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)

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

It has been postulated that the adenosine A1 receptor subtype, but also A2a receptors, are involved in mediating the beneficial properties of adenosine during ischemia and reperfusion. We investigated the effects of the selective A1 adenosine receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2A adenosine receptor agonists, 2-[p-(2-carboxyethyl)phenetylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680), 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA), on ischemia-reperfusion injury in Langendorff-perfused rat hearts. Global ischemia was induced for 15 min in paced hearts followed by 60 min reperfusion. Control hearts developed left ventricular dysfunction, as indicated by the increase in end diastolic pressure to 40.8 +/- 5.1 vs 5.9 +/- 1.0 mm Hg baseline, and in coronary perfusion pressure to 57.6 +/- 8.4 vs 28.8 +/- 2.2 mm Hg before ischemia. After 15 min of reperfusion, ventricular function (LVDP) recovered by 83%, but creatine kinase levels were still significantly increased (294 +/- 55 IUl(-1) vs basal), indicating the occurrence of myocardial injury. All adenosine agonists added to the perfusion medium 15 min prior to ischemia exerted protective effects against myocardial dysfunction and reperfusion injury. Thus, 2HE-NECA (100 nM), CGS 21680 (10 nM), CCPA (3 nM) and NECA (100 nM) significantly (P < 0.05) decreased end diastolic pressure by 50-75% as compared with the control group. Similarly, all compounds significantly (P < 0.05) reduced coronary perfusion pressure by 30-45% vs control. For all drugs, recovery of LVDP occurred immediately after restoration of coronary flow. At 15-min reperfusion the adenosine agonists decreased myocardial creatine kinase release by 80-95% (P < 0.05 vs control). These findings indicate that both A1 and A2A adenosine receptors are involved in protecting the myocardium against ischemia and reperfusion in isolated rat heart, even if through different mechanisms.
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PMID:Cardioprotective effects of adenosine A1 and A2A receptor agonists in the isolated rat heart. 914 17

OG-VI is a solution composed of 30 mM inosine, 30 mM sodium 5'-guanylate, 30 mM cytidine, 22.5 mM uridine, and 7.5 mM thymidine, expecting to use for total parenteral nutrition. We examined the effect of OG-VI on myocardial contractile dysfunction during reperfusion after ischemia (myocardial stunning) in dogs. Pentobarbital-anesthetized dogs were subjected to 20-min left anterior descending coronary artery ligation followed by 30-min reperfusion. Saline, OG-VI or its constituents [inosine and sodium 5'-guanylate mixture (IG), and cytidine, uridine, and thymidine mixture (CUT)], or 5-amino-4-imidazole carboxamide riboside (AICAr) was infused at 0.1 mL.kg-1.min-1, starting 30 min before the ischemia. The contractile function was determined by ultrasonometry and assessed as % segment shortening (%SS). %SS was markedly decreased by ischemia, and returned toward pre-ischemic level after reperfusion, although the recovery was incomplete. The %SS was almost completely recovered by OG-VI and IG, and to a lesser extent by AICAr; CUT was ineffective. In the presence of 1 mg.kg-1 of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, a selective adenosine A1 receptor antagonist), cardioprotective effect of OG-VI on stunned myocardium was still observed. In conclusion, infusion of OG-VI improved myocardial contractile dysfunction in stunned myocardium. This effect was more potent than its constituents and AICAr. Adenosine A1 receptors are not involved in the mechanism.
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PMID:Limitation of stunning in dog myocardium by nucleoside and nucleotide mixture, OG-VI. 922 40

We previously reported that hypoxic coronary vasodilatation (HCVD) is initiated by endothelial NO and sustained by adenosine. Prolonged ischemia/reperfusion impairs endothelium-dependent coronary vasodilatation, whereas transient ischemia (ie, preconditioning) protects the myocardium from subsequent ischemic events. Accordingly, we assessed whether prolonged ischemia/reperfusion impairs HCVD and whether preconditioning prevents this dysfunction. HCVD, elicited in isolated guinea pig hearts by a 1-minute exposure to 100% N2, consisted of an approximately 70% increase in coronary flow associated with enhanced nitrite/nitrate and adenosine overflow (+40% and 5-fold, respectively). After 30-minute global ischemia and 20-minute reperfusion, HCVD was decreased by approximately 60%, and the increases in nitrite/nitrate and adenosine overflow were abolished. Preconditioning (ie, three cycles of 5-minute global ischemia+5-minute reperfusion) prevented the impairment of HCVD and fully restored the increase in nitrite/nitrate overflow, but not that of adenosine. The protective effect of preconditioning was mimicked by perfusion with the adenosine A1 receptor agonist N6-cyclopentyladenosine and prevented by the A1 receptor antagonist N-0861. In addition, the A3 receptor agonist N6-(3-iodobenzyl)adenosine-5'-N-methyl-carboxamide had a similar protective effect. The bradykinin B2 receptor antagonist HOE 140 abolished the protective effect of preconditioning, whereas the NO synthase inhibitor N(omega)-methyl-L-arginine and the cycloxygenase inhibitor indomethacin did not. Our data indicate that preconditioning restores HCVD by a process that is triggered by activation of adenosine A1/A3 and bradykinin B2 receptors. The action of bradykinin is independent of NO and prostacyclin production. Once restored by preconditioning, HCVD is mediated by NO but no longer sustained by adenosine.
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PMID:Ischemic preconditioning prevents the impairment of hypoxic coronary vasodilatation caused by ischemia/reperfusion: role of adenosine A1/A3 and bradykinin B2 receptor activation. 928 44

Myocardial ischemia, even if it persists for a prolonged period of time, does not inevitably induce irreversible damage. Recent studies have identified 2 phenomena that are characterized by endogenous cardioprotective features, i.e., myocardial hibernation and ischemic preconditioning. Myocardial hibernation is characterized by chronic contractile dysfunction during persistent ischemia. The myocardium remains viable, and function is restored upon reperfusion. Ischemic preconditioning is characterized by delayed development of infarct size when prolonged and severe myocardial ischemia is preceded > or = 1 short-lasting episodes of ischemia and reperfusion. While ischemic preconditioning involves the activation of the adenosine A1 receptor, the bradykinin receptor, and activation of adenosine triphosphate (ATP)-dependent potassium channels, the mechanisms underlying myocardial hibernation are still unclear.
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PMID:Endogenous protective mechanisms in myocardial ischemia: hibernation and ischemic preconditioning. 929 53

We used adenosine A1 receptor agonist N6-1(phenyl-2R-isopropyl)-adenosine (PIA), A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and ATP-sensitive K+ (KATP) channel blockers sodium 5-hydroxydecanoate (5-HD) and glibenclamide (Glib), as probes to investigate the role and mechanism of adenosine in ischemic preconditioning (IPC) of noncontractile skeletal muscle against infarction, using the pig latissimus dorsi muscle flap model. Except for Glib, all drugs were delivered to each muscle flap by 10-min local intra-arterial infusion to avoid systemic effects. Muscle flaps that were subjected to 4 h of global ischemia and 48 h of reperfusion sustained 40 +/- 2% infarction. IPC with three cycles of 10 min ischemia and reperfusion, preischemic adenosine, or PIA treatment reduced (P < 0.05) muscle infarction to 24 +/- 2, 18 +/- 2, and 24 +/- 2%, respectively. The anti-infarction effect of IPC and adenosine was blocked by DPCPX, 5-HD, and Glib (P < 0.05). Preischemic adenosine treatment also maintained higher muscle contents of phosphocreatine, ATP, and energy charge potential and lower muscle contents of dephosphorylated metabolites and lactate during ischemia and a lower muscle myeloperoxidase (MPO) activity during reperfusion compared with the control (P < 0.05). Preischemic adenosine treatment did not increase muscle content of adenosine during ischemia or reperfusion. Furthermore, adenosine given at the onset of reperfusion was not effective in attenuating muscle MPO activity or infarction. Taken together, these observations indicate that adenosine, through A1 receptors, initiates the mechanism of IPC with postreceptor involvement of KATP channels in skeletal muscle. However, adenosine is unlikely to play a key role in the effector mechanism. Presently, the cause and role of energy sparing and neutrophil inhibitory effects associated with the anti-infarction effect of preischemic adenosine treatment are unknown.
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PMID:Effector mechanism of adenosine in acute ischemic preconditioning of skeletal muscle against infarction. 932 64

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

Administration of adenosine A1 receptor agonists in vivo is neuroprotective in various stroke models. Experiments using either mixed cultures of neurons and astrocytes or brain slices, in which several cell types are present, have demonstrated that activation of A1 receptors also id protective against hypoxia and/or hypoglycemia in vitro. In this study, we have examined the effect of the A1 agonist cyclopentyladenosine (CPA) on cellular damage, measured by efflux of lactate dehydrogenase (LDH), in highly enriched primary cultures of either neurons of astrocytes exposed to different metabolic insults. CPA reduced neuronal LDH release induced by a combination of hypoxia and substrate deprivation ("simulated ischemia"; IC50 = 28 nM) of by hypoxia alone (IC50 = 170 nM). In contrast, CPA had no effect on neuronal damage induced by substrate deprivation alone, not did it affect ischemic death to astrocytes. The neuroprotective effect of CPA during simulated ischemia and hypoxia were reversed by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). These data demonstrate that activation of an adenosine A1 receptor on neurons, but not astrocytes, is protective against cellular damage of death induced specifically by hypoxia as opposed to other metabolic insults such as hypoglycemia.
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PMID:Adenosine A1 receptor activation preferentially protects cultured cerebellar neurons versus astrocytes against hypoxia-induced death. 937 19

To determine whether intrinsic angiotensin II (ANG II) type 1 receptor (AT1-R) stimulation modulates recovery of postischemic mechanical function, we studied the effects of selective AT1-R blockade with losartan on proton production from glucose metabolism and recovery of function in isolated working rat hearts perfused with Krebs-Henseleit buffer containing palmitate, glucose, and insulin. Aerobic perfusion (50 min) was followed by global, no-flow ischemia (30 min) and reperfusion (30 min) in the presence (n = 10) or absence (n = 14) of losartan (1 mumol/l) or the cardioprotective adenosine A1 receptor agonist N6-cyclohexyladenosine (CHA, 0.5 mumol/l, n = 11). During reperfusion in untreated hearts (controls), left ventricular (LV) minute work partially recovered to 38% of aerobic baseline, whereas proton production increased to 155%. Compared with controls, CHA improved recovery of LV work to 79% and reduced proton production to 44%. Losartan depressed recovery of LV work to 0% without altering proton production. However, exogenous ANG II (1-100 nmol/l) in combination with losartan restored recovery of LV work during reperfusion in a concentration-dependent manner, suggesting that postischemic recovery of function depends on intrinsic AT1-R stimulation.
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PMID:Intrinsic ANG II type 1 receptor stimulation contributes to recovery of postischemic mechanical function. 961 59


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