Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils accumulate in skeletal muscle subjected to ischemia-reperfusion and appear to contribute to reperfusion-induced microvascular dysfunction. The overall objective of this study was to assess the role of the neutrophilic hydrolytic enzyme elastase in ischemia-reperfusion-induced granulocyte accumulation and microvascular dysfunction in skeletal muscle. We examined the effect of three structurally unrelated elastase inhibitors [eglin C, MeOsuc-Ala-Ala-Val-CH2Cl (MAAPV), or L-658758], administered at the onset of reperfusion, on neutrophil content and the increase in microvascular permeability induced by 4 h of ischemia and 0.5 h of reperfusion in the isolated canine gracilis muscle. Changes in vascular permeability (1 - sigma) were assessed by determining the solvent drag reflection coefficient for total plasma proteins (sigma) in the following groups: 1) 4.5 h of continuous perfusion (nonischemic), 2) ischemia-reperfusion alone, 3) ischemia-reperfusion + eglin C, 4) ischemia-reperfusion + MAAPV, and 5) ischemia-reperfusion + L-658758. Muscle neutrophil content was monitored by assessing tissue myeloperoxidase (MPO) activity in biopsies obtained at the end of the experiments. In nonischemic muscles, 1 - sigma and MPO activity averaged 0.13 +/- 0.03 and 0.7 +/- 0.2 units/g wet wt, respectively. Ischemia-reperfusion was associated with marked increases in microvascular permeability (1 - sigma = 0.39 +/- 0.02) and muscle MPO activity (8.9 +/- 1.2 units/g wet wt) that were attenuated by eglin C, MAAPV, and L-658758 (1 - sigma = 0.21 +/- 0.01, 0.22 +/- 0.02, and 0.21 +/- 0.03, respectively; MPO activity = 2.7 +/- 0.4, 2.1 +/- 0.8, and 2.8 +/- 1.8 units/g wet wt, respectively). These results suggest that granulocyte accumulation in postischemic skeletal muscle is dependent on the release of elastase from activated phagocytic cells. Moreover, neutrophilic elastase appears to play a major role in reperfusion-induced increases in microvascular permeability in skeletal muscle.
 ...
PMID:Protease inhibition attenuates microvascular dysfunction in postischemic skeletal muscle. 894 13

Amino acids, particularly glutamate, have been proposed to play an important role in the recovery of cardiac oxidative metabolism after ischemia. In this investigation, the metabolic and hemodynamic effects of glutamate infusion after coronary operations were studied. From 220 to 240 ml 0.1 mol/L l-glutamic acid solution was infused in 10 patients during 1 hour starting 2 hours after operation. A control group of 10 patients received an infusion of 240 ml saline solution. During glutamate infusion, there were significant increases in the uptake of glutamate (from 0.7 +/- 0.2 micromol/min in the basal state to a peak of 5.7 +/- 1.2 micromol/min at 20 minutes) and lactate (from 4.9 +/- 2.0 micromol/min in the basal state to 14.1 +/- 4.4 micromol/min at 60 minutes; p < 0.01), whereas the uptake and release of other substrates remained essentially unaffected. Arterial glutamate levels (in whole blood) increased from 103 +/- 10 micromol/L to 394 +/- 20 micromol/L at 60 minutes. Thirty minutes after discontinuation of the glutamate infusion, arterial levels had decreased to 129 +/- 17 micromol/L. The markedly improved utilization of lactate and the unchanged release of alanine together suggest that the oxidative metabolism of the heart was stimulated by glutamate. The metabolic changes were associated with improved myocardial performance. Left ventricular stroke work index increased from 26.8 +/- 2.1 gm x beat(-1) x m(-2) body surface area to 31.3 +/- 3.1 gm x beat(-1) x m(-2) body surface area during glutamate infusion. Metabolic support with amino acids may provide a means to improve recovery of metabolic and hemodynamic function of the heart early after cardiac operations.
 ...
PMID:Metabolic and hemodynamic effects of intravenous glutamate infusion early after coronary operations. 897 38

An isolated rat Langendorff heart preparation has been developed as a model in which to study the release of glutamate, aspartate and other amino acids during ischemia, anoxia and hypoglycemia. 15 min periods of ischemia resulted in large increases in perfusate levels of glutamate, aspartate, glycine, phosphoethanolamine, serine, alanine, taurine and glutamine. Amino acid levels returned towards pre-ischemic levels in subsequent perfusate collections. Anoxia (15 min duration) increased perfusate levels of most of the measured amino acids, with glutamate and aspartate being particularly affected. In contrast to ischemia, glutamate and aspartate levels declined slowly following reoxygenation. Hypoglycemia (15 min) resulted in small but significantly elevated levels of glutamate and glycine in heart perfusates. As the effects of ischemia or anoxia on glutamate and aspartate release from the heart appear to be comparable to those observed in the brain, it is proposed that the heart preparation may be a suitable model in which to study the ischemia-evoked release of these amino acids in the absence of complications arising from their depolarizing and excitotoxic actions on central neurons.
 ...
PMID:Release of the excitotoxic amino acids, glutamate and aspartate, from the isolated ischemic/anoxic rat heart. 897 34

An increase of cytosolic proteolytic activity during ischemic preservation and consecutive tissue degradation have recently been recognized as a major pathogenetic factor for liver injury during ischemia/reperfusion. In the present study, we propose a method for preventing proteolytic tissue disintegration, which results in improved recovery of the liver after transplantation. Livers were harvested from rats and stored for 24 hr at 4 degrees C in University of Wisconsin solution (group A). Others were additionally persufflated with gaseous oxygen via the inferior caval vein during this time (group B). At the end of ischemic preservation, proteolysis was confirmed in group A, with significantly elevated tissue levels of free alanine and free amino groups, whereas proteolysis was prevented in group B. After transplantation, the integrity of the graft was significantly improved in group B, in which there was a 50% reduction of plasma activities of alanine amino-transferase and a twofold increase in hepatic bile production after the onset of reperfusion, as compared with group A. Moreover, venous-systemic oxygen persufflation during cold preservation significantly attenuated the rise in plasma levels of malondialdehyde (MDA) after liver transplantation. In conclusion, venous-systemic oxygen persufflation during ischemic storage prevents tissue proteolysis and reduces parenchymal injury after transplantation in vivo; this technique may, thus, represent a useful adjunct in long-term liver preservation with University of Wisconsin solution.
 ...
PMID:Reduction of proteolysis by venous-systemic oxygen persufflation during rat liver preservation and improved functional outcome after transplantation. 903 24

We evaluated in rats, the effect of moderate hypothermia (30-31 degrees C) on extracellular levels of amino acids, with special emphasis on the excitatory amino acids (EAAs) glutamate and aspartate, lactate and pyruvate, after severe spinal cord compression. A laminectomy of Th7 and Th8 was made. A probe was inserted in a dorsal horn and microdialysis was performed for 1.5 h before and 4 h after applying severe compression for 5 min. Dialysate samples were collected at intervals of 10 min and analyzed by high-performance liquid chromatography. In normothermic (37.5 degrees C) animals there was a several-fold rise of glutamate that peaked in the first 10 min fraction after trauma. Hypothermic animals showed a similar increase after trauma, which was statistically significant until 20 min after injury. The level of glutamate was significantly higher in hypothermic animals from 20 to 70 min after injury, compared with normothermic animals. Aspartate also showed a marked increase following injury. The peak concentration was similar for both groups, whereas recovery was delayed in hypothermic animals. There was no significant difference between the normothermic and hypothermic animals for arginine, taurine, alanine, glutamine, histadine, glycine, threonine, tyrosine, and asparagine. No significant effect of hypothermia on lactate or lactate/pyruvate was noted. However, the mean level of lactate tended to be lower and recovery was quicker in hypothermic animals. The results of the present study suggest that moderate hypothermia does not attenuate extracellular accumulation of EAAs or markedly improve energy metabolism in our model. Instead, our findings raise the possibility that moderate hypothermia prolongs the duration of glutamate receptor overactivation. Since hypothermia effectively attenuates glutamate release in CNS and spinal cord ischemia models our results suggest different mechanisms of extracellular accumulation of EAAs in ischemia and trauma.
 ...
PMID:Effects of moderate hypothermia on extracellular lactic acid and amino acids after severe compression injury of rat spinal cord. 904 12

The interleukin 1beta converting enzyme (ICE) family plays a pivotal role in programmed cell death and has been implicated in stroke and neurodegenerative diseases. During reperfusion after filamentous middle cerebral artery occlusion, ICE-like cleavage products and tissue immunoreactive interleukin 1beta (IL-1beta) levels increased in ischemic mouse brain. Ischemic injury decreased after intracerebroventricular injections of ICE-like protease inhibitors, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD.FMK), acetyl-Tyr-Val-Ala-Asp-chloromethylketone, or a relatively selective inhibitor of CPP32-like caspases, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone, but not a cathepsin B inhibitor, N-benzyloxycarbonyl-Phe-Ala-fluoromethylketone. z-VAD.FMK decreased ICE-like cleavage products and tissue immunoreactive IL-1beta levels in ischemic mouse brain and reduced tissue damage when administered to rats as well. Only z-VAD.FMK and acetyl-Tyr-Val-Ala-Asp-chloromethylketone reduced brain swelling, and N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone did not attenuate the ischemia-induced increase in tissue IL-1beta levels. The three cysteine protease inhibitors significantly improved behavioral deficits, thereby showing that functional recovery of ischemic neuronal tissue can follow blockade of enzymes associated with apoptotic cell death. Finally, we examined the effect of z-VAD.FMK on excitotoxicity and found that it protected against alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-induced or to a lesser extent N-methyl-D-aspartate-induced excitotoxic brain damage. Thus, ICE-like and CPP32-like caspases contribute to mechanisms of cell death in ischemic and excitotoxic brain injury and provide therapeutic targets for stroke and neurodegenerative brain damage.
 ...
PMID:Inhibition of interleukin 1beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. 905 Aug 95

The aim of this study was to investigate the possible beneficial effect on perfused mouse liver of alanine as an exogenous substrate for gluconeogenesis. Livers from fed and fasted animals were perfused with oxygenated Krebs' Henseleit buffer for 30 min, then stored at 4 degrees C in University of Wisconsin solution for 48 h. Then reperfusion at 37 degrees C was performed according to two protocols. In the first one, reperfusion with alanine-free Krebs' Henseleit buffer was used for 1 h. 8 mM (3-(13)C) alanine was then added and perfusion was prolonged for a second hour. In the second one, the first hour of perfusion was omitted and the organs were reperfused directly for an hour in the presence of 8 mM (3-(13)C)alanine. 31P NMR was used to measure the NTP recovery of the livers. At the end of the reperfusions, 13C and 1H NMR spectra of perfusates and of glutamine extracted from these perfusates by HPLC were recorded. These data were analysed according to a model of liver metabolism assuming that the only substrate of the liver was (3-(13)C)alanine and endogenous substrates were metabolizable only through pyruvate. It was found that in the absence of initial alanine at reperfusion, livers from fasted mice recovered less NTP than those of fed ones (40 +/- 4% vs 60 +/- 5%, p <0.01), but not if this substrate is present at the beginning of reperfusion (61 +/- 5% vs 60 +/- 5%). This was confirmed by the amount of labelled metabolites produced. However, the dilution of 13C labelled metabolites by unlabelled ones did not indicate a larger concentration of endogenous substrates in livers from fed mice. The conclusion reached was that the lower pyruvate dehydrogenase activity of livers from fasted mice relatively to that from fed mice could be compensated for by the greater pyruvate concentration provided by alanine for the initial production of NTP after cold ischemia and warm reperfusion.
 ...
PMID:Beneficial effect of alanine on metabolic recovery of fasted livers submitted to cold ischemia. 907 3

Myocardial ischemic arrest, using a cold crystalloid cardioplegic solution, decreases intracellular concentrations of glutamate (from 6.2 +/- 0.5 to 4.5 +/- 0.45 micromol/g wet weight, n = 19, P < 0.05) and ATP (from 3.0 +/- 0.4 to 1.9 +/- 0.3 micromol/g wet weight, n = 9, P < 0.05) but not aspartate. After 20 min of normothermic reperfusion, the fall in glutamate and ATP was maintained (4.5 +/- 0.52 and 2.0 +/- 0.2 micromol/g wet weight, respectively), and there was a fall in aspartate (from 1.32 +/- 0.12 to 0.9 +/- 0.1 micromol/g wet weight). Myocardial arrest with cold blood cardioplegic solution did not cause a significant fall in tissue ATP, glutamate, or aspartate. However, after reperfusion all three fell significantly. With the exception of a fall in tissue valine during ischemia with cold crystalloid cardioplegic solution and a rise in alanine during ischemia with cold blood cardioplegic solution, there were no significant changes in tissue alanine, valine, leucine, or isoleucine during ischemia or after reperfusion using crystalloid or blood cardioplegic solutions. This work documents the changes in the intracellular concentrations of important metabolites in the hearts of patients undergoing coronary artery surgery using different myocardial protection techniques.
 ...
PMID:Changes in myocardial concentration of glutamate and aspartate during coronary artery surgery. 908 76

N-acetylaspartate (NAA) is found exclusively in neurons and their processes in the adult brain. Since the regional distribution of NAA may be imaged using magnetic resonance spectroscopic imaging (1H-MRSI), a regional measure of neuronal density may be noninvasively obtained. The technique may be particularly useful in the diagnosis of diseases where neurons are selectively injured, since these diseases do not result in definitive changes on conventional imaging studies. The goal of this study was to determine whether 1H-MRSI measurement of NAA defects neuronal loss following global ischemia. 1H-MRSI was performed in rats 24 h after global ischemia was induced by bilateral carotid occlusion plus hypotension. 1-H-MRSI showed that NAA was decreased by 28-74% in vulnerable regions, including the cortex, striatum, hippocampus, and, to a lesser extent, the thalamus. No change was observed in the brain stem or cerebellum. Regions where 1H-MRSI observed NAA was decreased also had histological evidence of selective neuronal necrosis and showed marked increase of lactate and alanine. These results show that 1H-MRSI detected loss of NAA in brain regions with selective neuronal loss, suggesting that 1H-MRSI measurements of NAA could detect neuronal loss in a variety of disease states where there is selective neuronal necrosis.
 ...
PMID:Effects of severe global ischemia on N-acetylaspartate and other metabolites in the rat brain. 917 35

Neuronal and glial cell swelling occurs rapidly in ischemia as part of the cytotoxic response. Astrocytic swelling is known to result in large extracellular increases in certain amino acids, including glutamate, aspartate and taurine, as part of the regulatory volume decrease (RVD) response inherent to these and other cells. RVD in astrocytic cultures is inhibited by anion channel blockers. In this study, we compared the effects of three anion channel blockers on the ischemia/reperfusion-evoked release of amino acids from the in vivo rat cerebral cortex. Twenty minutes of four vessel cerebral ischemia caused significant increases in cortical superfusate levels of aspartate, glutamate, GABA, taurine and phosphoethanolamine. During reperfusion there were delayed increases in the level of glycine, alanine and serine. Glutamine levels were not affected. Cl- channel blockers, 4-acetamido-4'-isothiocyanostrilbene-2,2'-disulfonic acid (SITS, 2 mM), 5-nitro-2-(3-phenyl-propylamino)benzoic acid (NPPB, 350 microM) and dipyridamole (200 microM) depressed basal releases of glutamate and taurine and the ischemia/reperfusion-evoked releases of aspartate, glutamate, taurine and phosphoethanolamine. The results suggest that diffusion of amino acids through an anion channel may be partially responsible for the elevated extracellular levels of excitotoxic and other amino acids that occur during cerebral ischemia/reperfusion.
 ...
PMID:Inhibition by anion channel blockers of ischemia-evoked release of excitotoxic and other amino acids from rat cerebral cortex. 920 27


<< Previous 1 2 3 4 5 6 7 8 9 10