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

We characterized the adenosine A1 receptor and the levels of its mRNA expression in the ventricles of 6- and 13-wk-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The binding of 2-chloro-[3H]cyclopentyladenosine ([3H]CCPA), an A1 agonist ligand, to ventricular membranes was saturable and reversible. The receptor density was significantly lower in SHR than in WKY at 13 wk. The dissociation constant values were not different among these groups. In Northern blot analysis using rat A1 receptor cDNA, levels of mRNA did not differ significantly in the two groups at 13 wk, but the level in SHR significantly exceeded that in WKY at 6 wk. Because plasma adenosine levels were reported to be increased at 13 wk in SHR and we found mRNA levels were similar at this age, the discrepancy between A1 receptor density and its mRNA levels might be related to the desensitization of A1 receptors. Although the implication of this decreased density of A1 receptors is not known, it may involve an increased susceptibility to ischemia.
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PMID:Adenosine A1 receptor and its gene expression in ventricles from spontaneously hypertensive rats. 885 94

Preconditioning with brief ischemia before a sustained period of ischemia reduces infarct size in the perfused heart. A cultured chick ventricular myocyte model was developed to investigate the role of adenosine receptor subtypes in cardiac preconditioning. Brief hypoxic exposure, termed preconditioning hypoxia, prior to prolonged hypoxia, protected myocytes against injury induced by the prolonged hypoxia. Activation of the adenosine A1 receptor with CCPA or the A3 receptor with C1-IB-MECA can replace preconditioning hypoxia and simulate preconditioning, with a maximal effect at 100 nM. While activation of the A2a receptor by 1 microM CGS21680 could not mimic preconditioning, its stimulation during preconditioning hypoxia, however, attenuated the protection against hypoxia-induced injury. Blockade of A2a receptors with the selective antagonist CSC (1 microM) during preconditioning hypoxia enhanced the protective effect of preconditioning. Nifedipine, which blocked the A2a receptor-mediated calcium entry, abolished the A2a agonist-induced attenuation of preconditioning. Isoproterenol, forskolin, and BayK 8644, which stimulated calcium entry, also attenuated preconditioning. Nifedipine blocked the increase in calcium uptake by these agents as well as their attenuating effect on preconditioning. The present study provides the first evidence that the adenosine A3 receptor is present on ventricular myocytes and can mediate simulation of preconditioning. The data demonstrate, for the first time, that activation of the A2a receptor antagonizes the preconditioning effect of adenosine, with increased calcium entry during the preconditioning stimuli as a novel mechanism.
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PMID:Direct preconditioning of cultured chick ventricular myocytes. Novel functions of cardiac adenosine A2a and A3 receptors. 887 27

Adenosine, synthesized by ecto-5'-nucleotidase, is cardioprotective against ischemia and reperfusion injury. We have previously reported that activation of protein kinase C increases ecto-5'-nucleotidase activity of the rat cardiomyocytes, raising the possibility that activation of protein kinase C protects cardiomyocytes from the irreversible cellular injury via activation of ecto-5'-nucleotidase. To test this hypothesis, cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode buffer solution. The cardiomyocytes were incubated with and without exposure to methoxamine (1 x 10(-6) mol/l) or phorbol 12-myristate 13-acetate (PMA. 1 x 10(-8) mol/l). Ecto-5'-nucleotidase activity increased 15 min after the onset of an exposure to either methoxamine or PMA. Adenosine release during hypoxia and reperfusion was augmented in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated cardiomyocytes, which was inhibited by alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase. Irreversible cellular injury assessed by the extent of release of lactate dehydrogenase and the trypan blue exclusion test following 60 min of hypoxia and 60 min of reoxygenation was attenuated in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated group, which was also blunted by AOPCP and 8-sulfophenyltheophylline, an adenosine receptor antagonist. An adenosine A1 receptor agonist, N6-cyclohexyladenosine, restored the cardioprotection under the treatment with PMA and AOPCP. We conclude that activation of ecto-5'-nucleotidase via protein kinase C contributes to the attenuation of the irreversible injury of the rat cardiomyocytes due to hypoxia and reoxygenation.
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PMID:Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes. 889 53

Prior studies have shown that sublethal anoxic/ischemic insults may "precondition" and thereby protect tissues such as heart and brain from subsequent insults. In hippocampal slices, we examined two hypotheses: (i) that anoxic preconditioning improves the ability of slices to recover synaptic activity following a second anoxic insult and (ii) that anoxic preconditioning involves adenosine receptors. Hippocampal slices were preconditioned by short periods of anoxia prolonged only until the onset of anoxic depolarization. The slices were then reoxygenated for 30 min, after which a second ("test") anoxic insult was induced. Amplitudes of evoked potentials recovered significantly better after "test" anoxic insults in preconditioned slices. In control slices, transient superfusion with adenosine or an adenosine A1 receptor agonist (2-chloroadenosine) 30 min prior to "test" anoxia markedly improved evoked potential recovery. Administration of 8-cyclopentyl-1,3-dipropylxanthine, an A1 receptor antagonist, blocked the protection afforded by preconditioning. These data support the hypothesis that adenosine, probably by its activation of A1 receptors, is involved in the neuroprotection afforded by anoxic preconditioning in hippocampal slices. Preconditioning insults may have a significant clinical impact, since certain surgical procedures may require, or produce, multiple periods of brain ischemia.
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PMID:Anoxic preconditioning in hippocampal slices: role of adenosine. 895 65

Although adenosine receptor-based treatment of cerebral ischemia and other neurodegenerative disorders has been frequently advocated, cardiovascular side effects and an uncertain therapeutic time window of such treatment have constituted major obstacles to clinical implementation. Therefore, we have investigated the neuroprotective effects of the adenosine A1 receptor agonist adenosine amine congener (ADAC) injected after either 5 or 10 min ischemia at 100 micrograms/kg. When the drug was administered at either 6 or 12 h following 5 min forebrain ischemia, all animals were still alive on the 14th day after the occlusion. In both ADAC treated groups neuronal survival was approximately 85% vs. 50% in controls. Administration of a single dose of ADAC at times 15 min to 12 h after 10 min ischemia resulted in a significant improvement of survival in animals injected either at 15 or 30 min, or at 1, 2, or 3 h after the insult. In all 10 min ischemia groups, administration of ADAC resulted in a significant protection of neuronal morphology and preservation of microtubule associated protein 2 (MAP-2). However, postischemic Morris' water maze tests revealed full preservation of spatial memory and learning ability in animals injected at 6 h. On the other hand, the performance of gerbils treated at 12 h postischemia was indistinguishable from that of the controls. Administration of ADAC at 100 micrograms/kg in non-ischemic animals did not result in bradycardia, hypotension, or hypothermia. The data indicate that when ADAC is used postischemically, the most optimal level of protection is obtained when drugs are given at 30 min to 6 h after the insult. Although the mechanisms involved in neuroprotective effects of adenosine A1 receptor agonists require further studies, the present results demonstrate the feasibility of their clinical applications.
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PMID:Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils. 898 84

The adenosine A3 receptor is expressed in brain, but the consequences of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A3 receptor agonist, 2-chloro-N6-(3-lodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA), and a selective A3 receptor antagonist, 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices from rat hippocampus. In the CA1 region, activation of A3 receptors had no direct effects on synaptically evoked excitatory responses, long-term potentiation, or synaptic facilitation. However, activation of A3 receptors with Cl-IB-MECA antagonized the adenosine A1 receptor-mediated inhibition of excitatory neurotransmission. The effects of Cl-IB-MECA were blocked by pretreatment with MRS 1191, which by itself had no effect on A1 receptor-mediated responses. The presynaptic inhibitory effects of baclofen and carbachol, mediated via GABA(B) and muscarinic receptors, respectively, were unaffected by Cl-IB-MECA. The maximal response to adenosine was unchanged, suggesting that the primary effect of Cl-IB-MECA was to reduce the affinity of adenosine for the receptor rather than to uncouple it. Similar effects could be demonstrated after brief superfusion with high concentrations of adenosine itself. Under normal conditions, endogenous adenosine in brain is unlikely to affect the sensitivity of A1 receptors via this mechanism. However, when brain concentrations of adenosine are elevated (e.g., during hypoxia, ischemia, or seizures), activation of A3 receptors and subsequent heterologous desensitization of A1 receptors could occur, which might limit the cerebroprotective effects of adenosine under these conditions.
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PMID:Activation of hippocampal adenosine A3 receptors produces a desensitization of A1 receptor-mediated responses in rat hippocampus. 898 83

Despite significant progress in understanding of the potential of adenosine A1 receptor-based therapies in treatment of cerebral ischemia and stroke, very little is known about the effect of selective stimulation of adenosine A2A receptors on the outcome of a cerebrovascular arrest. In view of a major role played by adenosine A2 receptors in the regulation of cerebral blood flow, we have investigated the effect of both acute and chronic administration of the selective adenosine receptor agonist 2-[(2-aminoethylamino)-carbonylethylphenylethylamino]-5'-N- ethylcarboxoamidoadenosine (APEC) and antagonist 8-(3-chlorostyryl)caffeine (CSC) on the outcome of 10 min ischemia in gerbils. Acute treatment with APEC improved recovery of postischemic blood flow and survival without affecting neuronal preservation in the hippocampus. Acute treatment with CSC had no effect on the cerebral blood flow but resulted in a very significant protection of hippocampal neurons. Significant improvement of survival was present during the initial 10 days postischemia. Due to subsequent deaths of animals treated acutely with CSC, the end-point mortality (14 days postischemia) in this group did not differ statistically from that seen in the controls. It is, however, possible that the late mortality in the acute CSC group was caused by the systemic effects of brain ischemia that are not subject to the treatment with this drug. Chronic treatment with APEC resulted in a statistically significant improvement in all studied measures. Although chronic treatment with CSC improved postischemic blood flow, its effect on neuronal preservation was minimal and statistically insignificant. Mortality remained unaffected. The results indicate that the acute treatment with adenosine A2A receptor antagonists may have a limited value in treatment of global ischemia. However, since administered CSC has no effect on the reestablishment of postischemic blood flow, treatment of stroke with adenosine A2A receptor antagonists may not be advisable. Additional studies are necessary to elucidate whether chronically administered drugs acting at adenosine A2 receptors may be useful in treatment of stroke and other neurodegenerative disorders.
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PMID:Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist. 899 4

Primary rat neuronal cultures can be preconditioned against ischemic damage by several mechanisms. In the present study we established a new model system in order to characterize the "time window of protection' obtained by preconditioning of neurons with adenosine. Ischemia was simulated by exposure of the cultures to iodoacetate (100 microM) for 150 min, with a post-ischemic reperfusion period of 60 min. Ischemic injury was assessed by the release of lactic dehydrogenase (LDH) to the medium during the ischemic period and ischemia-reperfusion damage by the Trypan blue exclusion test. Exposure of the neuronal cultures to the ischemic or ischemia-reperfusion insult resulted in severe damage to the neurons, manifested for the former insult in a 5.4-fold increase in the release of LDH and for the latter insult in an 8.5-fold increase in the proportion of stained cells by the Trypan blue exclusion test. Preconditioning by short exposure (5 min) of the cultures to iodoacetic acid (simulating sublethal ischemia), or to adenosine (1 mM) and the A1 adenosine receptor agonist N6-(R)-phenylisopropyladenosine (R-PIA; 1 and 100 microM), prior to the insult, partially protected the neurons against the damage. The time-course of the development and waning of the resistance against the two insults following preconditioning exhibited different patterns. The resistance obtained against the ischemic insult developed rapidly, being maximal for all substances at 10 min (the shortest time window studied), and lasted up to 1 h for iodoacetate, 3 h for R-PIA and 24 h for adenosine. In contrast, the protection induced by adenosine and R-PIA against ischemia-reperfusion injury developed relatively slowly, being maximal at 3 h, but lasted longer, up to 48 h. At this time the time-response curve exhibited a second peak of protection. The waning of protection against the two insults was found to continue into a period of increased sensitivity to the insults. This phenomenon was more intense for preconditioning with iodoacetate, and especially against the ischemic injury. The results suggest that in the neurons, different mechanisms may mediate the adenosine-induced preconditioning against the ischemic or ischemia-reperfusion injury. In addition, the results support the possibility that the relatively long "time window of protection', induced by adenosine and R-PIA against ischemia-reperfusion insult, reflects a combination of two different preconditioning mechanisms.
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PMID:Preconditioning of primary rat neuronal cultures against ischemic injury: characterization of the "time window of protection'. 900 30

There has been controversy regarding whether ATP-sensitive potassium channel activation protects hearts through adenosine A1 receptor activation or the converse. We addressed this issue by determining the effect of the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) on the cardioprotective activity of the ATP-sensitive potassium channel opener bimakalim. In isolated rat hearts subjected to 25 min of global ischemia and 30 min of reperfusion, bimakalim significantly reduced lactate dehydrogenase release and improved postischemic recovery of contractile function. Bimakalim increased the time to the onset of ischemic contracture (EC25 = 1.2 microM), compared with vehicle, and 10 microM DPCPX had no effect on this protective action (EC25 = 1.1 microM). The 10 microM concentration of DPCPX was sufficient to abolish the bradycardic and cardioprotective effects of the adenosine A1 receptor agonist (R)-(-)-N6-(2-phenylisopropyl)adenosine. DPCPX alone had no effect on the severity of ischemia/reperfusion damage. Glyburide completely abolished the cardioprotective effects of bimakalim. Bimakalim (1 microg/kg, intracoronarily) given over four periods of 5 min, interspersed with 10-min drug-free periods, before a 60-min occlusion and 3-hr reperfusion significantly reduced infarction size in anesthetized dogs (25 +/- 5 and 8 +/- 2% of the left ventricular area at risk for vehicle- and bimakalim-treated groups, respectively). DPCPX had no effect on the infarction-sparing activity of bimakalim (9 +/- 3% of the left ventricular area at risk). The protective effect of bimakalim was not accompanied by marked hemodynamic changes or by changes in regional myocardial blood flow. The results of this study suggest that the cardioprotective effects of ATP-sensitive potassium channel openers are not dependent on adenosine A1 receptor activation in rat or dog models of ischemia.
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PMID:Adenosine A1 receptor blockade does not abolish the cardioprotective effects of the adenosine triphosphate-sensitive potassium channel opener bimakalim. 902 61

We have studied the electrophysiological effects of glucose deprivation on morphologically identified striatal neurons recorded from a corticostriatal slice preparation. The large majority of the recorded cells were spiny neurons and responded to aglycemia with a slow membrane depolarization coupled with a reduction of the input resistance. In voltage-clamp experiments aglycemia caused an inward current. This current was associated with a conductance increase and reversed at -40 mV. The aglycemia-induced membrane depolarization was not affected by tetrodotoxin (TTX) or 6-cyano-7-nitroquinoxaline-2,3-dione plus aminophosphonovalerate, antagonists acting respectively on AMPA and NMDA glutamate receptors. Also, the intracellular injection of bis(2-aminophenoxy)ethane-N,N, N',N'-tetra-acetic acid, a calcium (Ca2+) chelator, and low Ca2+/high Mg2+-containing solutions failed to reduce this phenomenon. Conversely, it was reduced by lowering external sodium (Na+) concentration. A minority of the recorded cells had the morphological characteristics of large aspiny interneurons and the electrophysiological properties of "long-lasting afterhyperpolarization (LA) cells." These cells responded to aglycemia with a membrane hyperpolarization/outward current that was coupled with an increased conductance. This current was not altered by TTX, blockers of ATP-dependent potassium (K+) channels, and adenosine A1 receptor antagonists, whereas it was reduced by solutions containing low Ca2+/high Mg2+. This current reversed at -105 mV and was blocked by barium, suggesting the involvement of a K+ conductance. We suggest that the opposite membrane responses of striatal neuronal subtypes to glucose deprivation might account for their differential neuronal vulnerability to aglycemia and ischemia.
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PMID:Opposite membrane potential changes induced by glucose deprivation in striatal spiny neurons and in large aspiny interneurons. 904 23


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