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)

Adenosine (ADO) is an endogenous cardioprotective autacoid that exerts receptor-mediated cardioprotection from ischemic-reperfusion injury. This study tested the hypothesis that blood cardioplegia (BCP) supplemented with ADO reduces postischemic left ventricular dysfunction in ischemically injured hearts. Twenty-one anesthetized dogs on total bypass were subjected to 30 minutes of normothermic global ischemia. Cold (4 degrees C) potassium BCP was then delivered every 20 minutes for 60 minutes of cardioplegic arrest. In 7 dogs, unsupplemented BCP was used; in 7 dogs, BCP was supplemented with 400 mumol/L ADO; and, in 7 dogs, ADO receptors were blocked with 8-p-sulfophenyltheophylline (30 mg/kg) given with 400 mumol/L ADO in BCP. Preischemic and postischemic left ventricular systolic function was assessed by the slope and volume axis intercept of the end-systolic pressure-volume (impedance catheter) relationship (ESPVR). In unsupplemented BCP, the postischemic slope of the ESPVR was significantly depressed by 42% versus the preischemic value (from 6.8 +/- 1.2 mm Hg/mL to 3.9 +/- 0.4 mm Hg/mL; p < 0.05 versus the preischemic value). In contrast, BCP supplemented with ADO was found to restore the postischemic ESPVR slope to preischemic levels (7.7 +/- 1.0 mm Hg/mL versus 7.4 +/- 1.2 mm Hg/mL, respectively). This cardioprotection was reversed by 8-p-sulfophenyltheophylline (9.9 +/- 1.5 mm Hg/mL versus 4.5 +/- 0.7 mm Hg/mL; p < 0.05 versus the preischemic value). Postischemic plasma creatinine kinase activity was elevated equally in all groups over the baseline values. We conclude that ADO in BCP attenuates postcardioplegia dysfunction in severely injured hearts through the operation of receptor-mediated mechanisms.
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PMID:Adenosine in blood cardioplegia prevents postischemic dysfunction in ischemically injured hearts. 797 28

Adenosine, an important regulator of many cardiac functions, is produced by ectosolic and cytosolic 5'-nucleotidase. The activity of these enzymes is influenced by several ischemia-sensitive metabolic factors, e.g., ATP, ADP, H+, and inorganic phosphate. However, there is no clear evidence that adenosine itself affects 5'-nucleotidase activity. This study tested whether adenosine decreases the activity of ectosolic and cytosolic 5'-nucleotidase. Cardiomyocytes were isolated from adult male Wistar rats and suspended in the modified Hepes-Tyrode buffer solution. After stabilization, isolated cardiomyocytes were incubated with and without adenosine (10(-9) - 10(-4) M). Ectosolic and cytosolic 5'-nucleotidase activity was decreased by exogenous adenosine (ectosolic 5'-nucleotidase activity, 20.6 +/- 2.3 vs. 8.6 +/- 1.6 mumol/min per 10(6) cells [P < 0.05]; cytosolic 5'-nucleotidase activity, 2.47 +/- 0.58 vs. 1.61 +/- 0.54 mumol/min per 10(6) cells [P < 0.05] at 10(-6) M adenosine) after 30 min. The decrease in ectosolic and cytosolic 5'-nucleotidase activity was inhibited by 8-phenyltheophylline and pertussis toxin, and was mimicked by N6-cyclohexyladenosine, an adenosine A1 receptor agonist. Neither CGS21680C, and A2 receptor agonist, nor cycloheximide deactivated ectosolic and cytosolic 5'-nucleotidase. Thus, we conclude that activation of adenosine A1 receptors is coupled to Gi proteins and attenuates ectosolic and cytosolic 5'-nucleotidase activity in rat cardiomyocytes.
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PMID:Evidence for deactivation of both ectosolic and cytosolic 5'-nucleotidase by adenosine A1 receptor activation in the rat cardiomyocytes. 798 2

Oxygen free radicals have been implicated in the pathogenesis of ischemic cell injuries. These free radicals are normally scavenged by antioxidant enzymes. Adenosine is normally released during ischemia and protects against ischemic injuries by interacting with adenosine receptors (ARs). The mechanism underlying its cytoprotective action is unclear. In this report, we provide evidence that activation of a unique A3AR in rat basophilic leukemia cells (RBL-2H3) leads to a 2 to 3 fold increase in activity of superoxide dismutase, catalase and glutathione peroxidase and also increases in the activity of glutathione reductase. Similar increases in enzyme activity were elicited in bovine and human endothelial cells, rat cardiac myocytes and smooth muscle cells. Increases in enzyme activity were attenuated by theophylline (an antagonist of the A3AR) and by pertussis toxin, implicating a role of A3AR/Gi protein in the activation. Importantly, activation of the A3AR decreased the degree of lipid peroxidation in these cells. These data provide strong evidence that the cytoprotective action of adenosine during ischemic cell injuries is mediated, at least in part, via a novel mechanism-activation of the cellular antioxidant enzymes.
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PMID:Adenosine acts as an endogenous activator of the cellular antioxidant defense system. 800 80

Abnormal constriction of coronary resistive vessels can induce angina and myocardial ischemia. The possibility that a microvascular vasomotor dysfunction could cause ischemia is in contrast with the well-known traditional notion that a metabolically induced vasodilation could compensate for the effect of an epicardial coronary stenosis. Vasoconstrictor stimuli can plausibly act on vessels situated immediately proximal (prearterioles) to those that can be dilated by ischemia metabolites (arterioles). This functional 2-compartment model of resistive vessels is based on the ability of different substances to cause opposite actions on resistive vessels with different sizes. The possible mechanisms of prearteriolar dysfunction, observed in patients with syndrome X, single vessel disease after a successful PTCA and in a subset of chronic stable patients include: an organic reduction of total vascular section; vascular smooth muscle hyperreactivity to heterogeneous constrictor stimuli; an impaired flow-mediated endothelium-dependent vasodilation (possibly due to a reduced NO and/or EDHF synthesis). The first and third hypothesis can only account for anginal episodes at effort while the second model could explain episodes occurring at rest and without an increase in heart rate. Those mechanisms causing an imbalance between myocardial oxygen supply and demand, induce an increased release of adenosine in order to promote a compensating vasodilation. Adenosine can possibly avoid the occurrence of ischemia but, being a powerful algogenic stimulus, causes pain. It is worth noting that the presence of patchy prearteriolar dysfunction induces areas with excessive release of adenosine. Since total vascular section is extremely large a massive adenosine spill-over can occur with a consequential boosting of algogenic and vasodilatory effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mechanisms of coronary microvascular dysfunction]. 802 13

Adenosine has prominent cerebro-protective effect at total brain ischemia. Other nucleotides and nucleosides are less active or have no effect at all. It suggests participation of A-receptors. Adenosine is more effective than 8 other drugs that have protective effect in different models of brain ischemia (nimodipine, gamma-hydroxybutyrate etc).
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PMID:[Protective effect of adenosine in total brain ischemia]. 805 77

We used quantitative in situ hybridization and receptor autoradiography to study changes in adenosine receptors following hypoxia-ischemia (H-I) in the neonatal rat brain. Seven-day-old rat pups were subjected to a unilateral ligation of the common carotid artery followed by a 2 h 15 min hypoxic period (7.7% O2 in N2). Adenosine A1 receptor mRNA in cortex and several parts of hippocampus, and A2a mRNA was decreased in the ligated hemisphere 0 h, 1 h and 2 h following hypoxia. The binding of the A1 receptor selective antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) in the presence or in the absence of GTP decreased immediately after the hypoxic period in both hemispheres and returned thereafter gradually towards control. These results show that there are rapid changes in A1 receptor number on both sides of the brain, and of adenosine A1 and A2a receptor mRNA in the hemisphere that would later develop infarction. Decreases in adenosine receptors may worsen H-I brain damage and have consequences for the use of adenosine directed therapy.
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PMID:Changes in adenosine receptors in the neonatal rat brain following hypoxic ischemia. 809 76

Clinical characteristics: Angina pectoris represents a visceral pain caused by reversible myocardial ischemia. The majority of ischemic attacks are symptomless. When pain is manifested, it appears late during the ischemic event. The pain is complex in its quality and bears little relation to the region of myocardial ischemia. Pain shows a sensitive dependence on initial conditions suggesting a mechanism with deterministic chaotic dynamics for the association between myocardial ischemia and pain. Neurophysiological substrate: Ganglia are present within the heart, particularly in epicardial fat. The blood supply of intrinsic cardiac ganglia arises primarily from branches of the proximal coronary arteries. Both afferent and efferent neurons within the intrinsic cardiac nervous system exist, while the majority of neurons in that location may be local circuit neurons. Integration takes place not only in the intrinsic cardiac nervous system, but also in mediastinal, middle cervical, and stellate ganglia. Cardiac afferent receptors are also connected to cell bodies in dorsal root and nodose ganglia, as well as intrathoracic ganglia. Myocardial regions have no spatial representation in these ganglia. Adenosine, among a number of substances, can modulate the activity generated by cardiac afferent nerve endings and intrinsic cardiac neurons. Such effects appear to be exerted at A1 receptors. Adenosine as a pain messenger: During myocardial ischemia adenosine is released in large quantities into the interstitial space. The endothelium takes up the major amount of adenosine. Thus only small increments of adenosine are detected in the blood-stream. Given as an intravenous bolus to healthy volunteers or to patients with ischemic heart disease and angina pectoris, adenosine provokes angina pectorislike pain, which is similar to habitual angina pectoris with regard to quality and location. Pain is provoked in the absence of ECG signs of ischemia. Patients with asymptomatic myocardial ischemia are less sensitive to adenosine, whereas patients with Syndrome X are more sensitive with respect to adenosine-provoked pain. When adenosine is given intraarterially, including into the coronary arteries, pain is provoked in the corresponding vascular bed. Adenosine-provoked pain and ischemic pain are counteracted by previous administration of the adenosine receptor antagonist theophylline.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of pain in angina pectoris--a critical review of the adenosine hypothesis. 811 Jun 16

Increases in cytosolic free calcium concentration ([Ca2+]I) may play an important role in myocardial ischemic injury. An early effect of the rise in [Ca2+]I may be impaired postischemic contractile function if the ischemic myocardium is reperfused during the reversible phase of ischemic injury; furthermore, if the rise in [Ca2+]I is prolonged, a cascade of events may be initiated which ultimately results in lethal injury. With the development of methods for measuring [Ca2+]I, it has become possible to evaluate directly the role of increased [Ca2+]I in myocardial ischemic injury. Although it has been possible to show that inhibition of the transport processes which contribute to the early rise in [Ca2+]I attenuates stunning and the rise in [Ca2+]I concurrently, if increased [Ca2+]I plays an important role in ischemic injury, then it should be possible to show that interventions which alter the timecourse of ischemic injury also alter the timecourse of the rise in [Ca2+]I in a parallel manner. Recently, considerable effort has been expended to investigate the mechanisms underlying the preconditioning phenomenon, whereby repetitive brief periods of ischemia prior to a sustained period of ischemia protects the myocardium from injury during the sustained period of ischemia, and this has stimulated additional work to understand the possible involvement of adenosine as a mediator of preconditioning as well as to understand the protective effects of adenosine. Measurements of [Ca2+]I using 19F NMR of 5FBAPTA-loaded hearts have shown that preconditioning attenuates the rise in [Ca2+]I during 30 min of ischemia and reduces stunning during reflow. Adenosine pretreatment mimics the effects of preconditioning on the rise in [Ca2+]I and on stunning, but adenosine receptor antagonists do not eliminate the protective effects of preconditioning, although some adenosine antagonists also block hexose transport and under these conditions, the ability of preconditioning to attenuate the rise in [Ca2+]I is abolished and there is a corresponding loss of the protective effect of preconditioning on stunning. Although it has been suggested that the beneficial effect of preconditioning on infarct size can be eliminated by pretreatment with glibenclamide, in the isolated rat heart glibenclamide does not affect the attenuation of the rise in [Ca2+]I induced by preconditioning and does not affect stunning. All of these studies show a consistent relationship between the magnitude of the rise in [Ca2+]I during ischemia and the degree of stunning during reperfusion. The data suggest that increased [Ca2+]I plays a very important role in myocardial ischemic injury.
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PMID:Role of increased cytosolic free calcium concentration in myocardial ischemic injury. 811 51

Adenosine agonists and openers of the ATP-sensitive potassium (KATP) channel have been reported to limit infarct size (IS). We tested the hypothesis that these phenomena are interdependent. Anesthetized swine underwent 60 min of coronary artery occlusion and 90 min of reperfusion. Preconditioning was elicited by two cycles comprising 10 min of occlusion and 10 min of reperfusion (n = 7 swine). An intracoronary infusion of adenosine (Ado; n = 10) or (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; n = 7) replaced preconditioning ischemia. KATP channels were blocked with sodium 5-hydroxydecanoate (5-HD) in the absence (n = 6) or presence (n = 8) of R-PIA. Control pigs (n = 7) received saline vehicle. IS was assessed with tetrazolium and normalized as percentage of area at risk. Preconditioning resulted in a reduced IS compared with Control (3.9 +/- 1.8 vs. 43.5 +/- 6.9%, respectively; P < 0.0005). Ado and R-PIA also reduced IS [21.1 +/- 6.8 (P < 0.01) and 11.2 +/- 7.4% (P < 0.005), respectively]. 5-HD alone did not alter IS, but it abolished R-PIA-induced cardioprotection (IS 5-HD + R-PIA = 48.6 +/- 13.2%). Thus Ado A1-receptor agonists mimicked the cardioprotection of ischemic preconditioning. The Ado-induced limitation of IS was abolished by blockade of the KATP channel. We conclude that both Ado A1 receptors and KATP channels may be involved in ischemic preconditioning.
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PMID:Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel. 814 83

Experiments were carried out to test the hypothesis that preconditioning reduces the impairment of recovery of cardiac mechanical function and that this effect is mediated by activation of adenosine A1 receptors. Isolated hearts were Langendorff-perfused at 37 degrees C with oxygenated blood and paced at 3 Hz. They were divided into 5 groups, all subjected to 45 min global ischemia followed by one hour of reperfusion: 1) Control hearts (n = 7) which received no treatment or short ischemia before the long ischemia, 2) preconditioned hearts (n = 7), submitted to 5-min zero-flow global ischemia, followed by 5 min reperfusion before the long ischemia, 3) hearts pretreated with sulfophenyltheophylline (SPT 100 microM) before preconditioning and long ischemia (n = 6), 4) hearts in which preconditioning was substituted by administration of 10 microM phenyl-isopropyl-adenosine (PIA) over 5 min, and 5) hearts in which preconditioning was substituted by the administration of 1.5 mg adenosine over 5 min. Hemodynamic results show significant improvement of the postischemic recovery of left ventricular developed pressure (DP) by preconditioning. SPT pretreatment did not reverse the improvement of recovery, obtained by preconditioning, whereas PIA treatment could not mimic preconditioning. Adenosine treatment caused some improvement of recovery of DP, but which remained lower compared to that caused by preconditioning. The contracture developed during ischemia persisted in control hearts, whereas contracture disappeared in non-treated preconditioned hearts. SPT did not prevent the decrease in contracture by preconditioning although values remained slightly higher than in the non-treated preconditioned hearts. PIA did not substitute for preconditioning in preventing contracture. In the adenosine treated group, some decrease of contracture occurred during reperfusion, but values remained significantly higher than in preconditioning. We conclude that receptor A1 activation is not the main mechanism underlying improved functional recovery conferred by preconditioning since an A1 receptor blocker (SPT) cannot reverse the effect of preconditioning and an A1 receptor agonist (PIA) cannot mimic it. Administration of exogenous adenosine reduces functional impairment to a certain extent, but less than preconditioning.
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PMID:Improved functional recovery after ischemic preconditioning in the globally ischemic rabbit heart is not mediated by adenosine A1 receptor activation. 814 23


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