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)

Cardiac sarcolemmal Na(+)/H(+) exchange is critical for the regulation of intracellular pH, and its activity contributes to ischemia-reperfusion injury. It has been suggested that the membrane phospholipid environment does not modulate Na(+)/H(+) exchange. The present study was carried out to determine the effects on Na(+)/H(+) exchange of modifying the endogenous membrane phospholipids through the addition of exogenous phospholipase D. Incubation of 0.825 U of phospholipase D with 1 mg of porcine cardiac sarcolemmal vesicles hydrolyzed 34 +/- 2% of the sarcolemmal phosphatidylcholine and increased phosphatidic acid 10.2 +/- 0.5-fold. Treatment of vesicles with phospholipase D resulted in a 46 +/- 2% inhibition of Na(+)/H(+) exchange. Na(+)/H(+) exchange was measured as a function of reaction time, extravesicular pH, and extravesicular Na(+). All of these parameters of Na(+)/H(+) exchange were inhibited following phospholipase D treatment compared with untreated controls. Passive efflux of Na(+) was unaffected. Treatment of sarcolemmal vesicles with phospholipase C had no effect on Na(+)/H(+) exchange. We conclude that phospholipase D-induced changes in the cardiac sarcolemmal membrane phospholipid environment alter Na(+)/H(+) exchange.
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PMID:Altered cardiac Na(+)/H(+) exchange in phospholipase D-treated sarcolemmal vesicles. 1099 82

Stimulation of group I metabotropic glutamate receptors (mGluR 1 and 5) activates G-protein coupled-phospholipase C (PLC) to release 1,2-diacylglycerol (DAG) and arachidonic acid (ArAc). To elucidate the role of group I mGluR, we tested the effects of (S)-alpha-methyl-4-carboxy-phenylglycine (MCPG, mGluR 1 and 5 antagonist), 1-aminoindan-1,5-dicarboxylic acid (AIDA, mGluR 1a specific antagonist) and 2-methyl-6-(phenylethynyl) pyridine (MPEP, mGluR 5 antagonist) on ArAc release and neuronal survival after transient forebrain ischemia in gerbils. Ischemia resulted in (a) significant release of ArAc at 1-day reperfusion and (b) significant neuronal death in the hippocampal CA1 subfield after 6-day reperfusion. MCPG and MPEP decreased ArAc release and also significantly increased neuronal survival. AIDA was less effective in decreasing ArAc release and had no effect on neuronal death. These results suggest that activation of mGluR 5 may be an important pathway in ArAc release and neuronal death after transient ischemia.
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PMID:Neuroprotection by group I metabotropic glutamate receptor antagonists in forebrain ischemia of gerbil. 1106 23

Ten min forebrain ischemia/1-day reperfusion resulted in significant decreases in total phosphatidylcholine (PtdCho), phosphatidylinositol (PtdIns), and cardiolipin in gerbil hippocampus. CDP-choline restored cardiolipin levels, arachidonic acid content of PtdCho, partially but significantly restored total PtdCho, and had no effect on PtdIns. These data suggest that CDP-choline prevented the activation of phospholipase A(2) (rather than inhibiting phospholipase A(2) activity) but did not affect activities of PtdCho-phospholipases C and/or D, or phosphoinositide-phospholipase C. CDP-choline also provided significant protection for hippocampal CA(1) neurons.
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PMID:Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? 1122 16

Atrial natriuretic peptide (ANP) reduces ischemia and/or reperfusion damage in several organs, but the mechanisms involved are largely unknown. We used freshly isolated rat hepatocytes to investigate the mechanisms by which ANP enhances hepatocyte resistance to hypoxia. The addition of ANP (1 micromol/L) reduced the killing of hypoxic hepatocytes by interfering with intracellular Na(+) accumulation without ameliorating adenosine triphosphate (ATP) depletion and pH decrease caused by hypoxia. The effects of ANP were mimicked by 8-bromo-guanosine 3', 5'-cyclic monophosphate (cGMP) and were associated with the activation of cGMP-dependent kinase (cGK), suggesting the involvement of guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A/B ANP receptors. However, stimulating NPR-C receptor with des-(Gln(18), Ser(19),Gly(20),Leu(21),Gly(22))-ANP fragment 4-23 amide (C-ANP) also increased hepatocyte tolerance to hypoxia. C-ANP protection did not involve cGK activation but was instead linked to the stimulation of protein kinase C (PKC)-delta through G(i) protein- and phospholipase C-mediated signals. PKC-delta activation was also observed in hepatocytes receiving ANP. The inhibition of phospholipase C or PKC by U73122 and chelerythrine, respectively, significantly reduced ANP cytoprotection, indicating that ANP interaction with NPR-C receptors also contributed to cytoprotection. In ANP-treated hepatocytes, the stimulation of both cGK and PKC-delta was coupled with dual phosphorylation of p38 mitogen-activated protein kinase (MAPK). The p38 MAPK inhibitor SB203580 abolished ANP protection by reverting p38 MAPK-mediated regulation of Na(+) influx by the Na(+)/H(+) exchanger. In conclusion, ANP recruits 2 independent signal pathways, one mediated by cGMP and cGK and the other associated with G(i) proteins, phospholipase C, and PKC-delta. Both cGK and PKC-delta further transduce ANP signals to p38 MAPK that, by maintaining Na(+) homeostasis, are responsible for ANP protection against hypoxic injury.
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PMID:Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide. 1254 Jul 77

ATP-sensitive K(+) channels (K(ATP)channels) regulate insulin secretion by coupling intracellular metabolic changes to excitability of the plasma membrane in pancreatic beta-cells. The channels are closed when extracellular glucose levels are elevated due to enhanced feature. By contrast, cardiac-type K(ATP) channels, which open in response to metabolic stress during cardiac ischemia, shorten action potential durations. This may contribute to the cardioprotection by decreasing Ca(2+) influx through sarcolemma. By sensing intracellular ATP levels or ATP/ADP ratios, changes in activity of K(ATP) channels convert metabolic information into membrane excitability. In addition to channel regulation by nucleotide concentrations, the channel activity is also dependent on the concentrations of membrane phospholipids, including phosphatidyl inositol-4,5-bisphosphate (PIP(2)). The levels of PIP(2) in the membrane may determine the basal activity of the channels. This suggests that channel activity would be modulated by the pathway of receptor-coupled GTP-binding protein (G-protein) and phosphatidyl inositol phospholipase C (PI-PLC) stimulation, which brings about depletion of the membrane PIP(2) pool. Thus, K(ATP) channels not only provide interface of metabolic changes with electrical excitation, but also rapidly transmit extracellular signals through receptor-coupled G-protein and PI-PLC pathway via PIP(2) metabolism.
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PMID:Receptor-operated regulation of ATP-sensitive K+ channels via membrane phospholipid metabolism. 1257 Jul 10

The physiological role of the uracil nucleotide-preferring P2Y(6) and P2Y(4) receptors is still unclear, although they are widely distributed in various tissues. In an effort to identify their biological functions, we found that activation by UDP of the rat P2Y(6) receptor expressed in 1321N1 human astrocytes significantly reduced cell death induced by tumor necrosis factor alpha (TNF alpha). This effect of UDP was not observed in non-transfected 1321N1 cells. Activation of the human P2Y(4) receptor expressed in 1321N1 cells by UTP did not elicit this protective effect, although both receptors were coupled to phospholipase C. The activation of P2Y(6) receptors prevented the activation of both caspase-3 and caspase-8 resulting from TNF alpha exposure. Even a brief (10-min) incubation with UDP protected the cells against TNF alpha-induced apoptosis. Interestingly, UDP did not protect the P2Y(6)-1321N1 cells from death induced by other methods, i.e. oxidative stress induced by hydrogen peroxide and chemical ischemia. Therefore, it is suggested that P2Y(6) receptors interact rapidly with the TNF alpha-related intracellular signals to prevent apoptotic cell death. This is the first study to describe the cellular protective role of P2Y(6) nucleotide receptor activation.
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PMID:Tumor necrosis factor alpha-induced apoptosis in astrocytes is prevented by the activation of P2Y6, but not P2Y4 nucleotide receptors. 1262 23

Metabotropic glutamate receptors of the mGlu(1) and mGlu(5) subtypes exhibit a high degree of sequence homology and are both coupled to phospholipase C and intracellular Ca(2+) mobilization. However, functional differences have been detected for these receptor subtypes when they are coexpressed in the same neuronal populations. Experimental evidence indicates that mGlu(1) and mGlu(5) receptors play a differential role in models of cerebral ischemia and that only mGlu(1) receptors are implicated in the pathways leading to post-ischemic neuronal injury. The localization of mGlu(1) receptors in GABA-containing interneurons rather than in hippocampal CA1 pyramidal cells that are vulnerable to ischemia has prompted studies that have provided a new viewpoint on the neuroprotective mechanism of mGlu(1) receptor antagonists. The hypothesis predicts that these pharmacological agents attenuate post-ischemic injury by enhancing GABA-mediated neurotransmission.
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PMID:The distinct role of mGlu1 receptors in post-ischemic neuronal death. 1296 71

Various laboratories have reported that local subcutaneous or subdermal injection of VEGF(165) at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present study, we used the clinically relevant isolated perfused 6 x 16-cm pig buttock skin flap model to 1) test our hypothesis that VEGF(165) is a potent vasodilator and acute VEGF(165) treatment increases skin perfusion; and 2) investigate the mechanism of VEGF(165)-induced skin vasorelaxation. We observed that VEGF(165) (5 x 10(-16)-5 x 10(-11) M) elicited a concentration-dependent decrease in perfusion pressure (i.e., vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1, or U-46619. The VEGF(165)-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF(165) in NE-preconstricted skin flaps (pD(2) = 13.57 +/- 0.31) was higher (P < 0.05) than that of acetylcholine (pD(2) = 7.08 +/- 0.24). Human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 microg/ml) or a specific VEGF receptor-2 inhibitor (5 x 10(-6) M SU-1498) blocked the vasorelaxation effect of VEGF(165) in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF(165) in the skin vasculature is initiated by the activation of VEGF receptor-2. Furthermore, using pharmacological probes, we observed that the postreceptor signaling pathways of VEGF(165)-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, an increase in inositol 1,4,5-trisphosphate activity, release of the intra-cellular Ca(2+) store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEGF(165)-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF(165) protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.
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PMID:Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature. 1464 65

Clostridium perfringens gas gangrene is characterized by rapid tissue destruction, impaired host response, and, often, death. Phospholipase C (alpha -toxin) is the virulence factor most responsible for these pathologies. The present study investigated the efficacy of active immunization with the C-terminal domain of alpha -toxin (Cpa247-370) in a murine model of gas gangrene. Primary end points of the study were survival, progression of infection, and tissue perfusion. Secondary end points, which were based on findings of histologic evaluation of tissues, included the extent of tissue destruction and microvascular thrombosis, as well as the magnitude of the tissue inflammatory response. Survival among C-domain-immunized animals was significantly greater than that among sham-immunized control animals. Furthermore, immunization with the C-domain localized the infection and prevented ischemia of the feet. Histopathologic findings demonstrated limited muscle necrosis, reduced microvascular thrombosis, and enhanced granulocytic influx in C-domain-immunized mice. We conclude that immunization with the C-domain of phospholipase C is a viable strategy for the prevention of morbidity and mortality associated with C. perfringens gas gangrene.
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PMID:Immunization with the C-Domain of alpha -Toxin prevents lethal infection, localizes tissue injury, and promotes host response to challenge with Clostridium perfringens. 1527 5

Ischemic damage is greatly enhanced by preischemic hyperglycemia or hypercapnia, which affects many intracellular responses including protein kinase C (PKC) translocation. We explored whether hyperglycemic or hypercapnic ischemia affects lipid metabolism, especially ischemia-induced release of free fatty acids (FFAs) and diacylglycerols (DAGs). A change in intraischemic level of acidosis was induced either by injecting glucose (hyperglycemic, HG) or by adding CO(2) (hypercapnic, HC). Complete cerebral ischemia was induced, and the brain was frozen in situ after 3, 5, and 10 min at 37 degrees C. Frontoparietal neocortex was dissected for FFA and DAG lipid analysis by thin-layer chromatography and gas-liquid chromatography. Significant differences were shown between normoglycemic and either hypercapnic or hyperglycemic values for individual and total FFAs. A significant delay in the release of FFA in ischemia with hyperglycemia or hypercapnia was observed. Significant differences were also shown in individual DAG-acyl groups and total DAGs. Hyperglycemic or hypercapnic ischemia resulted in a significant decrease of DAG at 10 min of ischemia. This was unexpected because a previous study showed that PKC translocation was significantly enhanced under similar condition at this time point. Upon cellular depolarization, massive influx of calcium and FFA accumulation may decrease the PKC dependence of DAG for translocation. In addition, PKC activation may lead to a negative feedback inhibition of phospholipase C.
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PMID:Effects of hyperglycemia and hypercapnia on lipid metabolism during complete brain ischemia. 1556 45


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