© 1997 American Heart Association, Inc.
Articles |
Hypoxia-Induced Inhibition of Adenosine Kinase Potentiates Cardiac Adenosine Release
From the Institut für Herz und Kreislaufphysiologie (U.K.M.D., G.S., J.S.), Heinrich-Heine-Universität Düsseldorf (Germany), and the Center for Bioengineering (K.K.), University of Washington, Seattle.
Correspondence to Ulrich Decking, MD, Department of Physiology, Heinrich-Heine-University Düsseldorf, PO Box 10 10 07, 40001 Düsseldorf, Germany. E-mail ulrich.decking{at}uni-duesseldorf.de
Abstract To elucidate the physiological
role of the AMP-adenosine metabolic cycle and to
investigate the relation between AMP and adenosine formation,
the O2 supply of isolated guinea pig hearts was varied
(95% to 10% O2). The net adenosine formation rate
(AMP
adenosine) and coronary venous effluent
adenosine release rate were measured; free cytosolic AMP was
determined by 31P-nuclear magnetic resonance. Switching
from 95% to 40% O2 increased free AMP and
adenosine formation 4-fold, whereas free cytosolic
adenosine and venous adenosine release rose 15- to
20-fold. In the AMP range from 200 to 3000 nmol/L, there was a linear
correlation between free AMP and adenosine formation
(R2=.71); however, adenosine release
increased several-fold more than formation. At 95% O2,
only 6% of the adenosine formed was released; however, this
fraction increased to 22% at 40% O2, demonstrating
reduced adenosine salvage. Selective blockade of
adenosine deaminase and adenosine kinase indicated that
flux through adenosine kinase decreased from 85% to 35% of
adenosine formation in hypoxia. Mathematical model
analysis indicated that this apparent decrease in enzyme
activity was not due to saturation but to the inhibition of
adenosine kinase activity to 6% of the basal levels. The data
show (1) that adenosine formation is proportional to the AMP
substrate concentration and (2) that hypoxia decreases
adenosine kinase activity, thereby shunting myocardial
adenosine from the salvage pathway to venous release. In
conclusion, because of the normal high turnover of the
AMP-adenosine metabolic cycle,
hypoxia-induced inhibition of adenosine kinase causes
the amplification of small changes in free AMP into a major rise in
adenosine. This mechanism plays an important role in the high
sensitivity of the cardiac adenosine system to impaired
oxygenation.
Key Words: adenosine • adenosine kinase • hypoxia • 31P nuclear magnetic resonance spectroscopy
This article has been cited by other articles:
 |
|
 |
|
  A. Ohta, A. Ohta, M. Madasu, R. Kini, M. Subramanian, N. Goel, and M. Sitkovsky A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments J. Immunol., November 1, 2009; 183(9): 5487 - 5493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nakav, O. Naamani, C. Chaimovitz, G. Shaked, D. Czeiger, M. Zlotnik, and A. Douvdevani Regulation of adenosine system at the onset of peritonitis Nephrol. Dial. Transplant., October 26, 2009; (2009) gfp542v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hatfield, B. Belikoff, D. Lukashev, M. Sitkovsky, and A. Ohta The antihypoxia-adenosinergic pathogenesis as a result of collateral damage by overactive immune cells J. Leukoc. Biol., September 1, 2009; 86(3): 545 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Frick, C. F. MacManus, M. Scully, L. E. Glover, H. K. Eltzschig, and S. P. Colgan Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis J. Immunol., April 15, 2009; 182(8): 4957 - 4964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Sitkovsky, J. Kjaergaard, D. Lukashev, and A. Ohta Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia Clin. Cancer Res., October 1, 2008; 14(19): 5947 - 5952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Sitkovsky Damage control by hypoxia-inhibited AK Blood, June 15, 2008; 111(12): 5424 - 5425. [Full Text] [PDF]
|
|
|
|
|
|
J. C. Morote-Garcia, P. Rosenberger, J. Kuhlicke, and H. K. Eltzschig HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak Blood, June 15, 2008; 111(12): 5571 - 5580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ohta, D. Lukashev, E. K. Jackson, B. B. Fredholm, and M. Sitkovsky 1,3,7-Trimethylxanthine (Caffeine) May Exacerbate Acute Inflammatory Liver Injury by Weakening the Physiological Immunosuppressive Mechanism J. Immunol., December 1, 2007; 179(11): 7431 - 7438. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. P. Dzeja, P. Bast, D. Pucar, B. Wieringa, and A. Terzic Defective Metabolic Signaling in Adenylate Kinase AK1 Gene Knock-out Hearts Compromises Post-ischemic Coronary Reflow J. Biol. Chem., October 26, 2007; 282(43): 31366 - 31372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Caldwell, J. Tschoep, and A. B. Lentsch Lymphocyte function during hepatic ischemia/reperfusion injury J. Leukoc. Biol., September 1, 2007; 82(3): 457 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Haschemi, O. Wagner, R. Marculescu, B. Wegiel, S. C. Robson, N. Gagliani, D. Gallo, J.-F. Chen, F. H. Bach, and L. E. Otterbein Cross-Regulation of Carbon Monoxide and the Adenosine A2a Receptor in Macrophages J. Immunol., May 1, 2007; 178(9): 5921 - 5929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kong, K. A. Westerman, M. Faigle, H. K. Eltzschig, and S. P. Colgan HIF-dependent induction of adenosine A2B receptor in hypoxia FASEB J, November 1, 2006; 20(13): 2242 - 2250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Y. Tan, C. L. Richard, H. Zhang, D. W. Hoskin, and J. Blay Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway Am J Physiol Cell Physiol, September 1, 2006; 291(3): C433 - C444. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Barnes, H. Dobrzynski, S. Foppolo, P. R. Beal, F. Ismat, E. R. Scullion, L. Sun, J. Tellez, M. W.L. Ritzel, W. C. Claycomb, et al. Distribution and Functional Characterization of Equilibrative Nucleoside Transporter-4, a Novel Cardiac Adenosine Transporter Activated at Acidic pH Circ. Res., September 1, 2006; 99(5): 510 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ohta, E. Gorelik, S. J. Prasad, F. Ronchese, D. Lukashev, M. K. K. Wong, X. Huang, S. Caldwell, K. Liu, P. Smith, et al. A2A adenosine receptor protects tumors from antitumor T cells PNAS, August 29, 2006; 103(35): 13132 - 13137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Vallon, B. Muhlbauer, and H. Osswald Adenosine and kidney function. Physiol Rev, July 1, 2006; 86(3): 901 - 940. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Willems, M. E. Reichelt, J. G. Molina, C.-X. Sun, J. L. Chunn, K. J. Ashton, J. Schnermann, M. R. Blackburn, and J. P. Headrick Effects of adenosine deaminase and A1 receptor deficiency in normoxic and ischaemic mouse hearts Cardiovasc Res, July 1, 2006; 71(1): 79 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Eltzschig, P. Abdulla, E. Hoffman, K. E. Hamilton, D. Daniels, C. Schonfeld, M. Loffler, G. Reyes, M. Duszenko, J. Karhausen, et al. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia J. Exp. Med., December 5, 2005; 202(11): 1493 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. H. Adair Growth regulation of the vascular system: an emerging role for adenosine Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R283 - R296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gallos, T. D. Ruyle, C. W. Emala, and H. T. Lee A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis Am J Physiol Renal Physiol, August 1, 2005; 289(2): F369 - F376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S J. James, P. Cutler, S. Melnyk, S. Jernigan, L. Janak, D. W Gaylor, and J. A Neubrander Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1611 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Olsson Cardiovascular Ecto-5'-Nucleotidase: An End to 40 Years in the Wilderness? Circ. Res., October 15, 2004; 95(8): 752 - 753. [Full Text] [PDF]
|
|
|
|
|
|
P. Koszalka, B. Ozuyaman, Y. Huo, A. Zernecke, U. Flogel, N. Braun, A. Buchheiser, U. K.M. Decking, M. L. Smith, J. Sevigny, et al. Targeted Disruption of cd73/Ecto-5'-Nucleotidase Alters Thromboregulation and Augments Vascular Inflammatory Response Circ. Res., October 15, 2004; 95(8): 814 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Chaudary, Z. Naydenova, I. Shuralyova, and I. R. Coe The Adenosine Transporter, mENT1, Is a Target for Adenosine Receptor Signaling and Protein Kinase C{epsilon} in Hypoxic and Pharmacological Preconditioning in the Mouse Cardiomyocyte Cell Line, HL-1 J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 1190 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhang, D. M. Conrad, J. J. Butler, C. Zhao, J. Blay, and D. W. Hoskin Adenosine Acts through A2 Receptors to Inhibit IL-2-Induced Tyrosine Phosphorylation of STAT5 in T Lymphocytes: Role of Cyclic Adenosine 3',5'-Monophosphate and Phosphatases J. Immunol., July 15, 2004; 173(2): 932 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lukashev, A. Ohta, S. Apasov, J.-F. Chen, and M. Sitkovsky Cutting Edge: Physiologic Attenuation of Proinflammatory Transcription by the Gs Protein-Coupled A2A Adenosine Receptor In Vivo J. Immunol., July 1, 2004; 173(1): 21 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Y. Tan, M. Mujoomdar, and J. Blay Adenosine Down-Regulates the Surface Expression of Dipeptidyl Peptidase IV on HT-29 Human Colorectal Carcinoma Cells: Implications for Cancer Cell Behavior Am. J. Pathol., July 1, 2004; 165(1): 319 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Inbe, S. Watanabe, M. Miyawaki, E. Tanabe, and J. A. Encinas Identification and Characterization of a Cell-Surface Receptor, P2Y15, for AMP and Adenosine J. Biol. Chem., May 7, 2004; 279(19): 19790 - 19799. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B Blood, C. J Hunter, and G. G Power Adenosine mediates decreased cerebral metabolic rate and increased cerebral blood flow during acute moderate hypoxia in the near-term fetal sheep J. Physiol., December 15, 2003; 553(3): 935 - 945. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Jackson, Z. Mi, C. Zhu, and R. K. Dubey Adenosine Biosynthesis in the Collecting Duct J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 888 - 896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Headrick, B. Hack, and K. J. Ashton Acute adenosinergic cardioprotection in ischemic-reperfused hearts Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H1797 - H1818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lu, A. Pierron, and K. Ravid An Adenosine Analogue, IB-MECA, Down-Regulates Estrogen Receptor {alpha} and Suppresses Human Breast Cancer Cell Proliferation Cancer Res., October 1, 2003; 63(19): 6413 - 6423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Fredholm, A. P. IJzerman, K. A. Jacobson, K.-N. Klotz, and J. Linden International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors Pharmacol. Rev., December 1, 2001; 53(4): 527 - 552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Mubagwa and W. Flameng Adenosine, adenosine receptors and myocardial protection: An updated overview Cardiovasc Res, October 1, 2001; 52(1): 25 - 39. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. K.M. Decking, J. P. Williams, R. Dahmann, T. Stumpe, M. Kelm, and J. Schrader The nitric oxide-induced reduction in cardiac energy supply is not due to inhibition of creatine kinase Cardiovasc Res, August 1, 2001; 51(2): 313 - 321. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nishiyama, S. Kimura, H. He, K. Miura, M. Rahman, Y. Fujisawa, T. Fukui, and Y. Abe Renal interstitial adenosine metabolism during ischemia in dogs Am J Physiol Renal Physiol, February 1, 2001; 280(2): F231 - F238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-W. Gu, B. R. Ito, A. Sartin, N. Frascogna, M. Moore, and T. H. Adair Inhibition of adenosine kinase induces expression of VEGF mRNA and protein in myocardial myoblasts Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2116 - H2123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Rosenberg, Y. Li, M. Le, and Y. Zhang Nitric Oxide-Stimulated Increase in Extracellular Adenosine Accumulation in Rat Forebrain Neurons in Culture Is Associated with ATP Hydrolysis and Inhibition of Adenosine Kinase Activity J. Neurosci., August 15, 2000; 20(16): 6294 - 6301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. F. Pauly and C. J. Pepine D-Ribose as a Supplement for Cardiac Energy Metabolism Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 249 - 258. [Abstract] [PDF]
|
|
|
|
|
|
L. A Gustafson, C. J Zuurbier, J. E Bassett, J. P. F Barends, J. H.G.M van Beek, J. B Bassingthwaighte, and K. Kroll Increased hypoxic stress decreases AMP hydrolysis in rabbit heart Cardiovasc Res, November 1, 1999; 44(2): 333 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Winegrad, D. Henrion, L. Rappaport, and J. L. Samuel Self-Protection by Cardiac Myocytes Against Hypoxia and Hyperoxia Circ. Res., October 15, 1999; 85(8): 690 - 698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Carmeliet Cardiac Ionic Currents and Acute Ischemia: From Channels to Arrhythmias Physiol Rev, July 1, 1999; 79(3): 917 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Costa, P. Sulur, M. Angel, J. Cavalcante, V. Haile, B. Christman, and I. Biaggioni Intravascular Source of Adenosine During Forearm Ischemia in Humans : Implications for Reactive Hyperemia Hypertension, June 1, 1999; 33(6): 1453 - 1457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Dzeja and A. Terzic Phosphotransfer reactions in the regulation of ATP-sensitive K+ channels FASEB J, May 1, 1998; 12(7): 523 - 529. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. E. Alekseev, P. A. Brady, and A. Terzic Ligand-insensitive State of Cardiac ATP-sensitive K+ Channels: Basis for Channel Opening J. Gen. Physiol., February 1, 1998; 111(2): 381 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Gustafson and K. Kroll Downregulation of 5'-nucleotidase in rabbit heart during coronary underperfusion Am J Physiol Heart Circ Physiol, February 1, 1998; 274(2): H529 - H538. [Abstract] [Full Text] [PDF]
|
|