ESR signal amplitudes of these nitroxides was used as a sensitive index of oxygen concentration. Sequestration of the nitroxides decreased their reduction rate by ascorbate in comparison with nonsequestered nitroxides. Hearts were subjected to 60 min of global no-flow ischemia at 20 degrees C. Extracellular oxygen content (mean +/- SD) during aerobic perfusion was 1195 +/- 55 mumol/liter. The electron spin resonance signal from TEMPO laurate increased with the onset and progression of ischemia, consistent with a decrease in extracellular oxygen, while the signal for TEMPO choline was relatively unchanged. Extracellular oxygen content after 40 and 60 min of ischemia was reduced to 393 +/- 27 mumol/liter (p < .05) and 61 +/- 5 mumol/liter (p < .05), respectively. We conclude that spin-label oximetry can directly and precisely measure myocardial oxygen consumption at constant temperature during ischemia in the intact heart.
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PMID:Spin label oximetry to assess extracellular oxygen during myocardial ischemia. 895 35

Our purpose was to determine whether prolonged myocardial ischemia attenuates free radical production after early reperfusion. Twenty-two mongrel dogs underwent left anterior descending coronary artery occlusion for 20, 40, or 60 minutes followed by 30 minutes of reperfusion. Electron paramagnetic resonance spectroscopy was used to measure ascorbate free radical in the coronary vein effluent. Ascorbate free radical production during reperfusion was significantly (p < 0.05) reduced in the dogs undergoing 60 minutes of coronary artery occlusion compared with the dogs undergoing 40 and 20 minutes of occlusion. We conclude that prolonged myocardial ischemia results in less free radical production on reperfusion than do shorter periods of ischemia followed by reperfusion.
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PMID:Prolonged coronary artery occlusion-reperfusion sequences reduce myocardial free radical production: an electron paramagnetic resonance study. 896 65

Recently we have shown that ACE inhibitors and platelet activating factor antagonists inhibit iron-dependent lipid peroxidation in murine ventricular membranes and possess beneficial effects on ischemia and ischemia reperfusion-induced myocardial injury, which has been ascribed to their capacity to scavenge or impair oxygen free radical generation. In the present study we investigated the effects of beta-adrenoceptor blockers and calcium antagonists on iron-dependent lipid peroxidation (LPO) in murine ventricular membranes and compared them with the lazaroid U-74500A, a potent antioxidant. Fe(2+)-vitamin C induced LPO in a concentration- and time-dependent manner, measured as thiobarbituric acid reactive substances (TBARS) formation. Pretreatment of ventricular membranes with gallopamil, verapamil, propranolol and metaprolol at concentrations of 5 microM and higher inhibited Fe(2+)-vitamin C-induced LPO in a concentration-dependent manner with IC50 values of 192.8-208.3 microM; however, they were less potent than U-74500A (IC50 6.8 microM). In contrast, atenolol, timolol, diltiazem and nifedipine inhibited LPO at very high concentrations with IC50 values of 864.5-971.5 microM. Inhibition of LPO may not be due to the drugs' classical pharmacological actions, but rather to their characteristic chemical structures or physicochemical interactions with biological membranes. In view of the pathological importance of LPO in cardiac ischemic injury, inhibition of LPO by gallopamil, verapamil, propranolol and metaprolol may provide additional cardioprotective activity and thus reinforces their beneficial effects in the treatment of ischemic heart disease.
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PMID:Comparative antioxidant effects of beta-adrenoceptor blockers, calcium antagonists and U-74500A against iron-dependent lipid peroxidation in murine ventricular microsomal membranes. 901 Aug 29

The effect of intravenously administered ascorbate on the ischemic and reperfused rat skeletal muscle was investigated. Purine nucleotides and phospholipids in skeletal muscle from rats subjected to 4 h of ischemia followed by 1-h reperfusion were analyzed by high-performance liquid chromatography. In addition, ATP, phosphocreatine (PCr), Pi, and phosphomonoesters (PME) were analyzed by 31P-nuclear magnetic resonance at 202.4 MHz, and individual PME such as glucose-6-phosphate and IMP were quantified. PCr and ATP were exhausted after 4 h of ischemia and recovered poorly upon reperfusion in the soleus and tibialis muscle of untreated rats. Postischemic reperfusion resulted in significant loss of cardiolipin. Treatment with 55 mM ascorbate resulted in total restoration of PCr during reperfusion, and ATP recovered to 42% of control in the soleus. Recovery was improved in the tibialis as well, and the cardiolipin decrease was limited. A lower ascorbate concentration (5 mM) did not enhance postischemic recovery. Our findings show that a high dose of ascorbate improves the energetic state of rat skeletal muscle during postischemic reperfusion, probably due to its antioxidant function.
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PMID:Purine nucleotides and phospholipids in ischemic and reperfused rat skeletal muscle: effect of ascorbate. 903 25

Although the formation of oxygen-derived free radicals (or reactive oxygen species; ROS) and the release of endogenous opioid peptides (EOP) have been independently reported to be the major arrhythmogenic factors in ischemic hearts, possible relations between these two factors have seldom been investigated. Thus, we studied whether the ROS and EOP were related in the progression of ischemia-induced arrhythmias. Isolated rat hearts perfused in the Langendorff mode were treated with dynorphin A1-13 (kappa EOP receptor agonist), and/or allopurinol (xanthine oxidase inhibitor), before the onset of ischemia induced by ligating the left coronary arteries. Ischemic period lasted for 30 min, during which cardiac rhythms were recorded. At the end of ischemia, hearts were analyzed for the glutathione and ascorbate levels. Allopurinol (100 nmoles/heart) was effective in reducing the severity of arrhythmia (arrhythmia score: Mean +/- SEM 3.00 +/- 0.80 for allopurinol, 5.75 +/- 0.41 for placebo, p < 0.01), while dynorphin (10 micrograms/heart) potentiated the arrhythmia (6.71 +/- 0.52, p < 0.05 vs. placebo). Coadministration of allopurinol and dynorphin was capable of reducing arrhythmia (5.57 +/- 0.65) when compared with the administration of dynorphin alone (6.71 +/- 0.52, p < 0.05). Tissue oxidative stress was evaluated by the concentrations of glutathione (GSH) and ascorbate. Allopurinol did not significantly elevate tissue GSH concentrations (1.46 +/- 0.05 mumoles/g wet wt) in ischemic hearts, while dynorphin alone significantly decreased the GSH concentrations (0.96 +/- 0.08, p < 0.05) when compared with the placebo (1.32 +/- 0.03). The dynorphin-induced GSH decrease cannot be reversed by coadministration with allopurinol (0.90 +/- 0.104). Allopurinol significantly elevated tissue ascorbate levels (0.16 +/- 0.01) when compared with placebo (0.10 +/- 0.01, p < 0.05). Interestingly, dynorphin alone also elevated the tissue ascorbate concentrations (0.16 +/- 0.02). Coadministration of allopurinol and dynorphin further spiked the ascorbate levels (0.28 +/- 0.05, p < 0.01). In conclusion, the results suggested that ischemia-induced arrhythmia mechanisms might involve the formation of superoxide and other ROS, which were probably generated from the release of EOP (or EOP/EOP receptor interactions). Superoxide, the formation of which can be inhibited by allopurinol that exerted antiarrhythmic effect, was probably scavenged by ascorbate in myocardial ischemia. The ROS resulting from EOP/EOP receptor interactions were probably scavenged by glutathione system. Elevated ascorbate levels in dynorphin-treated hearts might result from the compensatory synthesis induced by decreased glutathione levels.
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PMID:The roles of reactive oxygen species and endogenous opioid peptides in ischemia-induced arrhythmia of isolated rat hearts. 910 Dec 52

Cerebral injury may occur not only during brain ischemia but also during reperfusion afterward. A characteristic event during reperfusion after cerebral ischemia, or reoxygenation after anoxia in hippocampal slices, is hyperoxidation of the electron carriers of the mitochondrial respiratory chain. Earlier studies suggested that mitochondrial hyperoxidation was produced by an oxyradical mechanism and was linked to neuronal damage. Present studies sought to test this hypothesis by determining whether antioxidants could suppress mitochondrial hyperoxidation and improve electrical recovery after anoxia in hippocampal slices. Both 500 microM ascorbate and 50 microM glutathione decreased post-anoxic hyperoxidation of NADH and improved electrical recovery in hippocampal slices. These data support a role of oxygen free radicals in promoting post-anoxic mitochondrial hyperoxidation and electrical failure, and suggest that these effects of anoxia or ischemia may be linked.
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PMID:Antioxidants, mitochondrial hyperoxidation and electrical recovery after anoxia in hippocampal slices. 913 72

A growing body of evidence supports the trigger role of free radicals in the delayed functional and metabolic myocardial recovery following cardiopulmonary bypass (CPB) in humans, thus opening the field to specific therapies. This clinical study was designed to evaluate, in 15 patients undergoing aortic valve replacement, whether the extent of CPB- and reperfusion-induced lipid peroxidation, ascorbate depletion, tissue necrosis, and cardiac dysfunction is reduced by orally administered EGb 761, a Ginkgo biloba extract with potent in vitro antiradical properties. Patients received either EGb 761 (Tanakan, 320 mg/day, n = 8) or a matching placebo (n = 7) for 5 days before surgical intervention. Plasma samples were obtained from the peripheral circulation and the coronary sinus at crucial stages of the operation (i.e., before incision, during ischemia, and within the first 30 minutes post-unclamping), and up to 8 days postoperatively. Upon aortic unclamping, EGb 761 inhibited the transcardiac release of thiobarbituric acid-reactive species (p < 0.05), as assessed by high-performance liquid chromatography, and attenuated the early (5-10 minute) decrease in dimethylsulfoxide/ascorbyl free radical levels, an electron spin resonance index of the plasma ascorbate pool (p < 0.05). EGb 761 also significantly reduced the more delayed leakage of myoglobin (p = 0.007) and had an almost significant effect on ventricular myosin leakage (p = 0.053, 6 days postoperatively). The clinical outcome of recovery of treated patients was improved, but not significantly, compared with untreated patients. Our results demonstrate the usefulness of adjuvant EGb 761 therapy in limiting oxidative stress in cardiovascular surgery and suggest the possible role of highly bioavailable terpene constituents of the drug.
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PMID:Ginkgo biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery. 914 Jun 89


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