adenosine-kinase has been researched along with Myocardial-Ischemia* in 6 studies
6 other study(ies) available for adenosine-kinase and Myocardial-Ischemia
Article | Year |
---|---|
Protecting murine hearts from ischaemia-reperfusion using selective inhibitors of adenosine metabolism.
1. By selectively modifying adenosine metabolism via adenosine deaminase or adenosine kinase inhibitors, it may be possible to enhance the receptor-mediated protective actions of adenosine in a site- and event-specific fashion. 2. We characterized cardioprotective actions of the adenosine deaminase inhibitor erythro-2-(2-hydroxy-3-non-yl)adenine (EHNA) and the adenosine kinase inhibitor iodotubercidin in C57/Bl6 mouse hearts subjected to 20 min global normothermic ischaemia and 40 min reperfusion. 3. Ventricular pressure development only recovered to 45 +/- 2% of baseline levels (67 +/- 5 mmHg) in untreated hearts, with sustained and pronounced diastolic contracture (25 +/- 2 mmHg). Treatment with 20 micromol/L EHNA increased recovery of ventricular pressure (107 +/- 9 mmHg), reduced postischaemic diastolic pressure (13 +/- 1 mmHg) and reduced loss of lactate dehydrogenase (LDH; an indicator of necrotic damage) by 50% (9 +/- 2 vs 19 +/- 2 IU/g). Adenosine kinase inhibition with 10 micromol/L iodotubercidin also improved pressure development (to 100 +/- 8 mmHg) and reduced LDH efflux (5 +/- 2 IU/g). 4. Protective actions were mimicked by adenosine and inhibited by adenosine receptor antagonism (50 micromol/L 8-rho-sulfophenyltheophylline) and mitochondrial K(ATP) channel inhibition (50 micromol/L 5-hydroxydecanoate). 5. Coinfusion of the inhibitors, 'trapping' formed adenosine, failed to exert protection and, in some instances, was detrimental. Although substantial benefit was gained by these agents in hearts from young animals, neither inhibitor was effective in 'aged' hearts (18 months). 6. Our data demonstrate that adenosine deaminase or kinase inhibition substantially limits injury during ischaemia-reperfusion. Protection involves adenosine receptor activation. However, cardioprotection via either enzyme inhibitor requires an alternative purine-salvage pathway to be functional and was reduced in aged hearts known to be increasingly susceptible to ischaemic damage. Topics: Adenosine; Adenosine Deaminase Inhibitors; Adenosine Kinase; Animals; Coronary Circulation; In Vitro Techniques; Mice; Mice, Inbred C57BL; Myocardial Ischemia; Myocardial Reperfusion Injury; Ventricular Pressure | 2005 |
Cardioprotection following adenosine kinase inhibition in rat hearts.
Adenosine kinase phosphorylates adenosine to AMP, the primary pathway for adenosine metabolism under basal conditions. Inhibition of adenosine kinase results in a site-specific increase in interstitial adenosine. Using a rat model of myocardial infarction, we examined the protective effects of adenosine kinase inhibition. Male Sprague-Dawley rats underwent 30 min regional occlusion followed by 90 min reperfusion. Infarct size, expressed as a percent of the area-at-risk, IS/AAR(%), was 58.0 +/- 2.1 % in untreated rats. Pretreatment with the adenosine kinase inhibitor, 5-iodotubercidin (1 mg/kg), limited infarct development to 37.5+/-3.7% (P < 0.001). The A(1) adenosine receptor (A(1)AR) antagonist, DPCPX (100 microg/kg), abolished the infarct-sparing effect of 5-iodotubercidin (IS, 62.8 +/- 1.3%). Similarly, the A(3) adenosine receptor (A(3)AR) antagonist, MRS-1523 (2 mg/kg), and the delta-opioid receptor (DOR) antagonist, BNTX, (1 mg/kg) abolished the reduction of IS produced by iodotubercidin. Pretreatment with the ROS scavenger, 2-MPG (20 mg/kg), or the PKC-delta antagonist, rottlerin (0.3 mg/kg) also abolished iodotubercidin-mediated cardioprotection. Furthermore, pretreatment with 5-HD, a mitochondrial K(ATP) (mitoK(ATP)) channel inhibitor, but not the sarcolemmal K(ATP) channel blocker, HMR-1098, abrogated the beneficial effects of adenosine kinase inhibition (IS, 59.5 +/- 3.8%). These data suggest that inhibition of adenosine kinase is effective in reducing infarct development via A(1)AR, A(3)AR and DOR activation. Data also suggest that this protection is mediated via ROS, PKC-delta and mitoK(ATP) channels. Topics: Adenosine Kinase; Animals; Enzyme Inhibitors; Heart Rate; Male; Myocardial Infarction; Myocardial Ischemia; Potassium Channels; Protective Agents; Protein Kinase C; Protein Kinase C-delta; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, G-Protein-Coupled; Signal Transduction | 2005 |
Receptor and non-receptor-dependent mechanisms of cardioprotection with adenosine.
The relative roles of mitochondrial (mito) ATP-sensitive K(+) (mitoK(ATP)) channels, protein kinase C (PKC), and adenosine kinase (AK) in adenosine-mediated protection were assessed in Langendorff-perfused mouse hearts subjected to 20-min ischemia and 45-min reperfusion. Control hearts recovered 72 +/- 3 mmHg of ventricular pressure (50% preischemia) and released 23 +/- 2 IU/g lactate dehydrogenase (LDH). Adenosine (50 microM) during ischemia-reperfusion improved recovery (149 +/- 8 mmHg) and reduced LDH efflux (5 +/- 1 IU/g). Treatment during ischemia alone was less effective. Treatment with 50 microM diazoxide (mitoK(ATP) opener) during ischemia and reperfusion enhanced recovery and was equally effective during ischemia alone. A(3) agonism [100 nM 2-chloro-N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide], A(1) agonism (N(6)-cyclohexyladenosine), and AK inhibition (10 microM iodotubercidin) all reduced necrosis to the same extent as adenosine, but less effectively reduced contractile dysfunction. These responses were abolished by 100 microM 5-hydroxydecanoate (5-HD, mitoK(ATP) channel blocker) or 3 microM chelerythrine (PKC inhibitor). However, the protective effects of adenosine during ischemia-reperfusion were resistant to 5-HD and chelerythrine and only abolished when inhibitors were coinfused with iodotubercidin. Data indicate adenosine-mediated protection via A(1)/A(3) adenosine receptors is mitoK(ATP) channel and PKC dependent, with evidence for a downstream location of PKC. Adenosine provides additional and substantial protection via phosphorylation to 5'-AMP, primarily during reperfusion. Topics: Adenosine; Adenosine Kinase; Adenosine Triphosphate; Animals; Cardiotonic Agents; Diazoxide; Drug Administration Schedule; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium Channels; Protein Kinase C; Purinergic P1 Receptor Agonists; Recovery of Function | 2003 |
Dual cardiac microdialysis to assess drug-induced changes in interstitial purine metabolites: adenosine deaminase inhibition versus adenosine kinase inhibition.
The purpose of this study was: 1) to evaluate a dual microdialysis technique coupled with local drug administration in the regionally ischemic rabbit heart, and; 2) to assess the ischemia-induced changes in interstitial fluid (ISF) adenosine during inhibition of adenosine deaminase or adenosine kinase.. Two microdialysis probes were implanted parallel to each other and separated by 5 mm in myocardium perfused by a branch of the left coronary artery. Probes were used to sample myocardial ISF and to deliver drugs locally to the myocardium; purine metabolite concentrations in the collected dialysate were used as indices of ISF levels. Three groups of pentobarbital-anesthetized rabbits were studied. In a control group (n = 6), both probes were perfused with Krebs-Henseleit buffer. In the second and third groups, one probe was perfused with buffer, whereas the other probe was perfused with buffer containing 1 mM erythro-2-(2-hydroxy-3-nonyl)adenine (EHNA) (n = 5), an adenosine deaminase inhibitor, or 10 microM iodotubercidin (n = 9), an adenosine kinase inhibitor. All animals were exposed to 30 min of regional myocardial ischemia followed by 60 min of reperfusion.. In the control group, similar increases in dialysate purine metabolites during ischemia were observed in both probes. Locally administered EHNA increased dialysate adenosine prior to ischemia and decreased dialysate inosine and hypoxanthine. During ischemia, the increase in dialysate adenosine in the EHNA-perfused probe was markedly augmented, while the increases in inosine and hypoxanthine were attenuated. In contrast, local infusion of iodotubercidin did not alter dialysate purine metabolites before ischemia, but there was a modest augmentation of adenosine during ischemia. These data illustrate the feasibility of dual microdialysis for assessing the effect of locally administered compounds on interstitial metabolite concentration in the regionally ischemic rabbit heart. Furthermore, adenosine deaminase inhibition has a more profound adenosine augmenting effect than adenosine kinase inhibition in the rabbit heart. Topics: Adenine; Adenosine; Adenosine Deaminase Inhibitors; Adenosine Kinase; Animals; Chromatography, High Pressure Liquid; Extracellular Space; Hypoxanthine; Inosine; Male; Microdialysis; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Rabbits; Tubercidin | 1998 |
Ion-exchange column chromatographic method for assaying purine metabolic pathway enzymes.
High energy phosphate levels fall rapidly during cardiac ischemia and recover slowly (more than one week) during reperfusion. The slow recovery of ATP may reflect a lack of purine metabolic precursors and/or increased activity of purine catabolic enzymes such as 5'-nucleotidase (5'-NT, EC 3.1.3.5) and adenosine deaminase (ADA, EC 3.5.4.4). The activity of enzymes involved in both the catabolism of ATP precursors (5-NT and ADA) and the restoration of ATP from slow synthetic pathways [adenosine kinase (AK, EC 2.7.1.20), adenine phosphoribosyl transferase (APRT, EC 2.4.2.7) and hypoxanthine phosphoribosyl transferase (HPRT, EC 2.4.2.8)] may directly affect the rate of ATP recovery. Strategies to enhance recovery will depend on the relative activity of these enzymes following ischemia. Their activity in different species and their response to ischemia are not well characterized. Hence, rapid assay methods for these enzymes would facilitate detailed time course studies of their activities in postischemic myocardium. We modified a single ion-exchange column chromatographic method using DEAE-Sephadex to determine the products of incubation of 5'-NT, AK, APRT and HPRT with their respective substrates. The uniformity of the final product measurement procedure for all assays permits the activities of the four enzymes to be rapidly determined in a single tissue sample and facilitates the study of a large number of samples. This technique should also be useful for enzymes of the pyrimidine metabolic pathway. Topics: 5'-Nucleotidase; Adenine Phosphoribosyltransferase; Adenosine Kinase; Chromatography, Ion Exchange; Humans; Hypoxanthine Phosphoribosyltransferase; Indicators and Reagents; Myocardial Ischemia; Myocardial Reperfusion Injury; Purines; Specimen Handling | 1998 |
Preservation of global cardiac function in the rabbit following protracted ischemia/reperfusion using monophosphoryl lipid A (MLA).
Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of lipopolysaccharide (lipid A) possesses immunomodulatory activity of the parent lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces myocardial infarct size and stunning in dogs following ischemia and reperfusion. The aim of this study was to evaluate the ability of monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged ischemia MLA pretreatment did not reduce infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and adenosine catabolite pools at the end of ischemia indicated a preservation of ATP and ADP and a decreased production of downstream adenosine catabolites including inosine, xanthine and uric acid. Adenosine kinase, but not 5'-nucleotidase (5'-NTase) or adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of adenosine catabolites during ischemia; (3) elevated myocardial adenosine kinase activity. Increased recycling of adenosine to phosphorylated nucleotides may result from MLA's affect on adenosine kinase, which could explain the drugs effect on adenylate and adenosine metabolite pools. Topics: 5'-Nucleotidase; Adenine Nucleotides; Adenosine Deaminase; Adenosine Kinase; Adjuvants, Immunologic; Analysis of Variance; Animals; Blood Pressure; Carbohydrate Sequence; Coronary Vessels; Energy Metabolism; Female; Heart; Heart Rate; Hemodynamics; Lipid A; Molecular Sequence Data; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Peroxidase; Purines; Rabbits; Reference Values; Ventricular Function, Left | 1996 |