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

The present report reviews the biochemical and physiological responses to adenosine receptor activation and how these responses underlie the ability of adenosine to couple energy demand with energy supply. In addition, activation of adenosine receptors pharmacologically is shown to initiate various reactions which could be responsible for the observed adenosine-mediated attenuation of the neuropathological consequences of brain ischemia. Also reported is the extent to which side effects such as hypothermia can contribute to the observed efficacy of adenosine agonist administration in the small animal model of ischemia. Data from various in vitro and in vivo ischemia studies is presented showing that neuroprotection can be achieved following pharmacological activation of adenosine receptors either through agonists with high affinity for A1 adenosine receptors or drugs which potentiate endogenous adenosine levels. In general the data support utilization of adenosine receptor activation as a means of attenuating ischemic brain damage.
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PMID:Therapeutic potential for adenosine receptor activation in ischemic brain injury. 161 14

Changes in second messenger and neurotransmitter system receptor ligand binding induced by transient forebrain ischemia were studied in the gerbil hippocampus. The animals were allowed variable periods of recovery ranging from 2 h to 7 days after 5-min bilateral carotid artery occlusion. The binding of second messenger systems ([3H]inositol 1,4,5-trisphosphate ([3H]IP3)to inositol 1,4,5-triphosphate, [3H]forskolin to adenylate cyclase and [3H]phorbol 12,13-dibutylate to protein kinase C) and neurotransmitter receptor systems ([3H]PN200-110 to L-type calcium channels. [3H]N6-cyclohexyl-adenosine to adenosine A1 and [3H]quinuclidinyl benzilate to muscarinic cholinergic receptor) were assayed using quantitative autoradiography. In the CA1 subfield, 2 h after ischemia, [3H]IP3, [3H]forskolin, and [3H]quinuclidinyl benzilate binding activities significantly decreased by 25, 17 and 13%, respectively, though no morphological abnormalities were obvious. Six hours after ischemia, the [3H]phorbol 12,13-dibutylate binding activity in the stratum oriens of the CA1 subfield increased by 15%. One day after ischemia, [3H]PN200-110 binding activity in this subfield decreased by 26%, and 7 days after ischemia, [3H]phorbol 12,13-dibutylate and [3H]N6-cyclohexyl-adenosine receptor binding activities decreased in this subfield. In particular, at 7 days after ischemia, [3H]IP3 binding activity in the CA1 subfield showed a complete decline. In the CA3 subfield, [3H]PN200-110 binding activity decreased 2 days after ischemia, and [3H]IP3 and [3H]N6-cyclohexyl-adenosine binding activities decreased 7 days after ischemia. In the dentate gyrus, the structure of which remained histologically intact after ischemic insult, [3H]IP3 and [3H]forskolin binding activities decreased 7 days after ischemia. In contrast, the [3H]phorbol 12,13-dibutylate binding activity increased in the molecular layer of the dentate gyrus 7 days after ischemia. These results indicate that marked alteration of intracellular signal transduction precedes neuronal damage in the hippocampal CA1 subfield and that the histologically intact CA3 and dentate gyrus also shows modulated neuronal transmission after ischemia.
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PMID:Autoradiographic analysis of second messenger and neurotransmitter system receptors in the gerbil hippocampus following transient forebrain ischemia. 165 Feb 82

The goal of this study was to clarify that blockade of adenosine receptors during myocardial ischemia causes further reductions in coronary blood flow due to platelet aggregation. Coronary perfusion pressure in 47 open-chest dogs was reduced such that coronary blood flow decreased to one fifth of the control value; thereafter, coronary perfusion pressure was maintained at the low levels. During hypoperfusion, coronary flow was kept low but constant with a massive release of adenosine. When 8-phenyltheophylline, an adenosine receptor antagonist, was infused during coronary hypoperfusion, coronary blood flow (18 +/- 2 ml/100 g/min) gradually decreased at 5-10 minutes of ischemia and reached almost zero at 20 minutes. Three minutes after the onset of ischemia, before further reduction of coronary flow, the microscopic examination revealed the existence of thromboembolization in the small coronary arteries, and the number of platelets in the regional coronary venous blood were significantly decreased, indicating that a further reduction of coronary flow due to treatment with 8-phenyltheophylline is attributed to thromboembolism caused by platelet aggregations. This reduction of coronary flow and formation of thromboembolism were inhibited by the treatments with dibutyryl cAMP, forskolin, and yohimbine, indicating that this thromboembolization during a lack of adenosine activity is due to platelet aggregation and that platelet aggregation caused by 8-phenyltheophylline is triggered by stimulation of alpha 2-adrenoceptors by released norepinephrine during ischemia. We demonstrate that adenosine, generated endogenously in response to ischemia, inhibits platelet aggregation. The finding that adenosine is not merely a vasodilator but that it also regulates thrombosis has major implications for designing new strategies of myocardial salvage.
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PMID:Endogenous adenosine inhibits platelet aggregation during myocardial ischemia in dogs. 165 46

alpha 2-Adrenoceptor but not alpha 1-adrenoceptor constriction of arterioles is selectively inhibited by tissue acidosis, ischemia, and increased metabolic rate. To further examine neural-local interactions, we studied the effect of adenosine receptor stimulation on alpha 1- or alpha 2-adrenoceptor constriction. Intravital microscopy was used to study large arterioles (133 +/- 3 microns diam; mean +/- SE), small arterioles (16 +/- 1 microns), and large venules (178 +/- 3 microns) of rat cremaster skeletal muscle. Concentration-response (diameter change) curves were obtained for bath-added norepinephrine in the presence of either rauwolscine or prazosin to provide selective alpha 1- and alpha 2-constriction, respectively. The adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (2.24 x 10(-8) M) significantly attenuated both alpha 1- and alpha 2-constriction by 5- to 20-fold; alpha 1-constriction was three- to fourfold more sensitive than alpha 2-constriction. Similar inhibitory effects were obtained with adenosine (2.24 x 10(-6) M). The adenosine receptor antagonist 8-[4-[N(2-aminoethyl)carbamoylmethoxy]phenyl]-1,3-dipropylxanthine (0.7 microM) reversed the inhibitory effect of adenosine, which implicates extracellular A2 adenosine receptors. Intrinsic tone in large vessels was unaffected by adenosine receptor stimulation but was completely inhibited in small arterioles. These findings suggest that both alpha 2- and especially alpha 1-adrenoceptor constriction and intrinsic tone (of small but not large arterioles) are inhibited by physiologically relevant concentrations of adenosine.
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PMID:Interactions between alpha-adrenoceptors and adenosine receptors on microvascular smooth muscle. 185 24

The effect of adenosine receptor antagonism on function and metabolism was examined in isolated hearts during low flow ischemia and reperfusion. Isovolumic rat hearts perfused at constant flow were subjected to 30 min of ischemia followed by 30 min of reperfusion. Infusion of vehicle or 10 microM 8-phenyltheophylline (8-PT) was initiated 10 min before ischemia and maintained throughout reperfusion. 8-PT infusion had no significant effects on hemodynamic parameters or metabolism preischemia. During ischemia, left ventricular developed pressure declined to approximately 15% of preischemic values in control and 8-PT hearts, and ATP and PCr decreased to approximately 73 and 60% of preischemic values. Inorganic phosphate (Pi) increased to 353 = 41 and 424 +/- 53% of preischemic values in control and 8-PT hearts, respectively. After reperfusion, function recovered to greater than 95% of preischemic levels in control and 8-PT hearts. Unlike control hearts, recovery of metabolites was significantly different during reperfusion in 8-PT hearts (P less than 0.05); ATP, phosphocreatine, and Pi recovered to 82 +/- 8, 71 +/- 8, and 281 +/- 27% of preischemic values, respectively. Venous purine washout was significantly greater (P less than 0.05) during reperfusion in 8-PT hearts (327 +/- 113 nmol) than in control hearts (127 +/- 28 nmol). Blockade of adenosine receptors appears to adversely affect metabolic but not functional recovery in the ischemic-reperfused myocardium.
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PMID:Adenosine antagonism decreases metabolic but not functional recovery from ischemia. 199 97

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

Myocardial flow maldistribution and transmural steal phenomena, due to excessive arteriolar dilation elicited by elevated adenosine release during exercise, might be the mechanism of myocardial ischemia in patients with syndrome X. The effect of the adenosine receptor blocker aminophylline (AM) on effort ischemia in patients with syndrome X was tested: following double blind, randomized intravenous infusion of aminophylline (6 mg/kg over 15 minutes) or placebo, 8 patients with syndrome X underwent exercise stress test. After AM administration there was an increase in work tolerance (AM = 7.7 +/- 1.2 minutes of exercise vs placebo = 5.6 +/- 0.9, p less than 0.01) paralleled by an increase of the ischemic threshold, evaluated through the rate pressure product (mmHg x beats/min x 1/100) at 0.1 mV of ST-segment depression or at peak exercise (AM = 278 +/- 55 vs placebo = 230 +/- 24, p less than 0.05). AM prevented the occurrence of ischemic ECG signs in all 8 patients. Thus, at a dosage which effectively inhibits adenosine receptors, aminophylline infusion exerts beneficial effect on exercise induced ischemia in syndrome X, possibly through the prevention of transmural steal phenomena, elicited by inappropriate adenosine release during effort.
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PMID:[Increase in tolerance to physical effort in patients with X syndrome after acute administration of aminophylline]. 268 20

Adenosine has been proposed as a metabolic factor involved in the regulation of cerebral blood flow. The evidence in support of this hypothesis, presented in this review, includes information on the adenosine receptors associated with cerebral blood vessels, the synthesis and metabolism of adenosine, and the release of adenosine from the brain. Adenosine dilates cerebral blood vessels, acting at an A2 receptor. The critical evidence implicating an involvement of adenosine in cerebrovascular regulation is derived from experiments with adenosine antagonists and potentiators. The antagonists include methylxanthine adenosine receptor antagonists and the enzyme adenosine deaminase. Potentiators include transport inhibitors, enzyme inhibitors, and adenosine precursors. Adenosine has been implicated in vascular regulation during hypoxia/ischemia, hypercapnia, seizures, severe hypotension, and hypoglycemia. Adenosine possesses a number of properties that can be used to minimize neuronal degeneration during cerebral insults, such as ischemia, including vasodilatation, reduction of excitatory transmitter release, reduction of membrane calcium permeability, inhibition of platelets, and neutrophil aggregation. Several recent studies have demonstrated that manipulation of central adenosine tone can alter the extent of cerebral ischemic damage, indicating a potential new therapeutic approach for the treatment of stroke.
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PMID:Adenosine in the control of the cerebral circulation. 270 69

The efficacy of the adenosine receptor blocker aminophylline on exercise capacity in patients with effort ischemia and documented coronary artery disease has been previously documented. In this study the effect of aminophylline on effort electrocardiographic (ECG) alterations and chest pain was tested in eight patients with syndrome X (anginal chest pain on effort, ischemic ECG changes during exercise, positive dipyridamole test, normal epicardial coronary arteries on angiography and absence of coronary spasm after ergonovine). After double-blind, randomized intravenous infusion of aminophylline (6 mg/kg body weight over 15 min) or placebo (20 ml of saline solution over 15 min), the eight patients with syndrome X underwent an upright bicycle exercise stress test on 2 consecutive days. After aminophylline, there was an increase in effort tolerance (aminophylline 7.7 +/- 1.2 min of exercise versus placebo 5.6 +/- 0.9, p less than 0.01) paralleled by an increase of the rate-pressure product (mm Hg x beats/min x 1/100) at 0.1 mV of ST segment depression or at peak exercise (aminophylline 278 +/- 55 versus placebo 230 +/- 24, p less than 0.05). Aminophylline provoked the abolition of ECG signs of ischemia in all eight patients. Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced chest pain and ischemia-like ECG changes in syndrome X. This effect occurs possibly through the prevention of myocardial flow maldistribution elicited by inappropriate adenosine release during effort in the presence of increased coronary resistance at the level of small intramural coronary arteries. This study, however, does not document the ischemic nature of effort-induced pain and ECG alterations in syndrome X.
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PMID:Improved exercise capacity with acute aminophylline administration in patients with syndrome X. 280 3

Exercise-induced ischemia is generally attributed to an increase in myocardial demand in the presence of coronary stenosis limiting flow supply. An additional mechanism--the occurrence of coronary steal due to excessive endogenous adenosine release--has also been hypothesized. The effect of adenosine receptor blocking by aminophylline in effort ischemia was tested in 8 patients with stable effort-induced angina pectoris, reproducible positive exercise stress tests and angiographically assessed coronary artery disease. Following double-blind, randomized intravenous infusion of aminophylline (3 mg/kg over 3 minutes) or placebo (20 ml of saline over 3 minutes), the patients underwent upright bicycle exercise stress tests on 2 consecutive days. After aminophylline, there was an increase in work tolerance (aminophylline 7.5 +/- 1.8 minutes of exercise vs placebo 5.4 +/- 1.5 minutes; p less than 0.05). There was a parallel increase in the ischemic threshold, evaluated with the rate-pressure product (mm Hg X beats/min X 100(-2)) at 0.1 mV of ST-segment depression (221 +/- 35 vs 184 +/- 20; p less than 0.01). Thus, at a dosage that should effectively inhibit adenosine receptors, aminophylline infusion exerts a beneficial effect on exercise-induced ischemia, possibly through the prevention of myocardial flow maldistribution elicited by excessive adenosine release during effort.
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PMID:Exercise capacity after acute aminophylline administration in angina pectoris. 290 50


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