Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was undertaken to determine whether endogenous adenosine modulates 'in vivo' neurotransmitter amino acid release via its presynaptic receptors. Two conditions were compared: neuronal depolarization by local infusion of veratridine (600 microM), and transient global ischemia by four-vessel occlusion. Both stimuli were applied for 20 min. Extracellular amino acid (glutamate, taurine/GABA, glycine) variations in concentration were determined in the rat hippocampus by microdialysis and HPLC. Modulation of adenosine receptor activity was objectified by continuous local infusion of an adenosine agonist (R-phenylisopropyladenosine R-PIA) or an antagonist (theophylline), starting one hour before stimulation of amino acid release. R-PIA (100 microM) significantly decreased the glutamate release (50%) evoked by veratridine, whereas it did not significantly modify the ischemia-induced glutamate release. In contrast, theophylline did not significantly affect veratridine-induced glutamate release, but it significantly potentiated glutamate efflux (400%) under ischemic conditions. Neither treatment altered the release of the other amino acids. These data suggest that endogenous adenosine appearing in the extracellular space during veratridine-induced depolarization cannot control glutamate release. In contrast, ischemia-induced glutamate release was strongly inhibited by the concomitant increase in extracellular adenosine.
 ...
PMID:Adenosine modulation of amino acid release in rat hippocampus during ischemia and veratridine depolarization. 849 45

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.
 ...
PMID:Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. 849 46

The aim of this study was to test whether transient inhibition of glucose uptake could precondition the rabbit heart. Rabbit hearts experienced 30 min regional ischemia followed by either 120 min (isolated heart protocol) or 180 min (in situ protocol) reperfusion. Infarct size was determined by tetrazolium staining. In isolated heart experiments, 15 min perfusion with glucose-free Krebs buffer starting 30 min prior to ischemia significantly limited infarct size to 9.9 +/- 2.6% of the risk zone as compared with 29.4 +/- 1.7% infarction in controls. This protection could be blocked (30.8 +/- 3.4%) by polymyxin B (50 microM), a protein kinase C inhibitor, but not by 8-(p-sulfophenyl)theophylline, an adenosine receptor inhibitor, suggesting the mechanism was similar to that of ischemic preconditioning but without involvement of adenosine receptors. Pyruvate and acetate inhibit glucose uptake without incurring a metabolic deficit. When 20 mM pyruvate or 1 mM acetate was added to the glucose-containing buffer for 15 min prior to ischemia, protection was evident (12.0 +/- 3.0% and 10.0 +/- 3.7% infarction, respectively). However, when acetate (1 mM) was present in the perfusate throughout the experiment, neither omission of glucose nor addition of pyruvate caused protection (26.1 +/- 2.2% and 28.9 +/- 4.7% infarction, respectively). Furthermore, when in situ hearts which preferably utilize lipid substrates were treated with pyruvate (2 g/kg i.v. 20 min before ischemia), infarct size was 40.3 +/- 3.0%, which did not differ from that in untreated hearts (38.6 +/- 3.2%). Hence transient inhibition of glucose uptake can precondition the heart, but only if other substrates which are utilized in preference to glucose are absent.
 ...
PMID:Transient inhibition of glucose uptake mimics ischemic preconditioning by salvaging ischemic myocardium in the rabbit heart. 852 49

Ischemic preconditioning has been shown to involve the activation of adenosine receptors, protein kinase C (PKC), and ATP-sensitive K+ (K ATP) channels. We investigated the effects of PKC activation and adenosine on K(ATP) current (I KATP) and action potentials in isolated rabbit ventricular myocytes. Responses to pinacidil (100 to 400 micromol/L), an opener of K(ATP) channels, were markedly increased by preexposure to the PKC activator phorbol 12-myristate 13-acetate (PMA, 100 nmol/L). I(KATP) measured at 0 mV was increased by PMA pretreatment from 0.55 +/- 0.32 to 3.25 +/- 0.47 nA (n=6, P < .01). We next determined whether PKC activation abbreviates the time required to turn on I(KATP) developed after an average of 15.1 +/- 2.4 minutes (n=8). Ten-minute pretreatment with PMA alone (PMA+MI) did not significantly alter this latency (11.9 +/- 2.0 minutes, n=8). Since adenosine receptor activation has been shown to play an important role in the preconditioning response, two groups of myocytes were studied with adenosine (10 micromol/L) included during MI. Without PMA, adenosine alone (MI+Ado) did not affect the latency to develop I(KATP) (12.3 +/- 1.5 minutes, n=8). However, if cells were pretreated with PMA and then subjected to MI in the presence of adenosine (PMA+MI+Ado), the latency was greatly shortened to 5.5 +/- 1.6 minutes (n=8;P < .02 versus MI, PMA+MI, and MI+Ado groups). This effect could not be reproduced by an inactive phorbol but was completely abolished by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline. The opening of K(ATP) channels may be cardioprotective because of the abbreviation of action potential duration (APD) during ischemia. Therefore, we tested whether PKC activation could modify the time course of APD shortening during MI. Consistent with the ionic current measurements, PMA pretreatment significantly accelerated APD shortening, but only when adenosine (10 micromol/L) was included during MI. The effects were not attributable to accelerated ATP consumption: PMA pretreatment did not alter the time required to induce rigor during MI, whether or not adenosine was included. Our results indicate that PKC activation increases the I(KATP) Induced by pinacidil or by MI. The latter effect requires concomitant adenosine receptor activation. The synergistic modulation of I(KATP) by PKC and adenosine provides an explicit basis for current paradigms of ischemic preconditioning.
 ...
PMID:Synergistic modulation of ATP-sensitive K+ currents by protein kinase C and adenosine. Implications for ischemic preconditioning. 859 3

To investigate the effects of the acute administration of aminophylline and nitroglycerin on effort ischemia, 20 patients with syndrome X underwent 3 bicycle exercise tests after sublingual nitroglycerin (0.3 mg) and after 90 minutes of oral administration of aminophylline (400 mg). Compared with the basal test, only aminophylline induced a significant increase in the time to ischemic threshold and to angina; these findings support the potential therapeutic role of this adenosine receptor blocking agents and suggest a possible role of "steal phenomenon" in the pathogenesis of effort angina in patients with syndrome X.
 ...
PMID:Different effects of acute administration of aminophylline and nitroglycerin on exercise capacity in patients with syndrome X. 871 25

PD 81,723 (PD) acts allosterically to increase agonist binding to A1 adenosine receptors and to enhance functional A1 receptor-mediated responses in the heart and other tissues. To determine if PD lowers the threshold for ischemic preconditioning (PC), pentobarbital-anesthetized dogs were subjected to 60 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. Ischemic PC was produced by either 2.5 or 5 minutes of LAD occlusion 10 minutes before the 60-minute occlusion. PD (100 micrograms/kg total dose, 5 to 50 mumol/L in coronary arterial blood) or vehicle was infused intracoronarily for 17.5 minutes before the 60-minute occlusion period in non-PC dogs or in dogs preconditioned with 2.5 minutes of ischemia. Myocardial infarct size was determined by triphenyltetrazolium staining and expressed as a percentage of the area at risk. Compared with the control group (26.3 +/- 3.6%, mean +/- SEM), infarct size was not significantly affected by 2.5 minutes of PC alone (23.4 +/- 4.2%) or by PD alone (26.5 +/- 1.7%) but was decreased by PD + PC (14.6 +/- 1.7%, P < .05) or by a longer period (5 minutes) of PC alone (12.5 +/- 3.3%). The intravenous administration of the selective antagonist of A1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (1 mg/kg), or the ATP-sensitive K+ channel blocker, glibenclamide (0.3 mg/kg), for 15 minutes before PD + PC blocked the protection (23.6 +/- 2.3% or 25.9 +/- 3.3%, respectively). None of the compounds studied affected systemic hemodynamics, collateral blood flow, or AAR. To determine which subtypes of canine adenosine receptors were affected by 10 mumol/L PD, radioligand binding studies were conducted using membranes derived from COS-7 cells expressing recombinant canine receptors and agonist radioligands. PD enhanced the binding of [125I]N6-4-amino-3-iodobenzyladenosine (125I-ABA) to A1 receptors by increasing the t1/2 for dissociation by 2.18-fold, but PD had no effect on the dissociation kinetics of 125I-ABA from A3 receptors or [125I]-[2-(4-amino-3-iodo-phenyl)ethylamino] adenosine from A2A receptors. Glibenclamide at concentrations up to 10 mumol/L had no effect on the binding of radioligands to recombinant canine A1, A2A, or A3 receptors. These data suggest that PD reduces the amount of time required for ischemia to produce preconditioning by enhancing adenosine binding to its A1 receptor. Glibenclamide prevents the protection afforded by A1 receptor activation by a mechanism not involving adenosine receptor blockade.
 ...
PMID:PD 81,723, an allosteric enhancer of the A1 adenosine receptor, lowers the threshold for ischemic preconditioning in dogs. 878 75

Preconditioning with brief ischemia before a sustained period of ischemia reduces infarct size in the perfused heart. A cultured chick ventricular myocyte model was developed to investigate the role of adenosine receptor subtypes in cardiac preconditioning. Brief hypoxic exposure, termed preconditioning hypoxia, prior to prolonged hypoxia, protected myocytes against injury induced by the prolonged hypoxia. Activation of the adenosine A1 receptor with CCPA or the A3 receptor with C1-IB-MECA can replace preconditioning hypoxia and simulate preconditioning, with a maximal effect at 100 nM. While activation of the A2a receptor by 1 microM CGS21680 could not mimic preconditioning, its stimulation during preconditioning hypoxia, however, attenuated the protection against hypoxia-induced injury. Blockade of A2a receptors with the selective antagonist CSC (1 microM) during preconditioning hypoxia enhanced the protective effect of preconditioning. Nifedipine, which blocked the A2a receptor-mediated calcium entry, abolished the A2a agonist-induced attenuation of preconditioning. Isoproterenol, forskolin, and BayK 8644, which stimulated calcium entry, also attenuated preconditioning. Nifedipine blocked the increase in calcium uptake by these agents as well as their attenuating effect on preconditioning. The present study provides the first evidence that the adenosine A3 receptor is present on ventricular myocytes and can mediate simulation of preconditioning. The data demonstrate, for the first time, that activation of the A2a receptor antagonizes the preconditioning effect of adenosine, with increased calcium entry during the preconditioning stimuli as a novel mechanism.
 ...
PMID:Direct preconditioning of cultured chick ventricular myocytes. Novel functions of cardiac adenosine A2a and A3 receptors. 887 27

Adenosine, synthesized by ecto-5'-nucleotidase, is cardioprotective against ischemia and reperfusion injury. We have previously reported that activation of protein kinase C increases ecto-5'-nucleotidase activity of the rat cardiomyocytes, raising the possibility that activation of protein kinase C protects cardiomyocytes from the irreversible cellular injury via activation of ecto-5'-nucleotidase. To test this hypothesis, cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode buffer solution. The cardiomyocytes were incubated with and without exposure to methoxamine (1 x 10(-6) mol/l) or phorbol 12-myristate 13-acetate (PMA. 1 x 10(-8) mol/l). Ecto-5'-nucleotidase activity increased 15 min after the onset of an exposure to either methoxamine or PMA. Adenosine release during hypoxia and reperfusion was augmented in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated cardiomyocytes, which was inhibited by alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase. Irreversible cellular injury assessed by the extent of release of lactate dehydrogenase and the trypan blue exclusion test following 60 min of hypoxia and 60 min of reoxygenation was attenuated in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated group, which was also blunted by AOPCP and 8-sulfophenyltheophylline, an adenosine receptor antagonist. An adenosine A1 receptor agonist, N6-cyclohexyladenosine, restored the cardioprotection under the treatment with PMA and AOPCP. We conclude that activation of ecto-5'-nucleotidase via protein kinase C contributes to the attenuation of the irreversible injury of the rat cardiomyocytes due to hypoxia and reoxygenation.
 ...
PMID:Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes. 889 53

Propentofylline is an atypical xanthine derivative that blocks adenosine uptake and has been shown to protect against ischemia-induced cerebral damage. We have studied the effect of propentofylline on recruitment of polymorphonuclear leukocytes during acute peritonitis induced by zymosan in mice. Following i.p. injection of zymosan, recruitment of polymorphonuclear leukocytes, reflected by myeloperoxidase activity in the peritoneal cavity, increased from 2 h onwards, peaked at 4 h and then decreased gradually. Propentofylline antagonized the zymosan-induced peritoneal myeloperoxidase accumulation in a concentration-dependent manner. This effect of propentofylline was counteracted by the non-selective adenosine receptor antagonist theophylline (50 mg/kg), and by the selective adenosine A2A receptor antagonists, 4-amino-8-chloro-1-phenyl-[1,2,4]-triazolo[4,3-a]quinoxaline (CP 66713) and 1,3-dipropyl-8-[3,4-dimethoxystyryl]-7-methylxanthine (KF 17387) (both at 2 mg/kg). The results indicate that propentofylline can reduce polymorphonuclear leukocyte recruitment in vivo and that this effect is related to an action on adenosine A2A receptors.
 ...
PMID:Propentofylline inhibits polymorphonuclear leukocyte recruitment in vivo by a mechanism involving adenosine A2A receptors. 891 20

The signal transduction of ischemic preconditioning involves activation of endogenous receptor-based systems, including alpha 1-adrenoceptors and adenosine receptors. Whereas preconditioning protects against ischemia-reperfusion injury, it is unknown whether this protective strategy might be useful clinically. Furthermore, human atrium has been successfully preconditioned, but it is unknown whether human ventricle can be functionally protected against hypoxia-reoxygenation. To study these questions, isolated rat ventricle and human ventricular trabeculae were suspended in an organ bath and subjected to 30 min of hypoxia and 60 min of reoxygenation. In the rat ventricle, preconditioning was induced by 5 min of rapid pacing at 3 Hz in hypoxic buffer without glucose (simulated ischemia), alpha 1-adrenoceptor stimulation (phenylephrine), or adenosine receptor stimulation (adenosine). In the human trabeculae the effects of preceding simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation were examined against hypoxia-reoxygenation. In the rat, pretreatment with simulated ischemia and alpha 1-adrenoceptor and adenosine receptor stimulation improved recovery of developed tension (56 +/- 3, 56 +/- 4, and 58 +/- 2%, respectively) compared with control trabeculae (25 +/- 2%) after hypoxia-reoxygenation (P < 0.05). In human trabeculae, simulated ischemic preconditioning and alpha 1-adrenoceptor and adenosine receptor stimulation augmented recovery of developed tension (65 +/- 5, 59 +/- 6, and 60 +/- 3%, respectively) compared with control (29 +/- 2%) after hypoxia-reoxygenation (P < 0.05). We conclude that functional cardioadaptation (preconditioning) against hypoxia-reoxygenation injury in rat and human myocardium exists and that alpha 1-adrenergic and adenosine receptor signaling participate in conferring this protection.
 ...
PMID:Ischemic preconditioning in human and rat ventricle. 894 92


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>