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

We investigated the ability of N6-cyclohexyladenosine (CHA), a potent and selective agonist of the adenosine A1 receptor, to attenuate elevations of levels of extracellular hippocampal glutamate and glycine that result from episodes of transient global cerebral ischemia (TGCI). A total of 30 New Zealand white rabbits were randomly assigned to receive 0 (n = 5), 0.1 (n = 8), 1.0 (n = 6), 10 (n = 6), or 100 (n = 5) microM CHA. The drug was dissolved in artificial CSF (vehicle) and administered via a microdialysis probe placed stereotactically into the dorsal hippocampus. A second microdialysis probe placed into the contralateral hippocampus of each animal was perfused with vehicle alone. Ten minutes of TGCI was induced by neck tourniquet inflation and deliberate hypotension from 0 to 10 min. Microdialysis samples were collected as follows: every 20 min preischemia (at -80, -60, -40, -20, and 0 min); every 5 min during ischemia and in the immediate reperfusion period (at 5, 10, 15, and 20 min); and every 20 min for the remainder of the reperfusion period (at 40, 60, and 80 min). Samples were then analyzed for their concentration of glutamate and glycine by HPLC. Following 10 min of ischemia, glutamate levels increased to a peak of 3.28 +/- 0.55 times baseline and returned to preischemic levels by 40 min, i.e., during reperfusion. Glycine concentrations increased to 5.41 +/- 0.91 times over baseline and remained elevated for the duration of the study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of cyclohexyladenosine on the periischemic increases of hippocampal glutamate and glycine in the rabbit. 135 2

We examined the anti-infarct effect of ischemic preconditioning in the rat heart. All hearts were subjected to 30 min of regional coronary ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium. The control group had an average infarct size of 31% of the risk zone. Three 5-min cycles of preconditioning ischemia limited the infarct size to 3.7%. Neither the adenosine receptor blocker PD 115,199 nor the ATP-sensitive potassium channel blocker, glibenclamide, could block this protection. Intracoronary adenosine A1-receptor agonist 2-chloro-N6-cyclopentyladenosine offered a significant anti-infarct protection to the isolated rat heart, however. Although one 5-min cycle of preconditioning did not protect the rat heart from infarction (31% infarction in risk zone), it did attenuate arrhythmias. We conclude that 1) the rat heart can be preconditioned, which argues against mitochondrial adenosinetriphosphatase being the mechanism of preconditioning; 2) the threshold for preconditioning is higher in rat than rabbit or dog; 3) a role for adenosine in preconditioning was only partially supported; and 4) a role for ATP-sensitive potassium channels was not supported.
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PMID:Ischemic preconditioning protects against infarction in rat heart. 141 59

The effects of adenosine in the nonischemic heart have been shown to be mediated via its binding to extracellular adenosine A1 and A2 receptors located predominantly on myocytes and endothelial cells, respectively. We tested the hypothesis that the beneficial effect of adenosine on postischemic myocardial function is mediated via an adenosine A1 receptor mechanism. Isolated rat hearts perfused at constant pressure (85 cmH2O) were subjected to 30 min of global no-flow ischemia (37 degrees C) and 45 min of reperfusion. Hearts treated with adenosine (100 microM) and the adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA; 0.25 microM) recovered 72 +/- 4 and 70 +/- 4% of preischemic left ventricular developed pressures (LVDP), respectively, after 45 min of reperfusion compared with untreated hearts (54 +/- 3% of preischemic LVDP). Adenosine and CHA hearts exhibited greater myocardial ATP contents than control hearts after 10 min of ischemia, but there were no differences in tissue ATP levels after 30 min of ischemia. In contrast, hearts treated with the adenosine A2 receptor agonist phenylaminoadenosine (0.25 microM) failed to demonstrate improved postischemic function (52 +/- 5%). The addition of the A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the cardioprotective effect of adenosine (57 +/- 4%). These results suggest that adenosine enhances postischemic myocardial function via an A1 receptor mechanism.
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PMID:Adenosine improves recovery of postischemic myocardial function via an adenosine A1 receptor mechanism. 144 99

Recent experimental data indicate a probable role of adenosine as an endogenous neuroprotective substance in brain ischemia. This nucleoside is rapidly formed during ischemia as a result of intracellular breakdown of ATP and it is subsequently transported into the extracellular space. With use of microdialysis and other techniques, a massive increase of interstitial adenosine has been measured during ischemia in different brain areas. Adenosine acts through two subtypes of receptors, A1 and A2, which are located on neurons, glial cells, blood vessels, platelets, and leukocytes and are linked via G-proteins to different effector systems such as adenylate cyclase and membrane ion channels. There is a very high density of A1-receptors in the hippocampus, an area with specific vulnerability to ischemia. In different in vivo and in vitro models of brain ischemia, the pharmacological manipulation of the adenosine system by adenosine receptor antagonists tended to aggravate ischemic brain damage, whereas the reinforcement of adenosine action by receptor agonists or inhibitors of cellular reuptake and inactivation showed neuroprotection. The up-regulation of adenosine A1-receptor number and affinity by chronic preadministration of the competitive antagonist caffeine also attenuated ischemic brain damage. The mechanisms underlying the neuroprotective effects of adenosine seem to involve both types of adenosine receptors, A1 and A2, but the A1-mediated pre- and postsynaptic neuromodulation may be of special importance. By inhibiting neuronal Ca2+ influx, adenosine counteracts the presynaptic release of the potentially excitotoxic neurotransmitters glutamate and aspartate, which may impair intracellular Ca2+ homeostasis via metabotrophic glutamate receptors or induce uncontrolled membrane depolarization via ion channel-linked glutamate receptors, especially of the N-methyl-D-aspartate (NMDA) type. In addition, adenosine directly stabilizes the neuronal membrane potential by increasing the conductance for K+ and Cl- ions, thereby counteracting excessive membrane depolarization. The latter triggers a number of pathological events including blockade of voltage-sensitive K+ currents, increase of NMDA receptor-mediated Ca2+ influx, and presumably also impairment of glutamate uptake by astrocytes. In the way of a vicious cycle, all these factors again tend to enhance extracellular glutamate levels and membrane depolarization, finally leading to cytotoxic calcium loading and neuronal cell death. In addition to its important neuromodulatory effects, which tend to reduce energy demand of the brain, adenosine acting via A2-receptors in brain vessels, platelets, and neutrophilic granulocytes may improve the cerebral microcirculation and thus oxygen and substrate supply to the tissue. There is evidence that the functional state of adenosine receptors is impaired during ischemia, limiting the time window of the adenosine action.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Adenosine and brain ischemia. 148 19

Recent studies have demonstrated that measurement of peripheral type benzodiazepine binding sites (PTBBS) levels may be useful as an index for quantification of neuronal damage. In the present study, we investigated the accuracy of this index as a marker of neuronal damage induced by transient forebrain ischemia in the rat (4-vessel occlusion model). Seven days after ischemia, a good correlation was found between the increase of PTBBS levels (measured using [3H]PK 11195 as a specific radioligand) in hippocampal, striatal and cortical homogenates and the duration of ischemia. The progression of PTBBS increase was examined from 3 h to 14 days of recirculation. Increase in the maximal number of binding sites (Bmax) rather than an effect on the affinity (KD) for the radioligand was found in the 3 brain regions. Treatment of the animals with 1,3 butanediol (BD) prior to ischemia resulted in a neuroprotective effect as assessed by an improved neurological score and histological studies. The protective effect of BD was also correlated with a reduced expression of PTBBS as compared to ischemic animals not treated with the drug. No protective effects, on neurological score or PTBBS level were afforded by MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, R-phenylisopropyladenosine (RPIA), an adenosine A1 receptor agonist, or BN 52021, an antagonist of platelet-activating factor (PAF). These results suggest that PTBBS provide a useful marker of neuronal damage in a transient forebrain ischemia model and confirm the beneficial effect on ischemic damage exerted by BD.
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PMID:Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: effect of neuroprotective drugs. 166 14

The purpose of this study was to determine if the cardioprotective effect of adenosine on the ischemic myocardium is mediated by interaction with specific adenosine receptor subtypes. Isolated rat hearts perfused at constant flow were subjected to global normothermic (37 degrees C) ischemia and the time to onset of ischemic contracture (TOIC) was used as a marker of myocardial ischemic injury. Hearts treated with adenosine and R-phenylisopropyladenosine (PIA), an adenosine A1 receptor agonist, exhibited a significantly greater TOIC than control hearts (18.60 +/- 0.40 and 16.64 +/- 1.15 min, respectively vs 9.12 +/- 0.66 min), whereas phenylaminoadenosine, an adenosine A2 receptor agonist, had no effect on TOIC (11.73 +/- 0.87 min). BW A1433U, an adenosine receptor antagonist, blocked the effects of adenosine and PIA on ischemic contracture time, and BW A1433U did not alter the ability of nifedipine or propranolol to delay the onset of ischemic contracture, thus indicating the specificity of this compound for the adenosine receptor. PIA-treated hearts exhibited significantly greater ATP levels throughout the ischemic period compared to control hearts, whereas hearts treated with BW A1433U showed a rapid decline in ATP content. These results suggest that the beneficial effects of adenosine on the ischemic myocardium are mediated by interaction with adenosine A1 receptors, and that endogenously formed adenosine plays a role in attenuating myocardial ischemic damage.
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PMID:Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart. 232 32

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

To assess the efficacy of the newly synthesized selective adenosine A1 receptor agonist, BN-063 (1-cyclopropylisoguanosine), against myocardial reperfusion injury, 31 rats underwent 45 min of left coronary artery occlusion and 1 h of reperfusion. Animals were randomly assigned to four groups: control, I0.5-R0.5, in which BN-063 (0.5 mg/kg i.v. bolus) was administered during both ischemia and reperfusion, R-0.5 and R-1.0, in which BN-063 was administered only during reperfusion at 0.5 and 1.0 mg/kg, respectively. The area at risk was determined by intravascular injection of blue dye during coronary artery occlusion, which was performed by retightening the ligature at the end of reperfusion, and infarct size was determined by incubation of heart slices in nitro blue tetrazolium chloride. A significant reduction in infarct size, as a percentage of the area at risk, was noted with all three BN-063 treatment groups (control: 63.5 +/- 4.0%, I0.5-R0.5: 39.6 +/- 3.7%, R-0.5: 37.5 +/- 3.5%, R-1.0: 38.1 +/- 5.2%). However, the I0.5-R0.5 group did not shown a more beneficial effect than the other two BN-063-treated groups. In addition, BN-063 exerted a protective effect on the number of ventricular premature contractions associated with reperfusion (control: 906 +/- 52, I0.5-R0.5: 325 +/- 61, R-0.5: 321 +/- 95, R-1.0: 340 +/- 46). The results of this study demonstrate that BN-063, through activation of adenosine A1 receptors, exerts antiarrhythmic and anti-infarct effects during myocardial ischemia-reperfusion. Therefore, BN-063 would be useful clinically in the treatment and prevention of acute myocardial infarction.
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PMID:BN-063, a newly synthesized adenosine A1 receptor agonist, attenuates myocardial reperfusion injury in rats. 755 8

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

Ischemia-reperfusion (I-R) injury of the lung occurs after lung transplantation, pulmonary thromboembolectomy, or cardiopulmonary bypass. In the heart, adenosine, A1 adenosine receptor agonists, and a brief period of preconditioning ischemia attenuate I-R injury. Moreover, in the lung, thromboxane is released during ischemia and is an important mediator of I-R injury. We previously reported that adenosine produces vasoconstriction in the feline pulmonary vascular bed by acting on A1 receptors to induce the release of thromboxane and that these vasoconstrictor responses are desensitized by low doses of A1 receptor agonists. Because A1 receptor agonists mimic the effect of preconditioning ischemia, we hypothesized, in contrast to previously proposed mechanisms, that small amounts of adenosine released during preconditioning ischemia desensitize A1 receptors. Also, we hypothesized that greater amounts of adenosine are released after longer periods of ischemia, which activate A1 receptors. Thus if desensitization of A1 receptors is the mechanism by which preconditioning attenuates I-R injury of the heart and A1 receptor activation during ischemia plays an important role in I-R injury of the lung, A1 receptor antagonists should provide a protective effect in I-R injury of the lung. In this study, 2 h of ischemia and 2 h of reperfusion of the left lower lobe in intact-chest, spontaneously breathing cats caused lung injury characterized by the presence of neutrophils, macrophages, and RBCs in alveoli and caused alveolar edema, which was blocked in a highly significant manner by the A1 receptor antagonists xanthine amine congener (XAC) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). An intralobar arterial infusion of XAC (30 min before ischemia) reduced the %injured alveoli (defined as presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 60 +/- 10 to 7 +/- 2%, which was not significantly different from controls (5 +/- 1%; P < 0.0001). DPCPX (iv) reduced the %injured alveoli to 13 +/- 7% when administered 30 min before ischemia and to 6 +/- 2% when administered after 1 h of reperfusion, not significantly different from controls (P < 0.0001). Preconditioning ischemia (10-min ischemia +10-min reperfusion) also reduced the %injured alveoli after 2 h ischemia and 2 h reperfusion to 23 +/- 13%, almost identical to 2 h ischemia and 1 h reperfusion. These data support the hypothesis that A1 receptor antagonists block I-R injury of the lung. A1 receptor antagonists may be useful in preventing I-R injury after transplant surgery and during surgical procedures associated with I-R injury of the heart, brain, kidney, and spinal cord.
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PMID:A1 adenosine receptor antagonists block ischemia-reperfusion injury of the lung. 761 26


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