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)

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
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PMID:Modulation of nerve and glial function by adenosine--role in the development of ischemic damage. 753 56

Protein kinase C (PKC) and the ATP-dependent K+ channel (KATP channel) have been implicated in the mechanism of ischemic preconditioning in animal models. This study investigated the role of KATP channels and PKC in preconditioning in human myocardium and whether KATP channels are activated via a PKC-dependent pathway. Right atrial trabeculae were superfused with Tyrode's solution and paced at 1 Hz. After stabilization, muscles underwent one of nine different protocols, followed by simulated ischemia (SI) consisting of 90 minutes of hypoxic substrate-free superfusion paced at 3 Hz and then by 120 minutes of reperfusion. Preconditioning consisted of 3 minutes of SI and 7 minutes of reperfusion. The experimental end point was recovery of contractile function after SI, presented here as percentage recovery (%Rec) of baseline function. %Rec was significantly improved by preconditioning by the KATP channel opener cromakalim (CK), and by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) compared with nonpreconditioned controls when these treatments were given before the SI insult (control group, 29.5 +/- 3.6%; preconditioned group, 63.5 +/- 5.4%, CK-treated group, 52.9 +/- 3.1%; and DOG-treated group, 48.0 +/- 3.5%; P < .01). The effects of CK could be blocked by the KATP channel blocker glibenclamide (%Rec, 17.8 +/- 3.5%). Preconditioning could be blocked by the PKC antagonist chelerythrine (%Rec, 24.1 +/- 5.0%) and the KATP blocker glibenclamide (%Rec, 24.8 +/- 3.1%). The effects of DOG could also be blocked by glibenclamide (%Rec, 23.1 +/- 2.3%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model. 755 38

The physiological regulation of the intracellular Ca2+ homeostasis and its pathological alteration has been studied in rat and gerbil hippocampal slices using ion-sensitive electrodes and the fluorescence imaging technique. The ischemia-induced intracellular Ca2+ rise, accentuated in the synaptic/dendritic layer of the vulnerable CA1 neurons was observed in vivo and could be replicated at an accelerated time course in the "ischemic" hippocampal slice superfused with unoxygenated, glucose-free medium. The intracellular Ca2+ loading, thought to be instrumental for the generation of postischemic nerve cell damage, seems to result from an increased Ca2+ release out of intracellular stores as well as from an enhanced synaptic Ca2+ influx. The latter is attributed to a depolarization-induced opening of the voltage-dependent Ca2+ channels and to an uncontrolled influx through "upregulated" NMDA receptor-operated channels. Such an ischemia-induced upregulation which is reported to occur physiologically by the activation of PKC, is reflected by the selective loss of the depressive control of the synaptic NMDA Ca2+ influx by adenosine. Ischemia also leads to a hypertrophy of astrocytes which may go along with an impairment of their physiological function to take up glutamate adding to the extracellular rise of the excitotoxic amino acids. A pathological activation of microglial cells and their transformation into macrophages, known to release oxygen radicals, may further add to neuronal damage. The observed neuroprotection by adenosine can be primarily ascribed to its limiting effect on a pathological membrane depolarization and its deleterious consequences. The more powerful neuroprotection by propentofylline, thought to act analogue to adenosine, seems to be achieved by additional mechanisms. This pharmacon depresses the ischemia-induced neuronal Ca2+ loading in vivo and in vitro, prevents the activation of astrocytes and interferes with the transformation as well as with the free radical formation of microglia-derived macrophages as demonstrated in complementary studies with fluorescence techniques on cell cultures.
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PMID:The use of ion-sensitive electrodes and fluorescence imaging in hippocampal slices for studying pathological changes of intracellular Ca2+ regulation. 789 1

In order to study the possible role of C kinase (PKC) on sodium pump of cerebral vessels, we used diacylglycerol (diC8: sn-1,2-dioctanoylglycerol) and phorbol esters (PMA: phorbol 12-myristate 13-acetate; PDA: phorbol 12,13-diacetate; 4 alpha-P: 4-alpha phorbol) as PKC activators, and examined their effects on Na,K-ATPase activity in rat brain microvessels (MVs). Rats were divided into non-treated (control; n = 9), four-vessel occlusion (4VO; 30-30 minutes ischemia and recirculation, n = 5), and middle cerebral artery occlusion (MCAO, n = 3) groups. MVs were passed through nylon meshes and were obtained by ultracentrifuge at 58000 g. Na,K-ATPase activity in MVs was determined by the phosphomolybdate method. DiC8 enhanced Na,K-ATPase activity at 10(-4) M in the control group, the 4VO group and the contralateral hemispheres of the MCAO group (139% +/- 0.06, 135% +/- 0.2, 133% +/- 0.18, mean +/- SE, p < 0.05, p < 0.01, Wilcoxon rank sum) respectively, but had no effects on MVs in the ipsilateral hemispheres of MCAO group (74% +/- 0.04). This activation by diC8 was inhibited by PKC inhibitors, staurosporine (3 x 10(8) M) and H7 (10(-6) M) in the control MVs. By contrast, PMA suppressed Na, K-ATPase at 10(-5) M in the control group (-25% +/- 0.07), but it tended to activate Na,K-ATPase activity in the ipsilateral hemispheres of the MCAO groups (33% +/- 0.09). PDA and 4 alpha-P did not have any consistent effects at the concentration examined. The cause of difference between the effects of diC8 and PMA is unclear at present, but it may stem from the mode of lipid-membrane interaction in these agents and the difference in the condition of cells as well.
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PMID:Effects of protein kinase C activators on Na, K-ATPase activity in rat brain microvessels. 797 18

In the model of transient brain ischemia of 6-min duration in gerbils we have estimated: 1. The concentration of brain gangliosides: A significant decrease to about 70% of control was observed selectively in the hippocampus at 3 and 7 d after ischemia. 2. The activity of Na+,K(+)-ATPase: The enzyme activity was not affected in either hippocampus nor in cerebral cortex. 3. The malonaldehyde (MDA) concentration: The levels of MDA had increased at 30 min after ischemia up to 123 and 129% of control in hippocampus and cerebral cortex, respectively. 4. Immunoreactivity of protein kinase C detected by Western blotting: In hippocampus the early translocation toward membranes was followed by a decrease in total enzyme content at 6, 24, 72, and 96 h of postischemic recovery. Also, a sharp increase of 50 kDa isoform (PKM) was noticed immediately and at the early recovery times. The behavior of these biochemical markers of ischemic brain injury in the hippocampus after the short (6 min) insult was contrasted with their reaction in the cerebral cortex as well as after prolongation of the ischemia to 15 min. These results taken together indicate that an early increase in PKC translocation followed by a decrease is the most symptomatic for selective, delayed, postischemic hippocampal injury, resulting from short duration (6 min) ischemia of the gerbil brain.
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PMID:Protein kinase C as an early and sensitive marker of ischemia-induced progressive neuronal damage in gerbil hippocampus. 829 17

Neurotransmitter receptor-coupled mechanisms have been recently recognized as important determinants of cell damage after central nervous system (CNS) trauma and ischemia. Many of these receptors exert their intracellular effects via second messenger systems. This study used in vitro autoradiographic radioligand binding to measure beta-adrenergic and muscarinic cholinergic receptors and adenylate cyclase and protein kinase C (PKC) binding sites two h after acute subdural hematoma in rats. Both beta-adrenergic and cholinergic receptor binding sites were unchanged in comparison to controls, while adenylate cyclase binding significantly decreased in the ischemic cortex under the hematoma. These changes may constitute a major limiting factor on receptor-linked therapeutic strategies in trauma and ischemia. Protein kinase C activation significantly increased in the ischemic area under the hematoma in these studies. This appears to be a response to calcium flux, which may be in part glutamate mediated.
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PMID:Early changes in second messenger but not receptor binding sites after acute subdural hematoma: an in vitro autoradiographic study. 839 84

The effect of incubation with the protein kinase C activator, 4 beta-phorbol 12,13-dibutyrate (beta-PDBu) on the electrophysiological responses to hypoxia and combined hypoxia and hypoglycemia was investigated in the rat hippocampal slice. Preincubation with beta-PDBu prevents adenosine-mediated inhibition of synaptic transmission under normoxic, normoglycemic conditions. beta-PDBu preincubation also reduces the adenosine-mediated hypoxia-induced depression of synaptic transmission revealing a substantial adenosine-independent hypoxia-induced depression of synaptic transmission. During combined hypoxia and hypoglycemia, slices preincubated in beta-PDBu display a significant shortening of the time of anoxic depolarization, an effect of beta-PDBu that is not mimicked by application of the adenosine antagonist cyclopentyltheophylline (8-CPT). It is concluded that the state of PKC activation may influence the electrophysiological responses to hypoxia and ischemia.
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PMID:Phorbol ester alters the electrophysiological responses to hypoxia and ischemic-like conditions in the rat hippocampal slice. 858 22

These studies of a model liver cell line evaluate the mechanisms responsible for regulated release of K+ ions during metabolic stress. Metabolic inhibition of HTC hepatoma cells by exposure to 2, 4-dinitrophenol (50 microM) and 2-deoxy-D-glucose (10 mM) stimulated outward currents carried by K+ of 974 +/- 75 pA at 0 mV (n = 20, p < 0.001). Currents were inhibited by chelation of intracellular Ca2+ or exposure to apamin (50 nM), an inhibitor of SKCa channels. In cell-attached recordings from intact cells, removal of metabolic substrates (25/28 cells) or exposure to metabolic inhibitors (32/40 cells) opened K+-selective channels with a conductance of 6.5 +/- 0. 2 pS. Channels had an open probability of 0.31 +/- 0.08 and opened in bursts averaging 3.55 +/- 0.27 ms in duration (n = 6). Metabolic stress was associated with rapid translocation of the alpha isoform of protein kinase C (PKCalpha) from cytosol to membrane; and down-regulation of PKCalpha by phorbol esters or exposure to the PKC inhibitor chelerythrine (10 microM) each inhibited currents. Moreover, intracellular perfusion with purified PKCalpha activated currents in a Ca2+- and concentration-dependent manner. These findings indicate that metabolic stress leads to opening of apamin-sensitive SKCa channels in hepatoma cells through a Ca2+- and PKC-dependent mechanism and suggest that PKCalpha may be selectively involved in the response. This mechanism functionally couples the metabolic state of cells to membrane K+ permeability and represents a potential target for modification of liver injury associated with ischemia and preservation.
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PMID:Metabolic stress opens K+ channels in hepatoma cells through a Ca2+- and protein kinase calpha-dependent mechanism. 866 72

Ischemic preconditioning (PC) has been shown to attenuate intracellular acidification during a subsequent period of ischemia, to minimize stunning, and to decrease infarct size, PKC activation has been suggested to be involved in this phenomenon. The present study is designed to test whether PKC activation could mimic and PKC inhibition could block the PC effects on intracellular acidification during ischemia and on stunning during reflow in Langendorff perfused rat hearts. Prior to 20 min of sustained global normothermic ischemia, groups of hearts were treated with the PKC activators 4 beta-phorbol 12-myristate 13-acetate (PMA) or 1,2-dioctanoyl-srt-glycerol (DOG), a group of hearts was treated with the PKC inhibitor chelerythrine (CH), a group was treated with DOG plus CH, a group was preconditioned with four cycles of 5 min of ischemia and 5 min of reflow, and a group was treated with CH during PC. Recovery of left ventricular developed pressure (% of initial, pretreatment, preischemic LVDP), measured after 20 min of reflow, was improved in hearts treated with DOG, but not PMA (80 +/- 3% (DOG), 55 +/- 3% (PMA) v 51 +/- 3% (control), P < 0.05 between DOG and control), although both caused a similar degree of PKC translocation (measured by fractionation followed by an assay of PKC activity using incorporation of 32P into histone). The improved recovery of LVDP in the PC group and in the DOG group was blocked by chelerythrine. Measurement of pH (by 31P NMR) showed that DOG reduced acidification at 15-20 min of ischemia, although the effect was not as great as PC, while PMA did not reduce acidification. The effect of DOG on pHi was attenuated by CH; however, the PC-induced attenuation of the fall in pHi, was not affected by CH. High energy phosphates (measured by 31P NMR) were not significantly different between any of the groups during ischemia or reflow. This study confirms that the protective effect of ischemic preconditioning on stunning in rat heart can be eliminated by inhibition of PKC, but suggests that the effect of PC on the fall in pHi during sustained ischemia is not mediated by PKC.
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PMID:Effect of ischemic preconditioning and PKC activation on acidification during ischemia in rat heart. 876 27

The protein serine/threonine kinases which are highly expressed in the central nervous system (CNS) are severely affected by brain ischemia. Irrespective of substantial differences among the particular members of this group of kinases, their responses to ischemic stress show a lot of similarities. Initially they are switched on by facilitated interaction with their specific activators/second messengers like cyclic AMP, 1,2-sn-diacylglicerol and particularly Ca2+, then they are translocated to highly specific regions of plasma membranes. After phosphorylation of target proteins, the kinases are deactivated by means of different routes. Activity of PKA is regulated by its direct access to cAMP. In the case of CaMKII, it is probably achieved by its extensive, inhibitory autophosphorylations, while PKC seems to be proteolytically degraded. These biphasic changes in serine/threonine kinases activity may play a critical role in the evolution of postischemic brain injury and provide a mechanism for a variety of short- and long-term signalling events.
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PMID:Protein serine/threonine kinases (PKA, PKC and CaMKII) involved in ischemic brain pathology. 876 9

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