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)

Myocardial ischemia and reperfusion have been shown to impair coronary vasorelaxation to endothelium-dependent vasodilators. To examine the time course of this dysfunction, occlusion of the left anterior descending (LAD) coronary artery (90 minutes) was followed by reperfusion for 0, 2.5, 5, 20, 180, or 270 minutes. Coronary arterial rings from the ischemic LAD and control left circumflex (LCx) arteries were tested for responsiveness to the endothelium-dependent receptor-mediated vasodilator, acetylcholine (ACh), and the endothelium-dependent nonreceptor-mediated vasodilator, A23187, as well as the endothelium-independent vasodilator, NaNO2. ACh relaxation was not impaired after 90 minutes of ischemia without reperfusion. However, 2.5 minutes of reperfusion resulted in depressed ACh responses (36 +/- 10% of control) that was further reduced to 16 +/- 6% at 20 minutes, and remained comparably depressed at every time thereafter. A23187 vasodilator responses were also attenuated after reperfusion, although the reduced response occurred later (that is, at 20 minutes). There was no significant decrease in response to NaNO2 in the LAD at any time or to any vasodilator in LCx control rings. Treatment with recombinant human superoxide dismutase (hSOD, 5 mg/kg/hr, that is, 15,545 SOD units/kg/hr), starting 10 minutes before reperfusion, preserved the vasodilator response to ACh (82 +/- 6%) and A23187, but treatment with the hydroxyl ion scavenger N-(2-mercapto proprionyl)-glycine (MPG) (8 mg/kg/hr) only protected the A23187 response. No damage to the surface of the endothelium was observed by scanning electron microscopy at any time point. Myocardial cell damage increased with time of reperfusion as assessed by increasing plasma CK activities and amounts of necrotic tissue indexed to area at risk. Significant myocardial injury occurred at 3 hours after reperfusion. These findings suggest that endothelial dysfunction resulting in reduced endothelium-derived relaxing factor release occurs before the development of myocardial cell necrosis and may be due to oxygen-derived free radicals produced rapidly on reperfusion.
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PMID:Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. 240 Oct 73

Reperfusion of ischemic myocardium is recognized as potentially beneficial because mortality is directly related to infarct size, and the latter is related to the severity and duration of ischemia. However, reperfusion is associated with extension of the injury that is additive to that produced by ischemia alone. The phenomenon of reperfusion injury is caused in large part by oxygen-derived free radicals from both extracellular and intracellular sources. The loci of oxygen-free radical formation include: myocardial sources (mitochondria), vascular endothelial sources (xanthine oxidase and other oxidases), or the inflammatory cellular infiltrate (neutrophils). Experimental studies have shown that free radical scavengers and agents that prevent free radical production can reduce myocardial infarct size in dogs subjected to temporary regional ischemia followed by reperfusion. Superoxide dismutase and catalase, which catalyze the breakdown of superoxide anion and hydrogen peroxide, respectively, limit experimental myocardial infarct size. The free radical scavenging agent N-(2-mercaptopropionyl)glycine (MPG) is reported to be effective in limiting infarct size. The ischemic-reperfused myocardium derives significant protection when experimental animals are pretreated with the xanthine oxidase inhibitor allopurinol. Neutrophils also serve as a significant source of oxygen-derived free radicals at the site of tissue injury. A number of agents have been shown to directly inhibit neutrophil-derived oxygen free radical formation and neutrophil accumulation within the reperfused myocardium. These agents include ibuprofen, nafazatrom, BW755C, prostacyclin, and iloprost. Thus, free radical scavengers and agents that prevent free radical formation can provide significant protection to the ischemic-reperfused myocardium.
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PMID:Free radical scavengers in myocardial ischemia. 243 51

The hypothesis was tested, if the addition of 2-mercaptopropionylglycine (MPG, Thiola) to a crystalloid cardioplegic solution provides superior myocardial protection as assessed by biochemical and morphological parameters. Five mongrel dogs underwent a 60-min hypothermic cardioplegic arrest (untreated group). In six dogs, MPG (1.5 mmol/l) was added to the crystalloid cardioplegic solution (treated group). Thereafter a reperfusion phase of 60 min was established. At the end of the reperfusion phase samples for mitochondrial respiration parameters and for mitochondrial energization were collected. Samples for ultrastructure and negative staining were taken at the end of ischemia, and after 15, 30 and 60 min of reperfusion. Hearts which were treated with the MPG-enriched cardioplegic solution showed a better ultrastructure (1 (1/1) vs 2 (2/2), p less than 0.001) and superior preservation of the mitochondrial ATPases (2.4 +/- 2.0 versus 8.4 +/- 2.7, p less than 0.05) as compared to the untreated group at the end of ischemia. At the end of reperfusion, mitochondrial respiration, and energization of the mitochondria was improved significantly with the addition of MPG as compared to the untreated group.
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PMID:Myocardial protection by 2-mercaptopropionylglycine during global ischemia in dogs. 247 Mar 81

The results of our experiments demonstrated that one hour of ischemia followed by one hour of reflow in the kidney caused a reduction in (Na+K+)ATPase activity and microsomal sulfhydryl content as well as an increase in microsomal lipid peroxidation. Renal venous malondialdehyde concentration was increased soon after reperfusion of the ischemic kidney. All these changes were rectified by an infusion of 0.123 mmol N-(2-mercaptopropionyl)glycine/kg over a 70 min period. On the other hand, an in vitro addition of 0.01-0.5 mM N-(2-mercaptopropionyl)glycine to a membrane preparation in the presence of H2O2 and Fe3+ did not prevent but rather potentiated the free radical effect on the enzyme activity. However, addition of superoxide dismutase alone or with catalase together with 2-MPG were effective in preventing the enzyme depression induced by H2O2. The results therefore indicate that free radical generation participates in the evolution of ischemia/reperfusion cell injury and thiol-reducing agents may be beneficial in alleviating the cell damage in vivo.
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PMID:Effects of N-(2-mercaptopropionyl)glycine on ischemic-reperfused dog kidney in vivo and membrane preparation in vitro. 283 50

Factors including complement activation, neutrophil infiltration, and oxygen-derived free radicals have been implicated in the pathogenesis of myocardial tissue injury during ischemia and reperfusion. Certain sulfhydryl-containing compounds have been shown to inhibit complement activation. The sulfhydryl compounds captopril and N-(2-mercaptopropionyl)-glycine (MPG) are antioxidant compounds that previously have been shown to protect the myocardium from ischemia and reperfusion-induced damage. In this study, captopril (an angiotensin-converting-enzyme inhibitor; ACEI) and MPG, and the non-sulfhydryl compound enalaprilat (also an ACEI) were tested for their ability to protect the isolated perfused rabbit heart against complement-induced injury. Both captopril and MPG protected hearts against complement-mediated increases in left ventricular end-diastolic pressure and increases in coronary arterial perfusion pressure in a concentration-dependent manner, whereas enalaprilat was not protective. The ability of these compounds to inhibit complement activation also was tested using an in vitro complement-mediated red blood cell hemolysis assay. These findings offer additional insight as to the mechanism whereby captopril, MPG, and possibly other sulfhydryl compounds, may be acting to provide cytoprotection during myocardial ischemia and reperfusion.
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PMID:Sulfhydryl compounds, captopril, and MPG inhibit complement-mediated myocardial injury. 830 10

We investigated microcirculatory changes in sodium taurocholate (ST)-induced pancreatitis. Groups of rats received as tracer either fluorescein isothiocyanate-dextran or acridine orange intravenously. The microcirculation of the exposed pancreas was observed by use of a video camera attached to an epi-illumination microscope. Vessel diameters and plaques of adherent leukocytes were measured with a digital image-analyzing system. In contrast to 0.4 ml of saline, intraductal infusion of ST (4%, 0.4 ml) induced a constriction of interlobular pancreatic arteries of 79 +/- 2% (P < 0.01) within 2 min. This constriction could not be antagonized by the leukotriene antagonist CGP-35949B. The radical scavengers superoxide dismutase (SOD) and N-(2-mercaptopropionyl)glycine (MPG) prevented the arterial constriction. Constriction of pancreatic arteries was accompanied by a decrease of erythrocyte velocity in the pancreatic capillaries. Flux in the head of the pancreas measured by laser-Doppler velocimetry decreased from 300 +/- 69 to 74 +/- 23 perfusion units (P < 0.01) after 446 +/- 159 s. Subsequently an increase of perfusion values was observed indicating reperfusion phenomena. ST induced leukocyte adherence to the walls of interlobular veins forming plaques constituting 39% of the observed venular cross section within 6 min. The leukotriene antagonist, SOD, or MPG prevented leukocyte adherence. Arterial constriction followed by ischemia-reperfusion and leukocyte adherence to venular endothelium during the reperfusion period represented the sequence of microcirculatory changes in ST-induced pancreatitis. The radical scavengers SOD and MPG prevented arterial constriction and leukocyte adherence to venular endothelium, indicating the involvement of free radicals in the pathogenesis of ST-induced pancreatitis in the rat.
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PMID:Arterial constriction, ischemia-reperfusion, and leukocyte adherence in acute pancreatitis. 833 66

Recent studies suggest that the hydroxyl radical (.OH) plays a pathogenetic role in postischemic ventricular dysfunction (myocardial "stunning"). This concept, however, is predicated exclusively on results obtained in anesthetized open-chest preparations, which are subject to the confounding influence of many unphysiological conditions and in which both myocardial stunning and free radical generation are greatly exaggerated. The lack of supporting evidence in more physiological animal models represents a major limitation of the .OH hypothesis of stunning. Furthermore, concern has been raised that myocardial stunning may be a period of "rest" necessary for full recovery, so that attenuation of the early phase of stunning by antioxidant therapy may have subsequent detrimental effects on the resting function and/or on the return of myocardial contractile reserve. To address these issues, in phase 1 of this study conscious unsedated dogs undergoing a 15-minute coronary artery occlusion received an intravenous infusion of normal saline (n = 22), of the .OH scavenger N-2-mercaptopropionyl glycine (MPG, n = 17), or of the iron chelator desferrioxamine (DF, n = 14). Compared with control dogs, the dogs treated with MPG or DF exhibited significantly greater postischemic wall thickening throughout the first 6 hours of reperfusion; the total deficit of wall thickening during this time interval was reduced 50% by MPG and 50% by DF. The magnitude of this beneficial effect was a function of the severity of ischemia, so that the dogs with the lowest collateral flows had the greatest improvement of wall thickening. The accelerated recovery produced by MPG and DF in the first 6 hours was not followed by any deterioration of resting wall thickening at 24 or 48 hours. Furthermore, in dogs treated with MPG or DF, the increase in wall thickening elicited by maximal inotropic stimulation (isoproterenol or dopamine) was similar before stunning and shortly after resting wall thickening had normalized (24 or 48 hours after reflow); thus, despite the fact that most of the early postischemic dysfunction had been eliminated by antioxidant therapy, there was no subsequent impairment of either resting function or contractile reserve. In phase 2, production of free radicals (measured with the spin trap alpha-phenyl N-tert-butyl nitrone) was markedly (> 80%) inhibited by the same doses of MPG and DF that attenuated stunning in phase 1.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Direct evidence that the hydroxyl radical plays a pathogenetic role in myocardial "stunning" in the conscious dog and demonstration that stunning can be markedly attenuated without subsequent adverse effects. 839 4

Peroxynitrite (ONOO-) is a potent inhibitor of myocardial aconitase. Because ONOO- reacts with sulfhydryl moieties, we investigated whether thiols protect against ONOO(-)-mediated inhibition of aconitase. Aconitase activity was examined in ventricular homogenates prepared from freshly isolated rat hearts. Peroxynitrite, but not the nitric oxide donor S-nitroso-N-acetyl-d,l-penicillamine (0.03-300 microM), inhibited aconitase activity (IC50 = 47 +/- 6 microM). L-Cysteine (0.03-3 mM), glutathione (0.03-3 mM), and N-(2-mercaptoproprionyl)-glycine (MPG, 0.1-3 mM) protected against the inhibitory effect of ONOO- (100 microM) with the rank order of potency of MPG > glutathione > L-cysteine. D-Cysteine (3 mM) had a protective effect similar to L-cysteine, but L-cystine, the oxidized form of L-cysteine, offered no protection. Ferrous ammonium sulfate (1 mM) markedly enhanced the protection provided by L-cysteine, but not by glutathione or MPG. Thiols protect myocardial aconitase against inhibition by ONOO- in a manner which is sulfhydryl group dependent and not stereospecific. The protection is related to the maintenance of the redox state of the iron-sulfur cubane cluster and cysteine residues at the active site of the enzyme. Both naturally occurring thiols and thiol-based drugs may be useful to protect the heart during ischemia-reperfusion injury where there is an excessive production of ONOO-.
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PMID:Thiols protect the inhibition of myocardial aconitase by peroxynitrite. 946 26

Post-ischemic reperfusion causes cardiac dysfunction and radical-induced lipid peroxidation (LPO) detectable by ESR spin trapping. This study deals with the applicability of the spin trapping technique to pharmacological investigations during myocardial reperfusion injury. The use of the spin trap phenylbutylnitrone (PBN, 3 mM) in isolated rat hearts demonstrated the release of alkoxyl radicals (aN = 1.39 mT, aHbeta = 0.19 mT) formed particularly within the first 15 min of reperfusion following 30 min of ischemia. The decline of radicals, after 10 min of reperfusion, was accompanied by recovery of function in 80% of the hearts. The radical concentration in the coronary effluent (maximum after 7.5 min) was reduced by the infusion of 1 mM mercaptopropionylglycine (MPG, 2.7+/-0.5 U/ml, p < 0.001) or 5 microM vitamin E (11.7+/-0.8 U/ml, p < 0.001), compared to the (PBN-containing) control (29.7+/-4.3 U/ml). Moreover, functional recovery (left ventricular developed pressure, LVDP 91.6 +/-20% of pre-ischemic level, p < 0.05) was improved by the hydrophilic radical scavenger MPG, compared to the (PBN-containing) control (LVDP 50.5+/-15.7% of baseline). PBN alone led to higher functional recovery (p < 0.05) and reduced VF (duration of ventricular fibrillation; 7.10+/-0.36 min/30 min, p < 0.05), compared to the untreated (PBN-free) control (LVDP 26.6+/-11.8%; VF 19.42+/-3.64 min/30 min). The Ca antagonist verapamil (0.1 microM), MPG, and the lipophilic vitamin E showed cardioprotection in the absence of PBN: post-ischemic recovery of LVDP was 25.4+/-6.8% (p < 0.05), 39.6+/-12.7% (p < 0.05) and 52.4+/-2.6% (p < 0.01), respectively, compared to the corresponding untreated control (13.3+/-6.6%). Whereas verapamil and vitamin E were able to protect the heart when present alone, they offered no additive effect in the presence of PBN. Therefore, PBN can be used to estimate the radical scavenger properties of an agent in the heart. However, because of the protective properties of PBN itself, the results of simultaneous investigations of the effects of other compounds, such as Ca antagonists or lipophilic radical scavengers, on heart function may be limited.
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PMID:PBN spin trapping of free radicals in the reperfusion-injured heart. Limitations for pharmacological investigations. 977 91

4-Hydroxy-2-nonenal (HNE) is a major lipid peroxidation product formed during oxidative stress. Because of its reactivity with nucleophilic compounds, particularly metabolites and proteins containing thiol groups, HNE is cytotoxic. The aim of this study was to assess the extent and time course for the formation of HNE-modified proteins during ischemia and ischemia plus reperfusion in isolated rat hearts. With an antibody to HNE-Cys/His/Lys and densitometry of Western blots, we quantified the amount of HNE-protein adduct in the heart. By taking biopsies from single hearts (n = 5) at various times (0, 5, 10, 15, 20, 35, and 40 min) after onset of zero-flow global ischemia, we showed a progressive, time-dependent increase (which peaked after 30 min) in HNE-mediated modification of a discrete number of proteins. In studies with individual hearts (n = 4/group), control aerobic perfusion (70 min) resulted in a very low level (296 arbitrary units) of HNE-protein adduct formation; by contrast, after 30-min ischemia HNE-adduct content increased by >50-fold (15,356 units, P < 0.05). In other studies (n = 4/group), administration of N-(2-mercaptopropionyl)glycine (MPG, 1 mM) to the heart for 5 min immediately before 30-min ischemia reduced HNE-protein adduct formation during ischemia by approximately 75%. In studies (n = 4/group) that included reperfusion of hearts after 5, 10, 15, or 30 min of ischemia, there was no further increase in the extent of HNE-protein adduct formation over that seen with ischemia alone. Similarly, in experiments with MPG, reperfusion did not significantly influence the tissue content of HNE-protein adduct. Western immunoblot results were confirmed in studies using in situ immunofluorescent localization of HNE-protein in cryosections. In conclusion, ischemia causes a major increase in HNE-protein adduct that would be expected to reflect a toxic sequence of events that might act to compromise tissue survival during ischemia and recovery on reperfusion.
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PMID:Formation of 4-hydroxy-2-nonenal-modified proteins in ischemic rat heart. 1007 77


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