UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-fos immediate early gene is induced by normal stimuli including light, stress, hyperosmolar solutions, and hormones. Ischemia, hypoxia, seizures, cortical injury, nerve section and other pathological stimuli can also induce c-fos. The induction can occur via increases in intracellular calcium that act through a Ca2+/cAMP element on its promoter, or via trophic and other factors that act through a serum response element (SRE) on its promoter. Several studies show that calcium entry via voltage sensitive calcium channels (VSCCs) is important for inducing c-fos. We have shown that calcium entry via the NMDA receptor is important for induction of c-fos mRNA by glutamate and cAMP in cultured cortical neurons. Moreover, the NMDA receptor appears to regulate translation of c-fos mRNA to Fos protein when cells are stimulated with other types of stimuli including vasoactive intestinal peptide, zinc, and fibroblast growth factor. These results suggest that toxins that elevate intracellular calcium will likely induce the c-fos gene in brain. The heat shock or stress genes are induced by a wide variety of stimuli including heavy metals, heat, oxidative and ischemic stress, prolonged seizures, hypoglycemia, calcium ionophores, and certain toxins. It is believed that denatured proteins stimulate heat shock factors to bind to heat shock elements on the promoters of all heat shock genes to induce gene transcription. We and others have shown that global and focal ischemia induce the hsp70 heat shock gene in brain. Mild ischemia induces hsp70 mRNA and HSP70 protein in neurons only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in gene expression as an index of neuronal injury: heat shock and the immediate early gene response. 809 Mar 62

There is now convincing evidence that excessive accumulation of the excitatory amino acid glutamate (Glu) in the extracellular space is toxic to neurons. However, the regulation of the release and uptake of Glu in producing this toxic concentration has not been adequately ascertained. The authors report that in hippocampal slices, the output of Glu significantly increased under in vitro ischemic states. Glu in the extracellular space increased fivefold. Since daurisoline, a drug that blocks N-type Ca2+ channels, or Ca(2+)-free solution potently and effectively lowered this stimulated output, it was hypothesized that the Glu output is mediated by Ca2+ influx in nerve terminals. When the slices were incubated for 30 minutes under ischemic state, daurisoline caused only small alterations in the postischemic accumulation of Glu. However, Glu accumulation was markedly attenuated by H-7, but not by calmidazolium, facilitated by PDB whereas 8-bromo-cAMP was without effect. It appears therefore that during a 30-minute ischemic insult, protein kinase C (PKC) was involved in the Glu accumulation of supernatant. A direct demonstration of this concept was obtained by showing significant increases in PKC activation in presynaptic nerve terminals (from 1.34 +/- 0.1 to 9.34 +/- 0.89 U) following 30 minutes of ischemia. DNQX, a non-NMDA receptor antagonist, potently reduced PKC activities and decreased extra Glu accumulation. Also observed was the inhibition of 1-[3H]-Glu uptake into synaptosomes by PDB. These results provide direct evidence that Ca2+ influx enhances Glu release, which in turn leads to inhibition of its reuptake, and is coupled with PKC activities in presynaptic nerve terminals.
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PMID:Accumulation of glutamate is regulated by calcium and protein kinase C in rat hippocampal slices exposed to ischemic states. 810 81

To determine ischemia-induced changes in phosphodiesterase (PDE), changes in the membranous binding sites of rolipram, a cAMP-selective PDE inhibitor, were examined in the gerbil brain following transient 5 min forebrain ischemia. Coinciding with the delayed neuronal death (DND) in the hippocampal CA1 region, affinities for cerebral rolipram bindings decreased on Day 4, when intrinsic cAMP, substrate for PDE, might increase. The number of rolipram binding sites was significantly reduced in the hippocampus Day 14, despite the lack of change on Day 4. This reduction in rolipram binding was in agreement with the previously reported late onset reduction of muscarinic receptors, progressing more slowly than DND. Slowly progressive mechanisms may be involved in the ischemia-induced reduction of the hippocampal rolipram binding sites which may be PDEs.
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PMID:Alterations in the binding of the phosphodiesterase inhibitor, rolipram, after transient ischemia in the gerbil brain. 812 28

Extracellular ATP concentration can rise because of its release by nerve terminals and by damaged cells during ischemia. After the activation of P2-purinergic receptors, ATP induces a positive inotropic effect and increases the L-type Ca2+ current via activation of a Gs protein but without cAMP production. In addition, ATP shifts the voltage characteristics of Ca2+ current toward hyperpolarized potentials. If ATP produced similar effects on the Na+ current (INa), this compound should also affect cardiac excitability and conduction. Using the whole-cell patch-clamp to record INa in rat ventricular cells, we show that extracellular application of ATP induced hyperpolarizing shifts in the current-voltage relation and the availability of INa. The ED50 for the shifts in both conductance and availability was obtained with 0.7 mumol/L ATP. Maximal shifts in conductance and availability were respectively 9.7 +/- 0.6 and 10.6 +/- 0.7 mV. The leftward shift of the availability curve is responsible for the decrease of INa amplitude at less polarized holding potentials. These effects were not cholera toxin sensitive and thus cannot be attributed to activation of the Gs protein. At 100 mumol/L, ATP gamma S and alpha,beta-methylene ATP could induce shift, whereas UTP and beta,gamma-methylene ATP as well as ADP and adenosine were without effect. Thus, depending on the resting membrane potential, ATP should either enhance excitability or favor slow conduction and weaken cardiac electrical homogeneity and consequently favor arrhythmia.
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PMID:Effect of extracellular ATP on the Na+ current in rat ventricular myocytes. 813 6

Current organ preservation strategies subject graft vasculature to severe hypoxia (PO2 approximately 20 Torr), potentially compromising vascular function and limiting successful transplantation. Previous work has shown that cAMP modulates endothelial cell (EC) antithrombogenicity, barrier function, and leukocyte/EC interactions, and that hypoxia suppresses EC cAMP levels. To explore the possible benefits of cAMP analogs/agonists in organ preservation, we used a rat heterotopic cardiac transplant model; dibutyryl cAMP added to preservation solutions was associated with a time- and dose-dependent increase in the duration of cold storage associated with successful graft function. Preservation was also enhanced by 8-bromo-cAMP, the Sp isomer of adenosine 3',5'monophosphorothioate, and types III (indolidan) and IV (rolipram) phosphodiesterase inhibitors. Neither butyrate alone nor 8-bromoadenosine were effective, and the cAMP-dependent protein kinase antagonist Rp isomer of adenosine 3',5'monophosphorothioate prevented preservation enhancement induced by 8-bromo-cAMP. Grafts stored with dibutyryl cAMP demonstrated a 5.5-fold increase in blood flow and a 3.2-fold decreased neutrophil infiltration after transplantation. To explore the role of cAMP in another cell type critical for vascular homeostasis, vascular smooth muscle cells were subjected to hypoxia, causing a time-dependent decline in cAMP levels. Although adenylate cyclase activity was unchanged, diminished oxygen tensions were associated with enhanced phosphodiesterase activity (59 and 30% increase in soluble types III and IV activity, respectively). These data suggest that hypoxia or graft ischemia disrupt vascular homeostasis, at least in part, by perturbing the cAMP second messenger pathway. Supplementation of this pathway provides a new approach for enhancing cardiac preservation, promoting myocardial function, and maintaining vascular homeostatic properties.
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PMID:Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model. 825 53

This study tested the hypothesis that a reperfused ischemic myocardial region of the dog heart would be unable to increase its function in response to amrinone, a specific cyclic AMP phosphodiesterase (cAMP-PDE) inhibitor, due to loss of cAMP-PDE activity in the region. The global contractility (+dp/dtmax), regional percent shortening (ultrasonic crystals), and developed force (miniature force gauge) were measured on a continuous basis throughout a 6-hour experiment and regional blood flow (radioactive microspheres) in open-chest pentobarbital-anesthetized mongrel dogs. The left anterior descending coronary artery (LAD) was isolated and ligated for 2 hours and allowed to reperfuse for 4 hours. This myocardial region was compared to a nonischemic region supplied by the circumflex artery. At the end of the 4-hour reperfusion period, 9 dogs were treated with amrinone (5 mg/kg) and three dogs were not treated with amrinone. The hearts were rapidly excised and frozen in liquid nitrogen. Cyclic AMP and cAMP-PDE activity was determined in homogenates of myocardial tissue. Blood flow decreased during occlusion in the LAD region and returned toward control with reperfusion. Flow increased nonsignificantly with amrinone. the basal cyclic AMP content of the two regions was not different. The cAMP-PDE activity was reduced 24% in the LAD region compared to the control region. There were no ischemia-induced changes in the enzyme characteristics. These experiments demonstrated increased global function in the ischemic reperfused myocardium after amrinone was administered (dP/dtmax: 2092 +/- 538 to 3277 +/- 688 mmHg/sec).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of ischemia-reperfusion on myocardial cyclic AMP and cyclic AMP phosphodiesterase: effects of amrinone on regional myocardial force and shortening. 826 38

Hydrogen peroxide (H2O2) is a reactive oxygen species that can be produced in the digestive tract by inflammatory cells or during reperfusion following ischemia. To evaluate a possible direct effect of H2O2 on epithelial secretory cells, well-differentiated colonic T84 cells were grown to confluence on permeable membranes and studied in Ussing chambers. In this model, where the measured short-circuit current (Isc) reflects electrogenic secretion, we observed that H2O2 stimulated a concentration-dependent and transient secretory response: 5.5 mM H2O2 produced a peak Isc of 12.4 microA/cm2 after 4 min, 2.2 mM H2O2 a peak Isc of 7.9 microA/cm2 after 4 min, and 1.1 mM H2O2 a peak Isc of 5.5 microA/cm2 after 16 min (N = 5). When 97 experiments using 5.5 mM H2O2 were reviewed, the mean peak Isc response was 8.9 +/- 0.5 microA/cm2. A similar secretory response was elicited whether H2O2 was added to the serosal, to the mucosal, or simultaneously to both sides of the T84 cell monolayer. This secretory response reflected transcellular chloride secretion because it was inhibited by the depletion of chloride in the medium and by the suppression of the Na+,K+,2Cl- co-transporter activity necessary for the chloride gradient driving chloride secretion. When T84 cell monolayer resistance was studied, 5.5 mM H2O2 produced a transient decrease in resistance, reflecting transcellular chloride secretion, and a gradual decline in resistance (75% of the initial value after 55 min). The secretory response to H2O2 was increased 2-fold in T84 cells maximally stimulated with 10 nM vasoactive intestinal peptide (VIP), a neuropeptide which acts via cAMP, demonstrating synergism between the two agents. In contrast, the secretory responses produced by H2O2 and carbachol, which acts through the Ca2+ pathway, were additive. A late inhibitory effect of H2O2 was also observed: in cells previously treated with 5.5 mM H2O2, the subsequent secretory responses to either VIP or carbachol were partially inhibited. These secretory effects were specific for the oxidant properties of H2O2 because they were inhibited by 450 U/mL catalase and by 5 mM dithiothreitol, but were unaffected by 50 microM deferoxamine B or Fe3+. H2O2 may be a potential modulator of intestinal or colonic secretion in certain pathologic conditions such as inflammation or ischemia-reperfusion.
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PMID:Modulation of human colonic T84 cell secretion by hydrogen peroxide. 830 84

We studied the alterations in binding of cyclic AMP as an indicator of particulate cyclic AMP-dependent protein kinase binding activity following transient cerebral ischemia in Mongolian gerbils and examined the effects of vinconate and pentobarbital against alterations in the binding. Animals were allowed to survive for 5 h and 7 days after 10 min of cerebral ischemia induced by bilateral occlusion of common carotid arteries. [3H]Cyclic AMP binding was significantly reduced in the hippocampus 5 h after ischemia, whereas the striatum showed no significant change in the binding. Seven days after ischemia, a severe reduction of [3H]cyclic AMP binding was noted in the dorsolateral striatum, hippocampal CA1 and CA3 sectors, and dentate gyrus. Intraperitoneal administration of vinconate (100 or 300 mg/kg) showed a significant elevation of [3H]cyclic AMP binding in the striatum, stratum pyramidale of hippocampal CA1 and CA3 sectors, and dentate gyrus 5 h after ischemia. By contrast, the intraperitoneal administration of pentobarbital (40 mg/kg) showed no significant alteration of [3H]cyclic AMP binding in most of these regions. However, vinconate and pentobarbital prevented a significant reduction of [3H]cyclic AMP binding in the dorsolateral striatum and stratum pyramidale of hippocampal CA3 sector 7 days after ischemia, although both drugs failed to prevent damage to the hippocampal CA1 sector. These results suggest that alteration in cyclic AMP binding may not be a major factor in causing ischemic neuronal damage.
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PMID:Changes of [3H]cyclic adenosine monophosphate binding in the gerbil brain following transient cerebral ischemia: an autoradiographic study and investigation of the effects of vinconate and pentobarbital. 838 51

Using [3H]MK-801, [3H]muscimol, [3H]cyclic AMP, and [3H]rolipram, we performed quantitative in vitro autoradiography to determine sequential alterations in the binding of N-methyl-D-aspartate and GABAA receptors, particulate cyclic AMP-dependent protein kinase, and cyclic AMP-selective phosphodiesterase, respectively, in the gerbil hippocampus following repeated brief ischemic insults. Changes from 1 h to 28 days after three 2-min ischemic insults at 1-h intervals were compared with those after 2 and 6 min of ischemia. We observed no alterations in the binding of all the four ligands throughout the observation period following 2 min of ischemia which produced no histological neuronal damage except for transient reductions in [3H]cyclic AMP binding during the early reperfusion period. [3H]Cyclic AMP binding in the CA1 subfield decreased one day after 6 min of ischemia and four days after three 2-min ischemic insults, and 62-65% of the binding was lost after 28 days. [3H]Rolipram binding in the CA1 subfield decreased one day after 6 min of ischemia and the binding was reduced by 45-50% after four and 28 days. Following three 2-min ischemic insults, [3H]rolipram binding decreased in the CA1 at one day, and decreased by 25-33% after 28 days. Both [3H]MK-801 and [3H]muscimol binding was preserved during the early reperfusion period after 6 min of ischemia and three 2-min ischemic insults. Reductions in [3H]MK-801 binding in CA1 were observed four days after ischemic insults when CA1 neuronal destruction was seen. After one month, approximately 50% of [3H]MK-801 binding was lost in CA1 in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in [3H]MK-801, [3H]muscimol, [3H]cyclic AMP, and [3H]rolipram binding in the gerbil hippocampus following repeated ischemic insults. 838 18

The potential usefulness of adenosine receptor stimulation in the therapy for ischemic brain disease is dependent upon retention of adenosine receptors and their transduction mechanisms after ischemia. The receptors most clearly associated with adenosine-dependent cerebral inhibition are the A1-type (A1-AR), which work via a Gi protein to inhibit adenylate cyclase. In brain membranes from rats recovering at various times after 15 min of complete cardiac arrest-induced ischemia, the levels of A1-AR decreased temporarily to 60% of the control values. However, agonist affinities for A1-AR, as well as guanine nucleotide-sensitive high-affinity binding, remain unchanged. The significant decrease of agonist affinities to A1-AR produced by calcium depletion in control membranes was markedly attenuated after ischemia. Moreover, the A1-AR agonist-induced inhibition of cAMP production parallels the decrease in these receptor numbers. It was blocked in the postischemic membranes but reverts to control levels upon extending the recovery period to one week after the insult. It is concluded that in addition to the lowering of the number of A1-AR binding sites, the coupling of A1 receptor activation to adenylate cyclase response is inhibited after ischemia, but not at the level of receptor-Gi protein interaction.
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PMID:Coupling of adenosine receptors to adenylate cyclase in postischemic rat brain. 839 99

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