Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Adenosine A1 receptor agonists given prior to myocardial ischemia limit ischemic injury in several species. However, the ability of adenosine receptor agonists to limit infarct size when given at reperfusion has proved controversial. We designed a three-center experimental study using a blinded, randomized treatment protocol to test the hypothesis that adenosine A1 receptor activation during early reperfusion can attenuate lethal reperfusion injury, thereby reducing infarct size. Sixty anesthetized rabbits (20 in each laboratory) underwent 30 minutes coronary artery occlusion followed by 120 minutes reperfusion. The selective adenosine A1 receptor agonist GR79236 (10.5 microg/kg, a dose shown to limit infarction in this model when given before ischemia) or vehicle were administered IV 10 minutes before reperfusion. Infarct size was assessed by tetrazolium staining and, after the randomization code was revealed, data from the three laboratories were pooled for statistical analysis. Infarct size was not modified by administration of GR79236. In the vehicle-treated group, the infarct-to-risk ratio was 28.9 +/- 2.7% (n = 24) compared with 31.9 +/- 2.6% (n = 26) in the GR79236-treated group (not significant). Risk zone volume was similar in the two groups (1.06 +/- 0.05 cm3 vs 1.00 +/- 0.05 cm3, respectively). A modest reduction in rate-pressure product was noted following the administration of GR79236, but this effect was transient. The same dose of GR79236 was found to limit infarct size when given prior to coronary artery occlusion. We conclude that A1 receptor activation does not modify lethal reperfusion injury in myocardium.
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PMID:Adenosine A1 agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study. 1130 Mar 61

Recent studies have demonstrated that the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA) produce a delayed phase of protection against infarction similar to the late phase of ischemic preconditioning (PC). However, the mechanism for adenosine A1 or A3 receptor-induced late PC remains unknown. The goal of this study was to determine whether the delayed cardioprotective effects of adenosine A1 or A3 receptors are mediated by cyclooxygenase-2 (COX-2), which is an obligatory mediator of ischemic PC. We found that COX-2 protein expression (Western blotting) did not increase 24 h after the administration of either CCPA (100 microg/kg iv) or IB-MECA (300 microg/kg iv) compared with controls. To probe the role of constitutive COX-2 expression, conscious rabbits were subjected to 30-min coronary occlusion followed by 72-h reperfusion. Twenty-four hours before the occlusion, the rabbits were pretreated with CCPA (100 microg/kg iv) or IB-MECA (300 microg/kg iv). Both CCPA and IB-MECA resulted in a marked (approximately 47%) reduction in infarct size vs. controls [36.2 +/- 4.0% of the risk region (n = 9), 31.2 +/- 4.7% (n = 9), and 59.5 +/- 3.8% (n = 9), respectively; P < 0.05], similar to that induced by the late phase of ischemic PC [31.8 +/- 3.2% (n = 9)]. The selective COX-2 inhibitor N-(2-[cyclohexyloxy]4-nitrophenyl)methanesulfonamide (NS-398, 5 mg/kg), which abolished the protective effect of ischemic late PC, failed to block the protection of either CCPA or IB-MECA, indicating that COX-2 does not mediate the delayed protection of either CCPA or IB-MECA [CCPA + NS-398, 29.1 +/- 3.4% (n = 7); IB-MECA + NS-398, 34.9 +/- 2.9% (n = 8)]. NS-398 in itself did not affect infarct size [54.9 +/- 3.7% (n = 9)]. Taken together, these results demonstrate that, in contrast to ischemia-induced late PC, the mechanisms of adenosine A1 or A3 receptor-induced late PC is independent of COX-2.
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PMID:Cyclooxygenase-2 does not mediate late preconditioning induced by activation of adenosine A1 or A3 receptors. 1145 3

Transient adenosine A1 receptor (A1R) activation induces a second window or delayed preconditioning against myocardial infarction 24-72 h later. Early generation of nitric oxide and delayed induction of nitric oxide synthase have been implicated in mediating delayed cardioprotection after ischemic preconditioning in rabbits. Recent evidence indicates that some of the regulatory roles of adenosine in cardiac tissue may be mediated by A1R-induced generation of nitric oxide. This study examined the role of nitric oxide in the mediation of A1R-induced delayed preconditioning against infarction. Pharmacologic preconditioning of rabbits with the selective A1R agonist 2-chloro-N6-cyclopentyladenosine 100 microg/kg (CCPA) significantly reduced myocardial infarct size compared with control animals, after 30 min regional ischemia and 2 h reperfusion in vivo 24 h later (27.3+/-4.7 vs. 46.0+/-3.7%, respectively; p = 0.001). Nonselective inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (10 mg/kg) before administration of CCPA did not affect this infarct limitation at 24 h. Selective inhibition of inducible nitric oxide synthase before the prolonged ischemic insult on day 2, with two structurally independent inducible nitric oxide synthase inhibitors, L-N(6)-(1-iminoethyl)-lysine (10 mg/kg) or aminoguanidine (300 mg/kg), did not abrogate the reduction in infarction observed by pharmacologic preconditioning with CCPA 24 h earlier. These results suggest that the second window or delayed protection against myocardial infarction observed 24 h after pharmacologic preconditioning with an adenosine A1 agonist occurs independently of either early generation of nitric oxide or subacute induction of inducible nitric oxide synthase.
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PMID:Delayed or second window preconditioning induced by adenosine A1 receptor activation is independent of early generation of nitric oxide or late induction of inducible nitric oxide synthase. 1148 78

Pretreatment of the brain with sublethal ischemia has been reported to induce neuronal resistance to otherwise lethal ischemia, a phenomenon designated as ischemic tolerance. The protective mechanisms of the phenomenon are not known yet, however, recent experimental data suggest the involvement of adenosine receptor activation in the acquisition of tolerance. In this study, the effect of theophylline, a non-selective adenosine receptor antagonist, and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1 receptor antagonist, were investigated to ascertain if these drugs could cancel the protective effect of ischemic tolerance in the gerbil. DPCPX or theophylline was administered at 3 h after a short preconditioning ischemia, and 21 h later animals were subjected to lethal ischemia of 5 min duration. DPCPX at a dose of 1.0 mg/kg (i.p) and theophylline at a dose of 20 mg/kg (i.p) significantly reduced the protective effect of preconditioning in the CA1 hippocampal neurons. These findings suggest the involvement of adenosine receptor activation for the development of ischemic tolerance phenomenon.
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PMID:Adenosine receptor antagonists cancelled the ischemic tolerance phenomenon in gerbil. 1148 58

Myocardial A1 adenosine receptor (A1AR) overexpression protects hearts from ischemia-reperfusion injury; however, the effects during anoxia are unknown. We evaluated responses to anoxia-reoxygenation in wild-type (WT) and transgenic (Trans) hearts with approximately 200-fold overexpression of A1ARs. Langendorff perfused hearts underwent 20 min anoxia followed by 30 min reoxygenation. In WT hearts peak diastolic contracture during anoxia was 45+/-3 mmHg, diastolic pressure remained elevated at 18+/-3 mmHg after reoxygenation, and developed pressure recovered to 52+/-4% of pre-anoxia. A1AR overexpression reduced hypoxic contracture to 29+/-4 mmHg, and improved recovery of diastolic pressure to 8+/-1 mmHg and developed pressure to 76+/-3% of pre-anoxia. Mitochondrial K(ATP) blockade with 100 microM 5-hydroxydecanoate (5-HD) increased hypoxic contracture to 73+/-6 mmHg in WT hearts, reduced post-hypoxic recoveries of both diastolic (40+/-5 mmHg) and developed pressures (33+/-3 %). In contrast, 5-HD had no effect on hypoxic contracture (24+/-8 mmHg), or post-hypoxic diastolic (10+/-2 mmHg) and developed pressures (74+/-3%) in Trans hearts. In summary, (i) A1AR overexpression improves myocardial tolerance to anoxia-reoxygenation, (ii) intrinsic mitochondrial K(ATP) channel activation decreases hypoxic contracture and improves functional recovery in wild-type hearts, and (iii) mitochondrial K(ATP) channels do not appear to play a major role in the functional protection from anoxia afforded by A1AR overexpression.
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PMID:A1 adenosine receptor overexpression decreases stunning from anoxia-reoxygenation: role of the mitochondrial K(ATP) channel. 1206 93

Superfusion with an oxygen and glucose deprived medium (in vitro ischemia) of rat hippocampal CA1 pyramidal neurons in tissue slices produced a rapid depolarization within 5 min and thereafter showed no functional recovery (irreversible membrane dysfunction), even if oxygen and glucose were reintroduced. We previously suggested that such a rapid depolarization is triggered by the accumulation of extracellular glutamate (Glu). As a result, we examined the effects of either the activation or inhibition of presynaptic receptors, which modulate Glu release from the nerve terminal, on the potential change produced by in vitro ischemia. The adenosine A1 receptor antagonist, 8-cyclopenthyl theophylline, A2a receptor antagonist, ZM241385, and A2b receptor antagonist, alloxazine, did not significantly alter either the latency or the maximal slope of the rapid depolarization. In addition, the GABAB receptor antagonist, 2-hydroxysaclofen, or the metabotropic Glu receptor type 4 antagonist, alpha-methylserine-O-phosphate, did not change either the latency or the maximal slope. The adenosine A(1) receptor agonist, 2-chloro-N6-cyclopentyladenosine, A2a receptor agonist, CGS2168, or A2b receptor agonist, 5'-(N-ethylcarboxamido)-adenosine, did not affect these parameters either. None of these drugs restored the membrane potential to the pre-exposure level after the reintroduction of oxygen and glucose. Simultaneous intracellular recordings from CA1 and CA3 pyramidal neurons in the same slices revealed the membrane of the CA3 neurons to be hyperpolarized when a rapid depolarization occurred in the CA1 neurons. These results suggest that presynaptic Glu release does not accelerate during the generation of the rapid depolarization induced by in vitro ischemia.
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PMID:The presynaptic modulation of glutamate release and the membrane dysfunction induced by in vitro ischemia in rat hippocampal CA1 neurons. 1246 77

Spiny neurons in the neostriatum die within 24 hr after transient global ischemia, whereas large aspiny (LA) neurons remain intact. To reveal the mechanisms of such selective cell death after ischemia, excitatory neurotransmission was studied in LA neurons before and after ischemia. The intrastriatally evoked fast EPSCs in LA neurons were depressed < or =24 hr after ischemia. The concentration-response curves generated by application of exogenous glutamate in these neurons were approximately the same before and after ischemia. A train of five stimuli (100 Hz) induced progressively smaller EPSCs, but the proportion of decrease in EPSC amplitude at 4 hr after ischemia was significantly smaller compared with control and at 24 hr after ischemia. Parallel depression of NMDA receptor and AMPA receptor-mediated EPSCs was also observed after ischemia, supporting the involvement of presynaptic mechanisms. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the inhibition of evoked EPSCs at 4 hr after ischemia but not at 24 hr after ischemia. Electron microscopic studies demonstrated that the most presynaptic terminals in the striatum had a normal appearance at 4 hr after ischemia but showed degenerating signs at 24 hr after ischemia. These results indicated that the excitatory neurotransmission in LA neurons was depressed after ischemia via presynaptic mechanisms. The depression of EPSCs shortly after ischemia might be attributable to the enhanced adenosine A1 receptor function on synaptic transmission, and the depression at late time points might result from the degeneration of presynaptic terminals.
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PMID:Depression of fast excitatory synaptic transmission in large aspiny neurons of the neostriatum after transient forebrain ischemia. 1248 90

It is well established that in the CNS, endogenous adenosine plays a pivotal role in neurodegeneration. A low, nanomolar concentration of adenosine is normally present in the extracellular fluid, but it increases dramatically during enhanced nerve activity, hypoxia or ischemia. In these pathological conditions, adenosinergic transmission-potentiating agents, which elevate adenosine level by either inhibiting its degradation (adenosine deaminase and kinase inhibitors) or preventing its transport, offer protection against ischemic or excitotoxic neuronal damage. The directly acting adenosine A1 receptor agonists are known to mediate neuroprotection, mostly by the blockade of Ca2+ influx, which results in the inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. More recent data have shown that antagonists of adenosine A2A receptors markedly reduce cerebral ischemic damage in animal models of focal and global ischemia. Moreover, these compounds attenuate the neuronal loss induced by excitatory amino acids (EAA). A neuroprotective effect of adenosine A2A receptor antagonists was also shown in animal models of Parkinson's disease (MPTP, 6-OHDA, methamphetamine). Hence, it might be suggested that adenosine A2A receptor antagonists may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events, since they not only reverse motor impairment but can act as neuroprotective compunds by promoting cell survival.
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PMID:Neuroprotective role of adenosine in the CNS. 1252 85

Adenosine activates a signal transduction pathway (STP) in the heart and the brain, conferring protection against ischemia-reperfusion insult. Activation of protein kinase C (PKC), probably mainly PKC-epsilon, has been demonstrated to be part of the heart STP, but its role in the neuronal pathway is less clear. Here, we provide proof for the participation of PKC-epsilon in the neuronal adenosine-activated STP. Primary rat neuronal cultures were exposed to chemical ischemia by iodoacetate, followed by reperfusion. The cultured neurons were protected against this insult by activation of the adenosine mechanism, by N6-(R)-phenylisopropyladenosine [R(-)-PIA], a specific A1 adenosine receptor agonist. Exposure of the cultures to bisindolylmaleimide I, a highly selective PKC inhibitor, abrogated the protection. The exposure of the cultures to R(-)-PIA was found to result in phosphorylation (activation) of PKC-epsilon. Furthermore, insertion into the cells of a specific peptide inhibitor of PKC-epsilon translocation (epsilonV1-2), also abrogated the protection conferred by R(-)-PIA. These results demonstrate that activation of PKC-epsilon is a vital step in the neuronal adenosine-activated STP.
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PMID:Protein kinase C-epsilon is involved in the adenosine-activated signal transduction pathway conferring protection against ischemia-reperfusion injury in primary rat neuronal cultures. 1255 3

This study examined the hypothesis that the activation of A1 adenosine receptor (A1AR) induces delayed cellular protection (DCP) in porcine coronary smooth muscle cells (PCSMC). The following groups of cultured PCSMC, subjected to simulated ischemia (SI) at 20 h were studied: (a) SI: with ischemia alone; (b) A1AR agonist chloro-N6-cyclopentyl adenosine (CCPA: CCPA (1 microM) alone; (c) CCPA + PKC inhibitor chelerythrine chloride (CCL): CCPA and 1 microM CCL; (d) CCPA + iNOS inhibitor S-methylthiourea (SMT): CCPA and 100 nM SMT; (e) CCPA + KATP channel blocker Glibenclamide (Glb): CCPA and 50 microM Glb; (f) CCPA + mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD): CCPA and 100 microM of 5-HD; (g) CCPA + A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX): CCPA and 1 microM DPCPX. The release of LDH into the medium as well as the amount of LDH remaining in the cells was used as a marker of cellular injury and cell viability. Up-regulation of A1AR, epsilon-PKC, iNOS and HSP 72i was detected through Westem blot analysis. The cellular resistance (%LDH remaining in the cells) acquired by PCSMC due to CCPA (59.42 +/- 1.57) was significantly blocked by CCL: 39.30 +/- 2.03; SMT: 41.37 +/- 1.98; Glb: 47.24 +/- 1.31; 5-HD: 47.69 +/- 1.40 and DPCPX: 42.92 +/- 0.79. CCPA increased the expression of A1AR (1.30 fold), epsilon-PKC (1.20 fold), iNOS (1.50 fold), and HSP 72i (1.70 fold) compared to the controls. CCPA-induced up-regulation of A1AR, epsilon-PKC, iNOS, HSP 72i, and the opening of both mitochondrial and sarcolemmal KATP channels may possibly participate in signaling cascade. Our study suggests that A1AR activation up-regulates iNOS, HSP 72i via epsilon-PKC signaling pathway to activate both mitochondrial and sarcolemmal KATP channels for cellular protection against SI in the cultured PCSMC.
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PMID:Mechanisms of delayed preconditioning with A1 adenosine receptor activation in porcine coronary smooth muscle cells. 1259 31


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