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

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

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

Preconditioning is known to decelerate degradation of the tissue adenine nucleotides during ischemia and to delay ischemic myocardial necrosis. However, it is not known whether these two phenomena are related. To obtain an insight into this question, the present study examined whether adenosine and B2 receptor antagonists, which block the infarct size-limiting effect of preconditioning, modify the interstitial purine levels during preconditioning and subsequent sustained ischemia. In pentobarbital anesthetized open-chest rabbits, a microdialysis probe was placed in the territory of a branch of the left coronary artery, and perfused with Ringer solution. Preconditioning was performed with 5 min ischemia/5 min reperfusion. Dialysate adenosine and inosine were elevated from the baseline values of 0.064 +/- 0.011 and 0.329 +/- 0.044 microM to 0.189 +/- 0.069 and 4.106 +/- 1.451 microM, respectively during preconditioning, but their elevation during a subsequent 20 min of ischemia was significantly lower compared with that in the non-preconditioned myocardium. This suppression of the purine accumulation during ischemia by preconditioning was not abolished by 2 micrograms/kg of Hoe 140, a specific B2 receptor antagonist, or by 10 mg/kg of 8-phenyltheophylline, a non-selective adenosine receptor antagonist. Since the doses of Hoe 140 and 8-phenyltheophylline are sufficient to block the infarct size-limiting effect of preconditioning, the present results suggest that there is a dissociation between the suppression of adenine nucleotide degradation during ischemia by preconditioning and the enhancement of myocardial resistance against infarction. Thus, it is unlikely that a reduction of adenine nucleotide utilization by preconditioning is sufficient to protect the myocardium against ischemic necrosis.
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PMID:Suppression of the degradation of adenine nucleotides during ischemia may not be a sufficient mechanism for infarct size limitation by preconditioning. 899 27

We have proposed that ischemic preconditioning in rabbit hearts is initiated by adenosine receptor stimulation resulting in activation of protein kinase C. If this theory is correct then any agonist which can activate PKC should also put the heart into a preconditioned state. This study sought to determine whether endothelin-1 (ET-1), which is known to activate protein kinase C can also mimic ischemic preconditioning. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 min reperfusion reduced infarct size to 5.6 +/- 0.7% (P < 0.01). Perfusion with either 10 PM ET-1 at constant coronary artery flow for 5 min in lieu of ischemia or 50 PM ET-1 with 10 nM nicardipine to block the former's coronary constructive effect was quite protective and equipotent with preconditioning. Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1.7% of the risk zone, respectively. This protection could be blocked by PD 156 707 (10 microM), a highly specific endothelin receptor antagonist. Chelerythrine (5 microM), a PKC inhibitor, also aborted protection (22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 microM), an adenosine receptor blocker, given during ET-1 administration did not block ET-1's protective effect indicating that adenosine was not involved in the effect. PD 156707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing that endothelin is not an important physiological mediator of ischemic preconditioning. We conclude that ET-1 can mimic ischemic preconditioning in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning.
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PMID:Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart. 901 41

In the total brain ischemia the cerebroprotective effect (CPE) of adenosine was pronounced in the following order: mouse > rat approximately guinea pig (males > females). The sensitizing effect (SE) of theophylline is the same in different species but is more pronounced in females compared to males. Newborn rats are much more tolerant to the total brain ischemia. The adenosine CPE increases and the theophylline SE decreases with age. The adenosine receptor component, evidently, contributes greatly to the natural tolerance of newborn animals to the total brain ischemia.
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PMID:[The biological range and characteristics of the importance of adenosine receptors for the resistance of the brain to total ischemia]. 902 83

Recent developments in cardiac physiology have focused on the mechanisms underlying preconditioning against ischemia-reperfusion injury. Sensing, transduction and cardioadaptation to the initial stimulus suggests species-specific differences in strategy. We and others have found that ischemic stress can trigger catecholamine (alpha1-adrenoreceptor)-dependent mechanisms of preconditioning. However, in rabbits and dogs, adenosine receptor mechanisms appear to predominate. In contrast, the role of the adenosine receptors in rat remains controversial. Anticipating a minor role for this metabolite, we examined its ability to induce protection in rat heart against a modest ischemic injury and also its relationship to the noradrenergic alpha1 pathway. Although redundant pathways for inducing adaptation to stress are possible, single transient ischemic stress surprisingly utilizes both alpha1-adrenoreceptors and adenosine P1 receptors in obligate roles. Thus blockade of either purinergic P1 or alpha1-adrenergic receptors abolished functional protection induced by single transient ischemic stimulus. Selective noradrenergic alpha1-adrenoreceptor stimulation was sufficient to protect cardiac recovery after modest ischemic injury, and was unaffected by purinergic blockades, suggesting that this is the primary stress adaptation pathway for rat. However, exogenous purinergic P1 stimulated protection was abolished in either reserpine pretreated, or alpha1-adrenoreceptor blockaded hearts. Therefore the cardioadaptive ischemic preconditioning mechanisms in rat may involve facilitative modulation of a primary pathway rather than redundancy.
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PMID:Facilitative interactions between noradrenergic and purinergic signaling during preconditioning of the rat heart. 904 31

Evidence supports the involvement of adenosine receptor stimulation and activation of K(ATP) channels in ischemic preconditioning of human myocardium. It is unknown, however, whether protection mediated by adenosine receptors is dependent upon the K(ATP) channel in the human heart. The purpose of this study was to determine whether adenosine-mediated protection against a simulated ischemia-reperfusion injury in human myocardium is dependent upon K(ATP) channels. Isolated human right atrial trabeculae were placed in tissue baths at 37 degrees C, oxygenated with a modified Tyrode solution, and field stimulated at 1 Hz. Trabeculae were subjected to 45 min of normothermic simulated ischemia (hypoxic, substrate-free buffer with pacing at 3 Hz.) and 60 min of reperfusion (I/R trabeculae). Trabeculae were preconditioned with simulated ischemia (IPC trabeculae) or adenosine receptor stimulation (adenosine, 125 micromol/l) for 5 min (ADO trabeculae) prior to simulated ischemic-reperfusion injury. Inhibition of the K(ATP) channel with glibenclamide (10 micromol/l) was combined with adenosine pretreatment (ADO+GLI trabeculae) or alone (GLI trabeculae) prior to simulated ischemic-reperfusion injury. Developed force (DF) at end reperfusion (mean+/-S.E.) was compared to baseline developed force, and tissue creatine kinase (CK) activity at end reperfusion was measured. I/R trabeculae showed 27+/-2% of baseline DF, whereas IPC trabeculae or ADO trabeculae showed 50+/-4% and 43+/-3% of baseline DF, respectively. ADO+GLI trabeculae showed 25+/-2% and GLI trabeculae showed 23+/-4% of baseline DF. Tissue CK activity was enhanced in the IPC and ADO trabeculae (433+/-63 U/g wet myocardium, and 415+/-28 U/g wet myocardium, respectively). I/R trabeculae had 196+/-26 U/g wet myocardium and ADO+GLI trabeculae had 277+/-38 U/g wet myocardium at end reperfusion. The results suggest that ischemic preconditioning and adenosine receptor stimulation confer functional protection against simulated ischemic-reperfusion, and adenosine mediated protection is eliminated by K(ATP) channel inhibition in human myocardium.
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PMID:Adenosine preconditioning of human myocardium is dependent upon the ATP-sensitive K+ channel. 904 32

This study was designed to examine whether theophylline, an adenosine receptor antagonist, affects cardiac adaptation to ischemia during progression of repetitive balloon inflations of percutaneous transluminal coronary angioplasty (PTCA). Theophylline abolished this cardiac adaptation, suggesting that endogenous adenosine is a key mediator for cardiac adaptation during PTCA.
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PMID:Effect of theophylline on adaptation of the heart to myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with stable angina pectoris. 905 52

Ischemic preconditioning reduces post-ischemic myocardial injury by activating myocellular adenosine A1 receptors. Adenosine A3 receptors have also been implicated but there is no evidence for A3 receptors in cardiac myocytes. The aim of this study was to develop a model of preconditioning in isolated cardiac myocytes to evaluate the role of the adenosine A1 and A3 receptors in preconditioning-induced protection from ischemic injury. Reverse transcription polymerase chain reaction (PCR) was also employed to establish the presence of adenosine A3 receptors in these cells. In the preconditioning studies, ischemic injury was simulated by exposing isolated rabbit myocytes (placed in the cell chamber and paced at l Hz) to buffer containing (in mM) 2'-deoxyglucose (20), NaCN (1), Na (+)-lactate (20), KCl (10) at pH 6.6 (37 degrees C). Changes of diastolic and systolic cell length were monitored with an optical-video edge imaging system, and hypercontracture was assessed as an index of irreversible cell injury. Preconditioning (2 min brief ischemia and 15 min reperfusion) significantly reduced cell injury resulting from a subsequent prolonged ischemia (10 min) and reperfusion (15 min), as indicated by a reduction in the incidence of cell hypercontracture from 67 +/- 6% to 29 +/- 5% (P < 0.001). Preconditioning-induced cardioprotection was only partially blocked by a maximally effective concentration (100 nM) of the adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (cell hypercontracture = 43 +/- 3%, P < 0.05 vs. control) but completely blocked by either the combination of DPCPX (100 nM) with the adenosine A1/A3 receptor antagonist DPCPX +8-(4-carboxyethylphenyl)-1,3-dipropylxanthine (BWA1433; 1 microM) or the non-selective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT; 100 microM) (cell hypercontracture = 64 +/- 4%, 59 +/- 5%, respectively; P = NS vs. control). In non-hypercontractured myocytes, preconditioning also substantially enhanced the recovery of the contractile amplitude and, similarly, this effect was only partially blocked by DPCPX but completely blocked by either the combination of DPCPX with BWA1433, or 8-SPT. These studies suggest that preconditioning protects isolated cardiac myocytes from ischemic injury independent of other cell types, and that maximal preconditioning-induced cardioprotection requires activation of both adenosine A1 and A3 receptors. Reverse transcription-PCR using primers for the rabbit receptor provide evidence for the presence of adenosine A3 receptors in these cells.
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PMID:Dual activation of adenosine A1 and A3 receptors mediates preconditioning of isolated cardiac myocytes. 905 60

The inhibitory neuromodulator adenosine is neuroprotective against damage induced by cerebral ischemia. Its vasodilator effects add to its suitability as a possible anti-stroke agent, but also account for unwanted side effects following systemic administration of adenosine receptor agonists. ATP breakdown during ischemia produces adenosine which effluxes out of the neuron. This review will focus on endogenously produced adenosine and its subsequent protection against ischemia-induced neuronal damage in some stroke models, but will also highlight possible disadvantages to increasing adenosine concentrations. In the advantages column, therapeutic benefits have been obtained by enhancing synaptic concentrations of endogenous adenosine using the adenosine uptake inhibitor propentofylline, but not dipyridamole. There is an emerging role for endogenous adenosine in preventing delayed cell death, e.g. following hypoxic pre-conditioning. One of the cons associated with enhancing the synaptic concentration of adenosine is the appearance of adenosine receptor desensitization over time. Thus, there is a therapeutic window of opportunity during which activation of an adenosine A1 receptor is beneficial to an ischemic neuron.
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PMID:Neuroprotective effects of adenosine in cerebral ischemia: window of opportunity. 906 44


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