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)

The objective of the present study was to characterize the role of adenosine in myocardial ischemic preconditioning in the canine heart. Preconditioning with 5 min of ischemia resulted in a marked reduction in infarct size after 60 min of left circumflex coronary artery occlusion and 5 h of reperfusion in barbital-anesthetized dogs compared with dogs that were not preconditioned (4.8 +/- 1.9 vs. 27.9 +/- 4.5%; P < 0.05). Pretreatment with either the nonselective adenosine receptor antagonist PD 115199 or the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked this protective effect, although in the absence of preconditioning neither of the antagonists affected infarct size. Intracoronary infusion of two different doses of adenosine or dipyridamole over a 5-min period before a prolonged 60-min occlusion period did not mimic preconditioning; however, intracoronary infusion of a combination of adenosine and dipyridamole produced a significant reduction in infarct size (13.6 +/- 4.1%), which was abolished by pretreatment with the ATP-dependent potassium (KATP) channel antagonist glibenclamide. These results suggest that activation of adenosine A1 receptors produces myocardial preconditioning in the canine heart by opening KATP channels.
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PMID:Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. 849 46

The characteristics of adenosine and inosine outflow evoked by 5 min of ischemia-like conditions in vitro (superfusion with glucose-free Krebs solution gassed with 95% N2/5% CO2) were investigated on rat hippocampal slices. The viability of the slices after "ischemia" was evaluated by extracellular recording of the evoked synaptic responses in the CA1 region. The evoked dendritic field potentials were abolished after 5 min of superfusion under "ischemia" but a complete recovery occurred after 5 min of reperfusion with normal oxygenated Krebs solution. No recovery took place after 10 min of "ischemia." The addition of the adenosine A1 receptor antagonist 8-phenyltheophylline to the superfusate antagonized the depression of the evoked field potentials caused by 5 min of "ischemia." Five minutes of "ischemia" brought about a six- and fivefold increase in adenosine and inosine outflow, respectively, within 10 min. Tetrodotoxin reduced the outflow of adenosine and inosine by 42 and 33%, respectively, whereas the removal of Ca2+ caused a further increase. The NMDA receptor antagonist D(-)-2-amino-7-phosphonoheptanoic acid and the non-NMDA antagonist 6,7-dinitroquinoxaline-2,3-dione brought about small, not statistically significant decreases of adenosine and inosine outflow. The glutamate uptake inhibitor dihydrokainate did not affect the outflow of adenosine and inosine. Inhibition of ecto-5'-nucleotidase by alpha,beta-methylene ADP and GMP did not affect basal adenosine outflow but potentiated "ischemia"-evoked adenosine outflow. It is concluded that ischemia-like conditions in vitro evoke a Ca(2+)-independent adenosine and inosine outflow, through a mechanism that partly depends on propagated nervous activity but does not involve excitatory amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Investigations into the adenosine outflow from hippocampal slices evoked by ischemia-like conditions. 851 75

Adenosine functions as a counterregulatory hormone in the myocardium by decreasing work and thereby protecting the myocardium against ischemia. Functional adenosine A1 receptors could serve as an important regulatory system in the developing preinnervated heart by balancing the humoral sympathetic input to the heart. The aims of this study were to determine if A1 adenosine receptors were functionally coupled to their Gi protein in the immature preinnervated heart and to determine if A1 adenosine receptors were present in greater numbers in the immature heart. One- to 3-day-old rat ventricular cardiomyocyte cultures were exposed to (1) control conditions; (2) isoproterenol, a beta-receptor agonist, (3) R-PIA, an A1 agonist, or (4) isoproterenol and R-PIA, cAMP levels were determined by RIA in each group. Adenosine A1 receptor density and the equilibrium dissociation constant were determined by binding of an adenosine A1 receptor antagonist in newborn, 1-week-old, 2-week-old, and adult rat hearts. A1 stimulation decreased the isoproterenol-induced increase in cAMP by 30%, demonstrating functional A1 receptors in immature preinnervated myocytes. The A1 receptor density in the newborn age group was twice the adult and 2-week-old level. We conclude that A1 receptors in the immature heart are functionally coupled to their effector and that A1 receptors are present in greater numbers in the immature heart.
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PMID:Ontogeny of rat myocardial A1 adenosine receptors. 853 70

The effects of TAK-044 on the extension of ischemia/reperfusion-induced myocardial infarction were studied in rats. Acute myocardial infarction was induced by occlusion of the left coronary artery for 1 h followed by reperfusion for 24 h. Infarct size and the area at risk were determined histochemically. Infarct size as a percentage of the area at risk (IS) was significantly reduced in a dose-dependent manner by TAK-044 administered 30 min before reperfusion (0.3-3.0 mg/kg, i.v.). Size-limiting effects similar to those in rats were also obtained in rabbits and dogs. In addition, TAK-044 administered 3 h after reperfusion also reduced the IS significantly. Preconditioning (5 min of LAD occlusion preceding 1 h of coronary occlusion) inhibited the extension of the IS. These effects of preconditioning and TAK-044 were inhibited by glibenclamide (0.1 mg/kg, i.v.; an inhibitor of the ATP-sensitive K channel) but not by DPCPX (1 mg/kg, i.v.; an adenosine A1 receptor antagonist). These results indicate that endogenous endothelin plays an important role in the extension of myocardial infarction and that the cardioprotective effects of TAK-044 can be partially explained by a mechanism similar to that of preconditioning in rats.
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PMID:Role of endogenous endothelin in the extension of myocardial infarct size studied with the endothelin receptor antagonist, TAK-044. 858 16

This study tested whether an irreversible agonist of the A1 adenosine receptor, m-DITC ADAC, can mimic the protective effect of ischemic preconditioning in the rabbit heart. Isolated Krebs buffer-perfused rabbit hearts experienced 30 mins of regional ischemia and 120 mins of reperfusion. Infarct size was measured with tetrazolium staining. In untreated hearts 32 +/- 2% of the risk zone infarcted while only 9 +/- 2% infarction was seen in hearts that were preconditioned with 5 mins of global ischemia followed by 10 mins of reperfusion (P < 0.05 versus control). Exposure to 200 nM of the A1-selective agonist 2-chloro-N6-cyclopentyladenosine (CCPA) for 5 mins followed by 10 mins of washout protected the hearts as well as preconditioning with 13 +/- 7% infarction (P < 0.05 versus control). Protection from CCPA was completely blocked by 200 nM DPCPX (8-cyclopentyl-1,3-dipropylxanthine) with 34 +/- 7% infarction (P < 0.05 versus CCPA) confirming that protection was via the A1 adenosine receptor. m-DITC ADAC, which irreversibly stimulates the A1 adenosine receptor, also protected the hearts with only 15 +/- 4% infarction (P < 0.05 versus control). It was concluded that m-DITC ADAC does mimic ischemic preconditioning and that an irreversible agonist might be a novel way to provide an extended window of protection to the heart from a single intracoronary injection.
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PMID:An irreversible A1-selective adenosine agonist preconditions rabbit heart. 864 May 99

Short periods of ischemia render the myocardium more resistant to a subsequent prolonged coronary occlusion resulting in a reduction of infarct size. This cardioprotective mechanism has been called ischemic preconditioning. Acute myocardial ischemia results in a rapid decline of high energy phosphates. After short periods of ischemia the high energy phosphate levels are better preserved and the increase of lactate is slower during the prolonged subsequent ischemia in the preconditioned group compared to control. The duration of ischemia needed for induction of the protective effect is 2.5 min in dogs and 20 min in our swine model. In porcine myocardium the protection is lost about 1 h after induction and a renewal is not possible at that time, but is 24 h later. For rabbits or dogs, but not in pigs, a late protection 24 h after induction or preconditioning has been shown ("second window of protection"). Adenosine or adenosine A1 receptor agonists, muscarinic M2 receptor agonists, alpha 1-receptor agonists and bradykinin B2 receptor agonists as well as opening of the K+ATP-channel substitute for ischemia in the induction of protection. Activation of protein kinase C results in protection in rats and rabbits, but not in dogs or pigs. Inhibition of protein kinase C translocation or kinase activity results in a loss of the protection induced by preceding ischemia. After blockade of the K+ATP-channel the protection induced by adenosine A1 receptor activation is lost. Therefore opening of the K+ATP-channel is a prerequisite for induction of the protective effect. Inhibition of the inhibitory G-protein by pertussis toxin has been shown to result in a loss of protection, therefore the Gi-protein seems to be involved in the evolution of protection. In humans during coronary angioplasty anginal pain and lactate production during a second balloon occlusion is diminished without any change in the regional myocardial perfusion. This adaptation is inhibited by blockade of the K+ATP-channel or of the adenosine A1 receptor. Intermittent cross-clamping before a longer occlusion during open-heart surgery results in a better preservation of high energy phosphates compared to controls without preceding short ischemia. These observations support the hypothesis that ischemic preconditioning also occurs in humans. Angina pectoris preceding the myocardial infarction may have preconditioned the human heart against the subsequent myocardial infarction, but studies concerning the influence of angina pectoris on short-term outcome after thrombolysis are conflicting. In the future, ischemic preconditioning or preconditioning with drugs may prolong the duration of ischemia tolerated without necrosis and improve the prognosis of patients by reducing the infarct size.
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PMID:-Myocardial protection by preconditioning. Experimental and clinical significance-. 865 Sep 86

1. The adenosine A1 receptor enhancer, PD 81,723, was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion cerebral ischemia. 2. Gerbils were injected with PD 81,723 (1, 10 and 125 mg/kg i.p.) 20 min before a 5-min episode of forebrain ischemia. The extent of ischemic injury was assessed by monitoring the increases in locomotor activity and from the degree of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. 3. By both criteria, PD 81,723, at all three dose levels, failed to protect against ischemia/reperfusion evoked cerebral injury.
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PMID:Adenosine A1 receptor enhancer, PD 81,723, and cerebral ischemia/reperfusion injury in the gerbil. 869 Feb 43

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
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PMID:Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen. 876 52

Agonists of adenosine A1 receptors have been frequently proposed as candidates for clinical development in treatment of cerebral ischemia and stroke. Numerous experimental studies have shown that pre- and postischemic administration of these drugs results in a very significant reduction of postischemic brain damage. However, only a few studies determined the impact of cerebral ischemia and drug treatment on postischemic recovery of spatial memory. The present paper demonstrates that preischemic i.p. administration of adenosine amine congener (ADAC) at 100 micrograms/kg in gerbils results in a significant (P < 0.05) reduction of postischemic mortality and hippocampal, cortical and striatal morbidity. Postischemic Morris' water maze tests show that preischemic treatment with ADAC also leads to a very significant (P < 0.001) reduction of postischemic spatial memory loss. Our results indicate feasibility of further consideration of adenosine A1 receptor agonists as a clinically applicable acute treatment of brain ischemia. Recent development of neuroprotective adenosine A1 receptor agonists that are free of cardiovascular side effects supports such development.
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PMID:Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist. 879 Sep 90

Exposing the myocardium to brief ischemia followed by reperfusion enhances myocardial resistance to infarction from a subsequent sustained ischemia. This phenomenon, termed preconditioning, is most likely to be triggered by adenosine A1 receptor activation, and the dependence of the preconditioning effect on the duration of preconditioning ischemia and the number of its repetition is probably through the interstitial adenosine level achieved by each preconditioning protocol. Our studies support the theory that activation of protein kinase C subsequent to stimulation of the A1 receptor enhances myocardial ischemic tolerance. The ATP-sensitive potassium channel may be involved in preconditioning, but its relation with protein kinase C is unclear, and the relative importance of this channel might be species dependent. The mechanism of preconditioning needs to be further elucidated in animal models and preconditioning in the human heart needs to be further characterized before we can adapt its biochemical basis to clinical therapy.
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PMID:Ischemic preconditioning against infarction: its mechanism and clinical implications. 880 6


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