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)

Compound resting membrane potential was recorded by the grease gap technique (37 degrees C) during glycolytic inhibition and chemical anoxia in myelinated axons of rat optic nerve. The average potential recorded under control conditions (no inhibitors) was -47 +/- 3 (SD) mV and was stable for 2-3 h. Zero glucose (replacement with sucrose) depolarized the nerve in a monotonic fashion to 55 +/- 10% of control after 60 min. In contrast, glycolytic inhibition with deoxyglucose (10 mM, glucose omitted) or iodoacetate (1 mM) evoked a characteristic voltage trajectory consisting of four distinct phases. A distinct early hyperpolarizing response (phase 1) was followed by a rapid depolarization (phase 2). Phase 2 was interrupted by a second late hyperpolarizing response (phase 3), which led to an abrupt reduction in the rate of potential change, causing nerves to then depolarize gradually (phase 4) to 75 +/- 9% and 55 +/- 6% of control after 60 min, in deoxyglucose and iodoacetate, respectively. Pyruvate (10 mM) completely prevented iodoacetate-induced depolarization. Effects of glycolytic inhibitors were delayed by 20-30 min, possibly due to continued, temporary oxidative phosphorylation using alternate substrates through the tricarboxylic acid cycle. Chemical anoxia (CN- 2 mM) immediately depolarized nerves, and phase 1 was never observed. However a small inflection in the voltage trajectory was typical after approximately 10 min. This was followed by a slow depolarization to 34 +/- 4% of control resting potential after 60 min of CN-. Addition of ouabain (1 mM) to CN--treated nerves caused an additional depolarization, indicating a minor glycolytic contribution to the Na+-K+-ATPase, which is fueled preferentially by ATP derived from oxidative phosphorylation. Phases 1 and 3 during iodoacetate exposure were diminished under nominally zero Ca2+ conditions and abolished with the addition of the Ca2+ chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 5 mM). Tetraethylammonium chloride (20 mM) also reduced phase 1 and eliminated phase 3. The inflection observed with CN- was eliminated during exposure to zero-Ca2+/EGTA. A Ca2+-activated K+ conductance may be responsible for the observed hyperpolarizing inflections. Block of Na+ channels with tetrodotoxin (TTX; 1 microM) or replacement of Na+ with the impermeant cation choline significantly reduced depolarization during glycolytic inhibition with iodoacetate or chemical anoxia. The potential-sparing effects of TTX were less than those of choline-substituted perfusate, suggesting additional, TTX-insensitive Na+ influx pathways in metabolically compromised axons. The local anesthetics, procaine (1 mM) and QX-314 (300 microM), had similar effects to TTX. Taken together, the rate and extent of depolarization of metabolically compromised axons is dependent on external Na+. The Ca2+-dependent hyperpolarizing phases and reduction in rate of depolarization at later times may reflect intrinsic mechanisms designed to limit axonal injury during anoxia/ischemia.
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PMID:Ion transport and membrane potential in CNS myelinated axons. II. Effects of metabolic inhibition. 932 77

By means of a simplified questionnaire, the NADYA group has gathered and analyzed data with regard to the age, sex, diagnosis, access route, duration, form of administration, complications, and quality of life, in 812 patients (62% male; 37% female) with At Home Enteral Nutrition (AHEN), and 19 patients (42% male; 57% female) with At Home Parenteral Nutrition (AHPN) corresponding the National Registry of 1995. The most frequent indication of AHEN was a neoplasm (41%), followed by neurological alterations (33%). The most common access route is the NGT (37%) followed by oral administration in 37%, PEG in 13% and surgical ostomics in 8%. The mean treatment time is 8 months. The index of complications/patient-year is 0.50 (gasterointestinal 0.17, and mechanical alterations 0.9). At the end of the study, 63% of the patients continued to receive AHEN, showing a mortality rate of 70%. The majority of the patients undergoing treatment presented a sever social disability (20%) or were bed ridden (18%). The most common indications for the AHPN are: radical enteritis (26%), Crohn's disease (21%), and mesenteric ischemia (16%). AIDS, motility alterations, and neoplasic diseases are scantly represented (10%). Tunneled catheters are used in 58% of the cases, and Port-a-Cath in 31%). The mean duration for the treatment was 7.9 months. An index of 0.47 hospitalization/patient-year was seen in relation to the nutritional treatment (mainly due to catheter septicemia). A mortality of 16% is noted, and 21% show a recovery of the oral route. 42% of the patients did not present an assessable social disability.
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PMID:[Artificial nutrition in the home. 1995 yearly report. NADYA-SENPE Group (Natiional Registry of Patient-Spanish Society for Parnteral and Enterlal Nutrition]. 966 56

We characterized the changes in nitric oxide (NO) levels in the brain during global forebrain ischemia and reperfusion and tested the ability of the natural flavonoid, quercetin, and a synthetic flavonoid, FB277, to increase the amount of available NO by elimination of the superoxide radicals produced during reperfusion. In Sprague-Dawley rats, we used a four-vessel occlusion model of forebrain ischemia (15 min) and reperfusion (30 min). Brain NO was measured on samples of cerebral cortex and cerebellum ex vivo by electron paramagnetic resonance (EPR) spectroscopy. The spin trap used was diethyldithiocarbamate sodium salt (DETC) associated with ferrous citrate. The complex Fe(DETC)2NO was detected at 77 K as a triplet signal at g = 2.035. Groups of animals were treated with quercetin or FB277 (3-morpholinomethyl-3',4',5,7tetramethoxyflavone) or polyethylene glycol-conjugated superoxide dismutase (PEG-SOD). In control (intact anesthetized animals), the signal was about 3 times greater in the cortex than in the cerebellum. During ischemia, the signal rose to 110% in cortex (NS) and 283% in cerebellum (P < 0.05). In reperfusion, it fell again to 91% of control in cerebellum (NS) and 35% in cortex (P < 0.05). Treatment by quercetin (5 mg/kg i.v.) of intact and ischemia-reperfusion groups did not significantly change the signal amplitude in the cerebellum, but did double it in the cortex (to 76% of control) for the ischemia-reperfusion group (P < 0.05). In contrast, FB277 (3.75 mg/kg i.v.) did not increase the signal in the cortex during ischemia-reperfusion, but did do so in the cerebellum (to 152% of control, P < 0.05). The results obtained for PEG-SOD (10,000 U/kg i.v.) were similar to those for FB277. In separate in vitro measurements, we found that quercetin but not FB277 efficiently scavenged superoxide. We hypothesize that quercetin but not FB277 scavenged superoxide anions released in the cortex during reperfusion, thus diminishing the amount of NO removed by the formation of peroxynitrite. The lack of effect of PEG-SOD may be related to the need for chronic treatment to obtain protection.
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PMID:Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. 989 May 69

Four types of bovine liver catalase (CAT) derivatives, succinylated (Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and polyethylene glycol conjugate (PEG-CAT), were synthesized and their pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of the CAT enzymatic activity was retained after chemical modification. Biodistribution studies showed that 111indium (111In)-Gal-CAT accumulated selectively in the liver parenchymal cells as 111In-CAT, whereas an increased amount of 111In-Suc-CAT and 111In-Man-CAT was delivered to liver nonparenchymal cells. 111In-PEG-CAT exhibited prolonged retention in plasma. Pharmacokinetic analysis revealed that the hepatic uptake clearances of 111In-Suc-CAT, 111In-Gal-CAT, and 111In-Man-CAT were much greater than that of 111In-CAT, whereas that of 111In-PEG-CAT was very small. In the ischemia/reperfusion injury model, in which hepatic injury was induced by occlusion of the portal vein for 30 min followed by 1 h reperfusion, the elevation of plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels was slightly inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase. Coinjection of mannosylated superoxide dismutase marginally improved the inhibitory effects of CAT derivatives. These results demonstrate that targeted CAT delivery to liver nonparenchymal cells via chemical modification is a promising approach to prevent hepatic injuries caused by reactive oxygen species. The potential usefulness of combining of CAT and superoxide dismutase derivatives is also demonstrated.
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PMID:Targeted delivery and improved therapeutic potential of catalase by chemical modification: combination with superoxide dismutase derivatives. 1021 2

Using a simplified questionnaire from the NADYA group, data referring to age, sex, diagnosis, access route, duration, form of administration, complications, and quality of life have been gathered from 1,400 patients (57% male, 43% female) who receive home enteral nutrition, and from 38 patients (20% male and 18% female) who receive home parenteral nutrition. All of these patients come from the 1996 national registry. The most common indication for home enteral nutrition are neoplasias (39%) followed by neurological alterations (33%). The most common access route is oral (48%), followed by a nasogastric tube in 34%, PEG in 10% and surgical ostomies in 7%. The average treatment duration is 6 months. There is an index of 0.74 complications/patient-year (gastrointestinal 0.28 and mechanical alterations 0.19). At the end of the year 58% of the patients continued to use at home enteral nutrition, with a death rate of 17%. The majority of the treated patients presented a severe social disability (28%) or was bed-ridden (22%). The most common indications for home parenteral nutrition are: neoplasia (42%), Crohn_s disease (10%), and mesenteric ischemia (10%). AIDS (8%), radical enteritis (5%), and motility disorders (5%) are less common. In 42% of the cases tunneled catheters are used, and port-a-cath are used in 53%. The average treatment duration is 6.9 months. 1.06 hospitalizations/patient-year have been registered in relation to the nutritional treatment (mainly catheter sepsis). A mortality of 29% is registered, and there is recovery of the oral route in 7.9% of the cases. 50% of the patients present a severe social disability.
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PMID:[Artificial nutrition in the home. Annual information 1996.Group NADYA-SENPE]. 1050 53

Questions as to the critical stress factor and primary targets of cold ischemia/reperfusion (CIR) injury were addressed by comparing mitochondrial defects caused by (1) CIR injury and (2) intracellular Ca2+ overload. CIR was simulated in transformed human umbilical vein endothelial cell cultures (tEC) by 8 h cold anoxia in University of Wisconsin solution and reoxygenation at 37 degrees C. Intracellular Ca2+ concentrations were changed by permeabilization of suspended cells with digitonin in culture medium (RPMI, 0.4 mM Ca2+). Binding of free Ca2+ by ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid in RPMI or mitochondrial incubation medium served as controls. Extracellular Ca2+ protected the cell membrane against permeabilization. Mitochondrial functions were determined before and after permeabilization of the cell membrane. After CIR, mitochondrial respiratory capacity declined, but oxygen consumption remained coupled to adenosine triphosphate (ATP) production. In contrast, Ca2+ overload caused uncoupling of mitochondrial respiration. High intracellular Ca2+ overload, therefore, does not reproduce cold ischemia/reperfusion injury in endothelial cells.
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PMID:Mitochondrial defects by intracellular calcium overload versus endothelial cold ischemia/reperfusion injury. 1111 72

The purpose of this study was to evaluate an intracellular solution with polyethylene glycol (PEG, molecular weight 20,000) as an impermeant, compared with University of Wisconsin (UW) and Euro-Collins (EC) solutions, after a 48-h cold storage (CS). The normothermic isolated perfused rat kidney (IPK) technique was used to assess renal function after CS. Five groups were studied: a control group (immediately reperfused, n = 10); one that received EC (n = 16); one that received UW (n = 16); and two that each received an intracellular (IC) solution, one with PEG (ICPEG, n = 16) and one without PEG (IC, n = 16). The perfusion flow rate was significantly greater in the PEG group and correlated with less significant cellular and interstitial edema and lower renal vascular resistance than in the IC, EC, and UW groups. Glomerular filtration rate was significantly higher in the PEG group during reperfusion than in the IC, EC, and UW groups. Proximal tubular functions were more efficient with PEG: fractional sodium reabsorption and total sodium reabsorption were significantly greater during reperfusion in the PEG group than in the IC, EC, and UW groups. Of greater interest is the protective effect of PEG on lipid peroxidation, which reflects ischemia/reperfusion damage. The second major effect is the dramatic ATP restoration during reperfusion, which outlines the preservation of oxidative phosphorylation after preservation by ICPEG. These results are supported by histological studies, particularly concerning brush border and mitochondrial preservation. Our results indicate that PEG is promising for cold ischemia and reperfusion injury protection.
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PMID:Protective effect of polyethylene glycol against prolonged cold ischemia and reperfusion injury: study in the isolated perfused rat kidney. 1135 15

Translocation of luminal bacteria and their products through the intestinal mucosa during ischemia-reperfusion (I/R) may modify I/R injury. To test this hypothesis, 16 germ-free pigs were studied prior to and after clamping the superior mesenteric artery (SMA) and 12 pigs served as controls. Nine pigs in the I/R and 5 in the control group received endotoxin intragastrically, 60 min before baseline. Gut absorption of an inert indicator (polyethyleneglycol [PEG] 3350), gut intraluminal PCO2 (tonometry), and systemic and regional hemodynamic variables were measured up to 4 h after baseline. Gut blood flow was stopped during clamping, some reactive hyperemia occurred up to 30 min after declamping in the I/R groups, independently of prior endotoxin administration. Gut intraluminal-arterial PCO2 gradients were elevated in I/R versus control groups during I and for some time during R, prior endotoxin had no effect. However, in controls without and with luminal endotoxin, PEG urinary excretion, as percentage of the dose administered, was 0.12 +/- 0.12 and 0.17 +/- 0.07, respectively, while it measured 1.82 +/- 0.70 in the I/R group and 0.55 +/- 0.37% in the I/R and endotoxin groups, respectively (P< 0.001). The data suggest that gut luminal endotoxin ameliorates I/R injury of the gut wall in germ-free pigs, without altering changes in gut perfusion adequacy and systemic hemodynamics.
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PMID:Gut luminal endotoxin reduces ischemia-reperfusion injury of the small gut in germ-free pigs. 1144 12

Covalent binding of 4 molecules of phosphatidylcholine palmitoyl to human recombinant superoxide dismutase (SOD) results in a compound (lecithinized SOD) that has a longer half-life and greater affinity to the cell membrane than unmodified SOD. We investigated whether lecithinized SOD played a protective role against myocardial ischemia-reperfusion injuries in rats. Rats underwent 45 min of myocardial ischemia by occluding the left coronary artery followed by 120 min of reperfusion. They were randomly assigned to receive either lecithinized SOD, polyethylene glycol conjugated SOD (PEG-SOD), unmodified SOD, free lecithin derivative, or PBS intravenously at 5 min prior to reperfusion. Myocardial infarct area assessed by TTC staining was smaller in lecithinized SOD group than PEG-SOD, unmodified SOD, free lecithin derivative or control group. Blood pressure and heart rate was similar in each group. ELISA demonstrated SOD level in the heart was significantly high in lecithinized SOD group, especially in the heart of ischemia at risk. Although serum SOD level of PEG-SOD was as high as lecithinized SOD, SOD level of the heart was low. These data suggested lecithinized SOD had a protective effect in myocardial ischemia-reperfusion injuries through its increased bioavailability.
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PMID:Lecithinized Cu, Zn-superoxide dismutase limits the infarct size following ischemia-reperfusion injury in rat hearts in vivo. 1147 86

Without a doubt PEG-SOD has been the enzyme most studied in PEGylation. One can say that it represents the preferred model to assess chemistries for PEG activation, analytical procedures suitable for conjugate characterization, the influence of PEG size in conjugate removal from circulation and elimination of immunogenicity and antigenicity, and the effect of route of administration. The effect of PEG conjugation was studied in vitro and in vivo models in comparison with the free enzyme and the following conclusions may be drawn: (1) At the blood vessel level, PEG-SOD has been shown to provide a greater resistance to oxidant stress, to improve endothelium relaxation and inhibit lipid oxidation. (2) In the heart, PEG-SOD proved to be at least as effective as native SOD in treatment of reperfusion-induced arrhythmias and myocardial ischemia. (3) In the lung, PEG-SOD appeared to be able to reduce oxygen toxicity and E. coli-induced lung injury, but not in the treatment of lung physiopathology associated with endotoxin-induced acute respiratory failure and in the reduction of asbestos-induced cell damage. (4) On cerebral ischemia/reperfusion injuries the effect of PEG-SOD was uncertain, also due to the difficulty of cerebral cell penetration. (5) In kidney and liver ischemia both enzyme forms were found to ameliorate reperfusion damage. In view of so much positive research on PEG-SOD, it is surprising that no approved application in human therapy has been established and approved.
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PMID:Polyethylene glycol-superoxide dismutase, a conjugate in search of exploitation. 1205 16


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