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

The studies reported in this article provide evidence that several complex mechanisms are involved in the ability of dopexamine HCl (DPX) in preventing ischemia-reperfusion induced organ damage. In a canine model of hemorrhagic shock in which shed-blood was reinfused, DPX prevented deterioration in renal blood flow via an action on beta-2 and DA-1 receptors, whereas its ability to preserve tubular function was essentially due its agonistic effects on DA-1 receptors. In a different experimental model in anesthetized rats, acute generation of oxygen free radicals (OFR) via intravenous administration of Xanthine (X) followed by Xanthine Oxidase (XO) resulted in depression of circulation and death of more than 80% of the animals within the observation period of 120 min. Pretreatment of the rats with DPX significantly enhanced survival rate in a dose dependent manner to about 70%. Neither dobutamine nor prenalterol, which are beta-1 adrenoceptor agonists and like DPX, potent chronotropic and inotropic agents were effective in preventing OFR induced lethal toxicity. In a separate series, a selective DA-1 receptor agonist felodopam had no protective effect and a DA-1 receptor antagonist SCH-23390 failed to antagonize the salutary effects of DPX. In contrast, salbutamol, a selective beta-2 adrenoceptor agonist significantly promoted the survival rate facilitated by DPX and a selective beta-2 adrenoceptor antagonist, ICI-558,551 significantly attenuated the survival rate. These later studies suggest that unlike in hemorrhagic shock, the beta-2 adrenoceptor agonistic properties are critical in the ability of DPX to attenuate lethal toxicity and these effects could be related to prevention of lipid peroxidation induced by oxygen free radicals.
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PMID:Efficacy and mechanisms of dopexamine in the prevention of ischemia-reperfusion induced organ damage: role of oxygen free radicals. 902 45

The effects of nonselective (theophylline), A1-(DPCPX) or A2A-selective (SCH 58261) adenosine receptor antagonists administered before or after neonatal hypoxia-ischemia (HI) were studied on the extent of brain injury in 7-day-old rats evaluated after 14 days. A possible effect of theophylline (20 mg/kg) on expression of immediate early genes was studied with in situ hybridization. Theophylline (20, 30 or 60 mg/kg) given prior to HI reduced brain damage by 48% (P < 0.001), 36% (P < 0.01) and 34% (P < 0.05), respectively, compared to control rats. This effect was not explained by changes in temperature, cerebral blood flow, blood gas/acid base status or blood glucose during the insult. Theophylline enhanced the upregulation of c-fos and NFGI-A during reperfusion but did not prevent the decrease in adenosine A1 receptor mRNA. Posttreatment with SCH 58261 (0.2 or 2 mg/kg) reduced brain damage by 19% (P < 0.05) and 14% (NS), respectively, compared to control rats which was unrelated to the core temperature. DPCPX (2 or 10 mg/kg) had no effect on the development of brain injury. In conclusion, nonselective and A2A adenosine receptor antagonists reduced brain injury in a model of HI in immature animals.
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PMID:Neonatal cerebral hypoxia-ischemia: the effect of adenosine receptor antagonists. 936 88

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.
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PMID:Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia. 971 65

Adenosine A(2A) receptor antagonists have been proved protective in different ischemia models. In this study we verified if the protective effect of the selective A(2A) antagonist, SCH 58261, could be attributed to the reduction of the excitatory amino acid outflow induced by cerebral focal ischemia. A vertical microdialysis probe was inserted into the striatum of male Wistar rats and, after 24 h, permanent right intraluminal middle cerebral artery occlusion (MCAo) was induced. Soon after waking, rats showed a definite contralateral turning behavior, which persisted up to 7 h after MCAo. During 4 h after MCAo, glutamate, aspartate, GABA, adenosine and taurine outflow increased. SCH 58261 (0.01 mg/kg, i.p.), administered 5 min after MCAo, suppressed turning behavior and significantly reduced the outflow of glutamate, aspartate, GABA and adenosine. At 24 h after MCAo, the rats showed severe sensorimotor deficit and damage in both the striatum and cortex. SCH 58261 significantly reduced cortical damage but did not protect against the sensorimotor deficit. The protective effect of SCH 58261 against turning behavior and increased outflow of excitatory amino acids in the first hours after MCAo suggests the potential utility of selective adenosine A(2A) antagonists when administered in the first hours after ischemia. Furthermore, this study, for the first time, proposes that turning behavior after permanent intraluminal MCAo, be used as a precocious index of neurological deficit and neuronal damage.
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PMID:The selective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. 1249 12

Adenosine released during cerebral ischemia is considered to act as a neuroprotectant, possibly through the inhibition of glutamate release. The involvement of A(1) and A(2A) receptors in the control of the rise of extracellular glutamate during ischemia was investigated by monitoring the effects of selective A(1) and A(2A) receptor antagonists on ischemia-evoked glutamate release in rat cerebrocortical slices.Slices were superfused with oxygen- and glucose-deprived medium and [(3)H]D-aspartate or endogenous glutamate was measured in the superfusate fractions. Withdrawal of Ca(2+) ions or addition of tetrodotoxin more than halved the ischemia-evoked efflux of [(3)H]D-aspartate or glutamate, compatible with a vesicular-like release. The glutamate transporter inhibitor DL-TBOA prevented the ischemia-evoked efflux of [(3)H]D-aspartate by about 40%, indicating a carrier-mediated efflux. The ischemia-evoked efflux of [(3)H]D-aspartate or glutamate was increased by the A(1) receptor antagonist DPCPX. The A(2A) antagonist SCH 58261 decreased [(3)H]D-aspartate or endogenous glutamate efflux (50 and 55% maximal inhibitions; EC(50): 14.9 and 7.6 nM, respectively); the drug was effective also if added during ischemia. No effect of either the A(1) or the A(2A) receptor antagonist was found on the ischemia-evoked efflux of [(3)H]D-aspartate in Ca(2+)-free medium. Our data suggest that adenosine released during cerebral ischemia can activate inhibitory A(1) and stimulatory A(2A) receptors that down- or up-regulate the vesicular-like component of glutamate release.
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PMID:Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. 1284 26

Glutamate extracellular accumulation is an early event in brain ischemia triggering excitotoxic neuron damage. We have investigated how to control the glutamate efflux from human cerebrocortical slices superfused in conditions simulating an acute ischemic insult (oxygen and glucose deprivation). The efflux of previously accumulated [3H]D-aspartate or endogenous glutamate increased starting 18 min after exposure to ischemia and returned almost to basal values in 6 min reperfusion with standard medium. Superfusion with Ca2+-free, EGTA (0.5 mM)-containing medium or with medium containing tetrodotoxin (TTX; 0.5 microM) inhibited the ischemia (24 min)-evoked [3H]D-aspartate efflux by about 50% and 65%, respectively. The ischemia (24 or 36 min)-evoked efflux of [3H]D-aspartate or endogenous glutamate was reduced at least 40% by the adenosine A(2A) receptor antagonist SCH 58261 (1 microM); the compound was effective when added up to 15 min after exposure to ischemia. No effect of SCH 58261 on the ischemia-evoked [3H]D-aspartate was found in Ca2+-free, EGTA-containing medium. To conclude, a significant component of the ischemia-evoked glutamate efflux in human cerebrocortical slices seems to occur by a vesicular-like mechanism. Endogenously released adenosine is likely to activate A(2A) receptors that enhance vesicular-like glutamate release during ischemia; A(2A) receptor antagonists would deserve consideration for their neuroprotective potential.
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PMID:Glutamate efflux from human cerebrocortical slices during ischemia: vesicular-like mode of glutamate release and sensitivity to A(2A) adenosine receptor blockade. 1552 22

Ischemia/reperfusion injury during liver transplantation is a major cause of primary nonfunctioning graft for which there is no effective treatment other than retransplantation. Adenosine prevents ischemia-reperfusion-induced hepatic injury via its A2A receptors. The aim of this study was to investigate the role of A2A receptor agonist on apoptotic ischemia/reperfusion-induced hepatic injury in rats. Isolated rat livers within University of Wisconsin solution were randomly divided into four groups: (1) continuous perfusion of Krebs-Henseleit solution through the portal vein for 165 minutes (control); (2) 30-minute perfusion followed by 120 minutes of ischemia and 15 minutes of reperfusion; (3) like group 2, but with the administration of CGS 21680, an A2A receptor agonist, 30 microg/100 ml, for 1 minute before ischemia; (4) like group 3, but with administration of SCH 58261, an A2A receptor antagonist. Serum liver enzyme levels were measured by biochemical analysis, and intrahepatic caspase-3 activity was measured by fluorometric assay; apoptotic cells were identified by morphological criteria, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorometric assay, and immunohistochemistry for caspase-3. Results showed that at 1 minute of reperfusion, there was a statistically significant reduction in liver enzyme levels in the animals pretreated with CGS (p < 0.05). On fluorometric assay, caspase-3 activity was significantly decreased in group 3 compared to group 2 (p < 0.0002). The reduction in postischemic apoptotic hepatic injury in the CGS-treated group was confirmed morphologically, by the significantly fewer apoptotic hepatocyte cells detected (p < 0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (p < 0.05); and by the TUNEL assay (p < 0.05). In conclusion, the administration of A2A receptor agonist before induction of ischemia can attenuate postischemic apoptotic hepatic injury and thereby minimize liver injury. Apoptotic hepatic injury seems to be mediated through caspase-3 activity.
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PMID:Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver. 1615 31

We investigated the protective effect of subchronic treatment of the A2A receptor antagonist, SCH 58261 (0.01 mg/kg, i.p.), administered 5 min, 6 h and 15 h after permanent right middle cerebral artery occlusion (MCAo). Twenty-four hours after ischemia, an extensive pallid area, evaluated by cresyl violet staining, is evident in the vascular territories supplied by the MCA, the striatum and the sensory motor cortex. The pallid area reflects the extent of necrotic neurons. Soon after waking, rats showed a definite contralateral turning behavior which was significantly reduced by SCH 58261 treatment. Twenty-four hours after MCAo, SCH 58261 significantly improved the neurological deficit and reduced ischemic damage in the striatum and cortex. Phospho-p38 mitogen-activated protein kinase (MAPK), evaluated by Western Blot, increased by 500% in the ischemic striatum 24 h after MCAo. SCH 58261 treatment significantly reduced phospho-p38 MAPK by 70%. Microglia was immunostained using the OX-42 antibody. Phospho-p38 MAPK and OX-42-immunoreactive cells are localized in the ventral striatum and frontoparietal cortex. Furthermore, both OX-42 and phospho-p38 MAPK-immunoreactive cells have overlapping morphological features, typical of reactive microglia. SCH 58261 reduced phospho-p38 MAPK immunoreactivity in the striatum and in the cortex without changing the microglial cell morphology. These results indicate that the protective effect of the adenosine antagonist SCH 58261 during ischemia is not due to reduced microglial activation but involves inhibition of phospho-p38 MAPK and suggest that treatment with the A2A antagonist from the first hour to several hours after ischemia may be a useful therapeutic approach in cerebral ischemia.
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PMID:The selective A2A receptor antagonist SCH 58261 protects from neurological deficit, brain damage and activation of p38 MAPK in rat focal cerebral ischemia. 1644

Selective dopamine (D) receptor agonists either slightly improve (D2 and D3) or do not affect (D1 and D4) the tolerance of the brain to global ischemia. As for D and 5-HT (hydroxytryptamine) antagonists, only D1 antagonist SCH 23390 and 5-HT2 antagonist ketanserin produce a small neuroprotective effect, while D2, D4, 5-HT(2B) and 5-HT(2C) antagonists are not active. Simultaneous injection of D2 (raclopride), D3 (GR 103691), and D4 (L 745870) receptor blockers also does not protect the brain. These results are not at variance with a widespread hypothesis that the accumulation of extracellular 5-HT and especially D in the brain causes the neuron damage. The effect of ketanserine is not increased by D2 or D4 blockers, but the introduction of D3 blocker GR 103691 (+88%) and especially the simultaneous injection of D2,3,4 antagonists improve the effect of ketanserine (+134%). The neuroprotective effect of the last combination is not lower but even exceeds that of some neuroleptics. This fact shows the possibility to increase the tolerance to cerebral ischemia by simultaneously blocking D and 5-HT-receptors.
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PMID:[Influence of the selective ligands of dopamine and 5-hydroxytryptamine receptors on the tolerance to global cerebral ischemia]. 1720 58

Myocardial ischemia/reperfusion (I/R) injury is partly mediated by thrombin. In support, the functional inhibition of thrombin has been shown to decrease infarct size after I/R. Several cellular responses to thrombin are mediated by a G-protein coupled protease-activated receptor 1 (PAR1).However, the role of PAR1 in myocardial I/R injury has not been well characterized. Therefore, we hypothesized that PAR1 inhibition will reduce the amount of myocardial I/R injury. After we detected the presence of PAR1 mRNA and protein in the rat heart by RT-PCR and immunoblot analysis,we assessed the potential protective role of SCH 79797, a selective PAR1 antagonist, in two rat models of myocardial I/R injury. SCH 79797 treatment immediately before or during ischemia reduced myocardial necrosis following I/R in the intact rat heart. This response was dose-dependent with the optimal dose being 25 microg/kg IV. Likewise, SCH 79797 treatment before ischemia in the isolated heart model reduced infarct size and increased ventricular recovery following I/R in the isolated heart model with an optimal concentration of 1 microM. This reduction was abolished by a PAR1 selective agonist. SCH 79797-induced resistance to myocardial ischemia was abolished by wortmannin, an inhibitor of PI3 kinase; L-NMA, a NOS inhibitor; and glibenclamide, a nonselective K(ATP) channel blocker. PAR1 activating peptide,wortmannin, L-NMA and glibenclamide alone had no effect on functional recovery or infarct size. A single treatment of SCH 79797 administered prior to or during ischemia confers immediate cardioprotection suggesting a potential therapeutic role of PAR1 antagonist in the treatment of injury resulting from myocardial ischemia and reperfusion.
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PMID:SCH 79797, a selective PAR1 antagonist, limits myocardial ischemia/reperfusion injury in rat hearts. 1746 33


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