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)

As part of our ongoing research on cardiac hypoxia tolerance we have conducted 31P nuclear magnetic resonance (NMR) studies of isolated, perfused, working hearts from freshwater turtles, animals that are well known for their ability to tolerate prolonged periods of anoxia. A striking feature of turtle heart spectra is an extremely high concentration of NMR visible phosphodiesters (PDEs). Cardiac spectra from mammals, on the other hand, typically exhibit only a small resonance in the PDE region. Our aim in this study was to compare myocardial PDE profiles between the highly hypoxia tolerant western painted turtle (Chrysemys picta bellii) and the relatively hypoxia sensitive softshelled turtle (Trionyx spinifer) in order to begin to rest the hypothesis that high constitutive levels of cytosolic PDEs may play a role in conferring hypoxia and ischemia tolerance on the myocardium. We also collected 31P-NMR spectra of PCA extracts of tissue from these species and from Kemp's ridley sea turtles (Lepidochelys kempi), as well as spectra from isolated hearts and PCA extracts of red-eared sliders (Trachemys [formerly Pseudemys] scripta]). Total NMR visible phosphodiesters make up 24 +/- 8.6% of the total NMR visible phosphorus in Chrysemys hearts, 20.7 +/- 5.9% in Trachemys hearts, but only 12.2 +/- 5.1% in Trionyx hearts (P < 0.05). We have identified three distinct PDEs in turtle hearts: glycerophosphorylcholine (GPC); glycerophosphorylethanolamine (GPE); and serine ethanolamine phosphodiester (SEP). SEP is the dominant compound in Chrysemys and Trachemys (79.3 +/- 10.2% and 84.7 +/- 3.7% of total PDE, respectively), while GPC is most abundant in Trionyx (74.0 +/- 4.3% of total PDE) and Lepidochelys (not quantitated). The function of this class of compounds is unclear but it has been suggested that cytosolic PDEs may function as lysophospholipase inhibitors, a role that would decrease the rate of membrane phospholipid turnover. Our comparative data suggest that cytosolic PDEs could play a role in phospholipid sparing during anoxic or ischemic stress in turtles but a direct test of this hypothesis awaits future experimentation.
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PMID:31P-NMR determinations of cytosolic phosphodiesters in turtle hearts. 950 28

The regional selectivity and mechanisms underlying the toxicity of the serine/threonine protein phosphatase inhibitor okadaic acid (OA) were investigated in hippocampal slice cultures. Image analysis of propidium iodide-labeled cultures revealed that okadaic acid caused a dose- and time-dependent injury to hippocampal neurons. Pyramidal cells in the CA3 region and granule cells in the dentate gyrus were much more sensitive to okadaic acid than the pyramidal cells in the CA1 region. Electron microscopy revealed ultrastructural changes in the pyramidal cells that were not consistent with an apoptotic process. Treatment with okadaic acid led to a rapid and sustained tyrosine phosphorylation of the mitogen-activated protein kinases ERK1 and ERK2 (p44/42(mapk)). The phosphorylation was markedly reduced after treatment of the cultures with the microbial alkaloid K-252a (a nonselective protein kinase inhibitor) or the MAP kinase kinase (MEK1/2) inhibitor PD98059. K-252a and PD98059 also ameliorated the okadaic acid-induced cell death. Inhibitors of protein kinase C, Ca2+/calmodulin-dependent protein kinase II, or tyrosine kinase were ineffective. These results indicate that sustained activation of the MAP kinase pathway, as seen after e.g., ischemia, may selectively harm specific subsets of neurons. The susceptibility to MAP kinase activation of the CA3 pyramidal cells and dentate granule cells may provide insight into the observed relationship between cerebral ischemia and dementia in Alzheimer's disease.
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PMID:Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. 973 50

We studied the effects of LEX032, a novel serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester (L-NAME) induced leukocyte-endothelium interactions in vivo, utilizing intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME, a nitric oxide (NO) inhibitor, for 90 min resulted in a significant and time-dependent increase in leukocyte rolling, leukocyte adherence, and transmigration of leukocytes, compared to control rats superfused with Krebs-Henseleit (K-H) solution. However, systemic administration of LEX032 (15 mg/kg bolus injection followed by a 15 mg/kg per hour infusion) to L-NAME superfused rats significantly attenuated leukocyte rolling and adherence along the venular endothelium of the rat mesentery, and also inhibited transmigration of leukocytes through the microvascular endothelial wall. Moreover, no significant changes were observed in mean arterial blood pressure or local venular shear rates following systemic administration of LEX032. Our data demonstrate that systemic inhibition of serine proteases by LEX032 reduces enhanced leukocyte-endothelium interactions provoked by inhibition of NO synthesis. These results also explain some of the beneficial effects exerted by serine protease inhibitors in ischemia-reperfusion and other inflammatory states.
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PMID:Effects of LEX032, a novel recombinant serine protease inhibitor, on N(G)-nitro-L-arginine methyl ester induced leukocyte-endothelial cell interactions. 976 25

The report concerns mechanisms for the increase of extracellular levels of ethanolamine and phosphoethanolamine in CNS regions, such as the hippocampus, in transient brain ischemia, hypoglycemia, seizures, etc. L-Serine (2.5-10 mM), D-serine (10 mM), or ethanolamine (10 mM) was administered for 20 min via a microdialysis tubing to the hippocampus of unanesthetized rabbits. The concentrations of primary amines were determined in the dialysates. When levels were elevated 10-100 times in the extracellular fluid, L-serine caused a dose-dependent increase of the concentration of extracellular ethanolamine. Ethanolamine caused a corresponding, although somewhat smaller, increase in serine levels. Furthermore, L-serine also induced an increased concentration of phosphoethanolamine that was delayed in time relative to the peak of ethanolamine. D-Serine was as effective as L-serine in raising ethanolamine levels but had no effect on phosphoethanolamine. Ethanolamine, but not L-serine, also increased extracellular glutamate/aspartate levels in an MK-801-dependent fashion. A similar effect, but delayed in time, was observed with D-serine. These effects were inhibited by MK-801. The concentrations of other amino acids were not significantly affected. The characteristics of the effects are suggestive of base exchange reactions between serine and ethanolamine and between ethanolamine and serine glycerophospholipids, respectively, in neuronal plasma membranes.
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PMID:Effect of serine and ethanolamine administration on phospholipid-related compounds and neurotransmitter amino acids in the rabbit hippocampus. 979 41

Cerebral ischemia and intracerebral hemorrhage cause extensive damage to neurons, disrupt the extracellular matrix, and increase capillary permeability. Multiple substrates participate in the cellular damage, including free radicals and proteases. Matrix metalloproteinases and serine proteases are two classes of proteases that are normally present in brain in latent forms, but once activated, contribute to the injury process. These enzymes have a unique role in the remodeling of the extracellular matrix and in the modulation of the capillary permeability. Intracerebral injection of the matrix metalloproteinase, type IV collagenase, attacks the basal lamina around the capillary and opens the blood-brain barrier. Extracellular matrix-degrading proteases are induced by immediate early genes and cytokines, and regulated by growth factors. Activity of the matrix metalloproteinases is tightly controlled by activation mechanisms and tissue inhibitors of metalloproteinases. During ischemia and hemorrhage, multiple matrix metalloproteinases and serine proteases are produced along with their inhibitors. These proteolytic enzymes are involved in the delayed injury that accompanies the neuroinflammatory response. Synthetic inhibitors to metalloproteinases reduce proteolytic tissue damage, and may limit secondary neuroinflammation.
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PMID:Matrix metalloproteinases in cerebrovascular disease. 980 4

Glycine consists of a single carbon molecule attached to an amino and a carboxyl group. Its small size helps it to function as a flexible link in proteins and allows for the formation of helices, an extracellular signaling molecule, recognition sites on cell membranes and enzymes, a modifier of molecular activity via conjugation and glycine extension of hormone precursors, and an osmoprotectant. There is substantial experimental evidence that free glycine may have a role in protecting tissues against insults such as ischemia, hypoxia, and reperfusion. This impressive catalogue of functions makes an interesting contrast with glycine's perceived metabolic role as a nonessential amino acid. Glycine interconverts with serine to provide a mechanism for the transfer of activated one-carbon groups. Glycine has just been viewed as a convenient source of nitrogen to add to solutions of nutrients. Although this may have unexpected benefits when such solutions are used in clinical practice, it does raise the specter of a possible confounding effect in experiments when glycine is added to control solutions to make them isonitrogenous.
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PMID:Glycine. 982 14

We previously reported that bradykinin (BK; 1-1000 nM) facilitates norepinephrine (NE) release from cardiac sympathetic nerves. Because BK production increases in myocardial ischemia, endogenous BK could foster NE release and associated arrhythmias. We tested this hypothesis in guinea pig and human myocardial ischemia models. BK administration (100 nM) markedly enhanced exocytotic and carrier-mediated NE overflow from guinea pig hearts subjected to 10- and 20-min ischemia/reperfusion, respectively. Ventricular fibrillation invariably occurred after 20-min global ischemia; BK prolonged its duration 3-fold. The BK B2 receptor antagonist HOE140 (30 nM) blocked the effects of BK, whereas the B1 receptor antagonist des-Arg9-Leu8-BK (1 microM; i.e., 2.5 x pA2) did not. When serine proteinase inhibitors (500 KIU/ml aprotinin and 100 microg/ml soybean trypsin inhibitor) were used to prevent the formation of endogenous BK, NE overflow and reperfusion arrhythmias were diminished. In contrast, when kininase I and II inhibitors (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid and enalaprilat, each 1 microM) were used to prevent the degradation of endogenous BK, NE overflow and reperfusion arrhythmias were enhanced. B2 receptor blockade abolished these effects but was ineffective if kininases were not inhibited. B2 receptor stimulation, by either exogenous or endogenous BK, also markedly enhanced carrier-mediated NE release in the human myocardial ischemia model; conversely, inhibition of BK biosynthesis diminished ischemic NE release. Because atherosclerotic heart disease impairs endothelial BK production, in myocardial ischemia BK could accumulate at sympathetic nerve endings, thus augmenting exocytotic and carrier-mediated NE release and favoring coronary vasoconstriction and arrhythmias.
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PMID:Bradykinin promotes ischemic norepinephrine release in guinea pig and human hearts. 1002 27

Brief periods of in vitro hypoxia/ischemia induce apoptosis of cultured renal epithelial cells, but the underlying mechanisms remain unknown. We show that partial ATP depletion (approximately 10-65% of control) results in a duration-dependent induction of apoptosis in Madin-Darby canine kidney (MDCK) cells, as evidenced by internucleosomal DNA cleavage (DNA laddering and in situ nick end labeling), morphological changes (cell shrinkage), and plasma membrane alterations (externalization of phosphatidylserine). The ATP-depleted cells display a significant upregulation of Fas, Fas ligand, and the Fas-associating protein with death domain (FADD). Exogenous application of stimulatory Fas monoclonal antibodies also induces apoptosis in nonischemic MDCK cells, indicating that they retain Fas-dependent pathways of programmed cell death. Furthermore, cleavage of poly(ADP)ribose polymerase (PARP) is evident after ATP depletion, indicating activation of caspases. Indeed, the apoptotic cells display a significant increase in caspase-8 (FLICE) activity. Finally, apoptosis induced by ATP depletion is ameliorated by pretreatment with inhibitors of caspase-8 (IETD), caspase-1 (YVAD), or caspase-3 (DEVD) but is not affected by inhibitors of serine proteases (TPCK). Our results indicate that partial ATP depletion of MDCK cells results in apoptosis and that Fas- and caspase-mediated pathways may play a critical role.
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PMID:Partial ATP depletion induces Fas- and caspase-mediated apoptosis in MDCK cells. 1036 72

Extracellular levels of amino acids in the myocardial interstitium are sensitive indicators of myocyte function. Lowered ATP leads to a rapid extracellular appearance of amino acids with a high intra- to extracellular concentration ratio, such as taurine and glutamate. Nitrogen fluxes are reflected by glutamine, while alanine, glycine, serine and leucine are markers of proteolysis. In addition, degradation of membrane phospholipids is reflected by other primary amines, such as phosphoethanolamine. The time course of these changes was determined before, during and after cardioplegic heart arrest. Two regions of the heart were monitored in 20 patients by means of microdialysis sampling. After only 20 min of heart arrest, extracellular taurine, glutamate and phosphoethanolamine increased transiently up to 25 times the basal level. Ten-20 min later, glutamine increased by 6 times. A doubling of alanine, glycine, serine and leucine levels took place 30 min after release of the aortic cross-clamp. After 2 h, all were at levels similar to those recorded 15-30 h later. Levels of taurine and glutamate in the anterior wall of the heart correlated significantly with those of its lateral wall. The response to surgery and heart arrest was studied in a group of patients with ischemic heart disease as well as in another group of patients, who underwent heart surgery for nonischemic reasons. The response of taurine and glutamine was significantly higher for the patients with ischemic heart disease, in spite of a shorter mean time of heart arrest. No sex differences were recorded. High levels of amino acids coincided frequently with clinical events, which were suggestive of ischemia, but were also recorded in a few patients without diagnosed events. We conclude that monitoring of extracellular amino acids is valuable for evaluation and development of cardioprotective strategies.
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PMID:Extracellular amino acids as markers of myocardial ischemia during cardioplegic heart arrest. 1039 96

In order to evaluate the role of a hemorrhage versus that of a transient increase in intracranial pressure in subarachnoid hemorrhage, the two components were induced separately in rabbits. Extracellular glutamate, sampled from the hippocampus with microdialysis, was used to evaluate the degree of CNS tissue damage. In four rabbits, autologous arterial blood was infused in the cisterna magna in a volume that would not affect the intracranial pressure. The other group of animals was infused with saline to elevate the intracranial pressure from 10 to > 100 mmHg. The increase of intracranial pressure per se did not induce significant changes in extracellular glutamate. However, 20-60 min after infusion of blood, a significant glutamate increase was recorded. Furthermore, aspartate, alanine, glycine and serine were also raised. The results indicate that blood in the subarachnoid space damages the brain primarily by inducing ischemia. Furthermore, the parameters employed gave no indication that an increase in intracranial pressure had a deleterious effect on CNS tissue.
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PMID:Subarachnoid blood infusion versus raised intracranial pressure: effects on the amino acid pattern in the extracellular fluid of the rabbit hippocampus. 1040 14


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