Skip to main content

Advertisement

SpringerLink
Log in

Adenosine: trigger and mediator of cardioprotection

  • INVITED REVIEW
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Adenosine, a purine nucleoside, is ubiquitous in the body, and is a critical component of ATP. Its concentration jumps 100-fold during periods of oxygen depletion and ischemia. There are four adenosine receptors: A1 and A3 coupled to Gi/o and the high-affinity A2A and low-affinity A2B coupled to Gs. Adenosine is one of three autacoids released by ischemic tissue which are important triggers of ischemic preconditioning (IPC). It is the A1 and to some extent A3 receptors which participate in the intracellular signaling that triggers cardioprotection. Unlike bradykinin and opioids, the other two autacoids, adenosine is not dependent on opening of mitochondrial KATP channels or release of reactive oxygen species (ROS), but rather activates phospholipase C and/or protein kinase C (PKC) directly. Another signaling cascade at reperfusion involves activated PKC which initiates binding to and activation of an A2 adenosine receptor that we believe is the A2B. Although the latter is the low-affinity receptor, its interaction with PKC increases its affinity and makes it responsive to the accumulated tissue adenosine. A2B agonists, but not adenosine or A1 agonists, infused at reperfusion can initiate this second signaling cascade and mimic preconditioning’s protection. The same A2B receptors are critical for postconditioning’s protection. Thus adenosine is both an important trigger and a mediator of cardioprotection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Auchampach JA, Gross GJ (1993) Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs. Am J Physiol 264:H1327–H1336

    PubMed  CAS  Google Scholar 

  2. Auchampach JA, Jin X, Moore J, Wan TC, Kreckler LM, Ge Z-D, Narayanan J, Whalley E, Kiesman W, Ticho B, Smits G, Gross GJ (2004) Comparison of three different A1 adenosine receptor antagonists on infarct size and multiple cycle ischemic preconditioning in anesthetized dogs. J Pharmacol Exp Ther 308:846–856

    PubMed  CAS  Google Scholar 

  3. Auchampach JA, Rizvi A, Qiu Y, Tang X-L, Maldonado C, Teschner S, Bolli R (1997) Selective activation of A3 adenosine receptors with N 6-(3-iodobenzyl) adenosine-5′-N-methyluronamide protects against myocardial stunning and infarction without hemodynamic changes in conscious rabbits. Circ Res 80:800–809

    PubMed  CAS  Google Scholar 

  4. Baxter GF, Hale SL, Miki T, Kloner RA, Cohen MV, Downey JM, Yellon DM (2000) Adenosine A1 agonist at reperfusion trial (AART): results of a three-center, blinded, randomized, controlled experimental infarct study. Cardiovasc Drugs Ther 14:607–614

    PubMed  CAS  Google Scholar 

  5. Billah MM, Anthes JC (1990) The regulation and cellular functions of phosphatidylcholine hydrolysis. Biochem J 269:281–291

    PubMed  CAS  Google Scholar 

  6. Bolli R, Dawn B, Xuan Y-T (2003) Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc Med 13:72–79

    PubMed  CAS  Google Scholar 

  7. Brooks G, Hearse DJ (1996) Role of protein kinase C in ischemic preconditioning: player or spectator? Circ Res 79:627–630

    PubMed  CAS  Google Scholar 

  8. Budde JM, Velez DA, Zhao Z-Q, Clark KL, Morris CD, Muraki S, Guyton RA, Vinten-Johansen J (2000) Comparative study of AMP579 and adenosine in inhibition of neutrophil-mediated vascular and myocardial injury during 24 h of reperfusion. Cardiovasc Res 47:294–305

    PubMed  CAS  Google Scholar 

  9. Chen W, Glasgow W, Murphy E, Steenbergen C (1999) Lipoxygenase metabolism of arachidonic acid in ischemic preconditioning and PKC-induced protection in heart. Am J Physiol 276:H2094–H2101

    PubMed  CAS  Google Scholar 

  10. Cohen MV, Philipp S, Krieg T, Cui L, Kuno A, Solodushko V, Downey JM (2007) Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways. J Mol Cell Cardiol 42:842–851

    PubMed  CAS  Google Scholar 

  11. Cohen MV, Yang X-M, Downey JM (2007) The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation 115:1895–1903

    PubMed  Google Scholar 

  12. Cohen MV, Yang X-M, Liu GS, Heusch G, Downey JM (2001) Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial KATP channels. Circ Res 89:273–278

    PubMed  CAS  Google Scholar 

  13. Costa ADT, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD (2005) Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res 97:329–336

    PubMed  CAS  Google Scholar 

  14. Deussen A, Brand M, Pexa A, Weichsel J (2007) Metabolic coronary flow regulation—current concepts. Basic Res Cardiol 101:453–464

    Google Scholar 

  15. Deussen A, Stappert M, Schäfer S, Kelm M (1999) Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation 99:2041–2047

    PubMed  CAS  Google Scholar 

  16. Eaton P, Fuller W, Bell JR, Shattock MJ (2001) αB crystallin translocation and phosphorylation: signal transduction pathways and preconditioning in the isolated rat heart. J Mol Cell Cardiol 33:1659–1671

    PubMed  CAS  Google Scholar 

  17. Eckle T, Krahn T, Grenz A, Köhler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K, Eltzschig HK (2007) Cardioprotection by ecto-5′-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115:1581–1590

    PubMed  CAS  Google Scholar 

  18. Förster K, Paul I, Solenkova N, Staudt A, Cohen MV, Downey JM, Felix SB, Krieg T (2006) NECA at reperfusion limits infarction and inhibits formation of the mitochondrial permeability transition pore by activating p70S6 kinase. Basic Res Cardiol 101:319–326

    PubMed  Google Scholar 

  19. Fredholm BB, Ijzerman AP, Jacobson KA, Klotz K-N, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    PubMed  CAS  Google Scholar 

  20. Goto M, Liu Y, Yang X-M, Ardell JL, Cohen MV, Downey JM (1995) Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res 77:611–621

    PubMed  CAS  Google Scholar 

  21. Goto M, Miura T, Iliodoromitis EK, O’Leary EL, Ishimoto R, Yellon DM, Iimura O (1991) Adenosine infusion during early reperfusion failed to limit myocardial infarct size in a collateral deficient species. Cardiovasc Res 25:943–949

    PubMed  CAS  Google Scholar 

  22. Gres P, Schulz R, Jansen J, Umschlag C, Heusch G (2002) Involvement of endogenous prostaglandins in ischemic preconditioning in pigs. Cardiovasc Res 55:626–632

    PubMed  CAS  Google Scholar 

  23. Griffiths EJ, Halestrap AP (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion. Biochem J 307:93–98

    PubMed  CAS  Google Scholar 

  24. Guo Y, Bolli R, Bao W, Wu W-J, Black RG Jr, Murphree SS, Salvatore CA, Jacobson MA, Auchampach JA (2001) Targeted deletion of the A3 adenosine receptor confers resistance to myocardial ischemic injury and does not prevent early preconditioning. J Mol Cell Cardiol 33:825–830

    PubMed  CAS  Google Scholar 

  25. Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddiqui MAQ, Das DK (2001) Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 33:1929–1936

    PubMed  CAS  Google Scholar 

  26. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM (2002) Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res 55:534–543

    PubMed  CAS  Google Scholar 

  27. Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM (2005) Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol 288:H971–H976

    CAS  Google Scholar 

  28. Hausenloy DJ, Wynne AM, Yellon DM (2007) Ischemic preconditioning targets the reperfusion phase. Basic Res Cardiol 102:445–452

    PubMed  CAS  Google Scholar 

  29. Hausenloy DJ, Yellon DM, Mani-Babu S, Duchen MR (2004) Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol 287:H841–H849

    CAS  Google Scholar 

  30. Headrick JP (1996) Ischemic preconditioning: bioenergetic and metabolic changes and the role of endogenous adenosine. J Mol Cell Cardiol 28:1227–1240

    PubMed  CAS  Google Scholar 

  31. Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, Garcia-Dorado D, Di Lisa F, Schulz R, Heusch G (2005) Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res 97:583–586

    PubMed  CAS  Google Scholar 

  32. Heusch G (2004) Postconditioning: old wine in a new bottle? J Am Coll Cardiol 44:1111–1112

    PubMed  Google Scholar 

  33. Inagaki K, Begley R, Ikeno F, Mochly-Rosen D (2005) Cardioprotection by ε-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an ε-protein kinase C-activating peptide. Circulation 111:44–50

    PubMed  CAS  Google Scholar 

  34. Juhaszova M, Zorov DB, Kim S-H, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ (2004) Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 113:1535–1549

    PubMed  CAS  Google Scholar 

  35. Kilpatrick EL, Narayan P, Mentzer RM Jr, Lasley RD (2002) Cardiac myocyte adenosine A2a receptor activation fails to alter cAMP or contractility: role of receptor localization. Am J Physiol 282:H1035–H1040

    CAS  Google Scholar 

  36. Kin H, Zatta AJ, Lofye MT, Amerson BS, Halkos ME, Kerendi F, Zhao Z-Q, Guyton RA, Headrick JP, Vinten-Johansen J (2005) Postconditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res 67:124–133

    PubMed  CAS  Google Scholar 

  37. Kis A, Baxter GF, Yellon DM (2003) Limitation of myocardial reperfusion injury by AMP579, an adenosine A1/A2A receptor agonist: role of A2A receptor and Erk1/2. Cardiovasc Drugs Ther 17:415–425

    PubMed  CAS  Google Scholar 

  38. Kitakaze M, Funaya H, Minamino T, Node K, Sato H, Ueda Y, Okuyama Y, Kuzuya T, Hori M, Yoshida K-i (1997) Role of protein kinase C-α in activation of ecto-5′-nucleotidase in the preconditioned canine myocardium. Biochem Biophys Res Commun 239:171–175

    PubMed  CAS  Google Scholar 

  39. Klotz K-N (2000) Adenosine receptors and their ligands. Naunyn-Schmiedeberg’s Arch Pharmacol 362:382–391

    Google Scholar 

  40. Kohl C, Linck B, Schmitz W, Scholz H, Scholz J, Tóth M (1990) Effects of carbachol and (-)-N 6-phenylisopropyladenosine on myocardial inositol phosphate content and force of contraction. Br J Pharmacol 101:829–834

    PubMed  CAS  Google Scholar 

  41. Korichneva I, Hoyos B, Chua R, Levi E, Hammerling U (2002) Zinc release from protein kinase C as the common event during activation by lipid second messenger or reactive oxygen. J Biol Chem 277:44327–44331

    PubMed  CAS  Google Scholar 

  42. Krieg T, Cui L, Qin Q, Cohen MV, Downey JM (2004) Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF. J Mol Cell Cardiol 36:435–443

    PubMed  CAS  Google Scholar 

  43. Krieg T, Landsberger M, Alexeyev MF, Felix SB, Cohen MV, Downey JM (2003) Activation of Akt is essential for acetylcholine to trigger generation of oxygen free radicals. Cardiovasc Res 58:196–202

    PubMed  CAS  Google Scholar 

  44. Krieg T, Qin Q, McIntosh EC, Cohen MV, Downey JM (2002) ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. Am J Physiol 283:H2322–H2330

    CAS  Google Scholar 

  45. Krieg T, Qin Q, Philipp S, Alexeyev MF, Cohen MV, Downey JM (2004) Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS. Am J Physiol 287:H2606–H2611

    CAS  Google Scholar 

  46. Kuno A, Critz SD, Cui L, Solodushko V, Yang X-M, Krahn T, Albrecht B, Philipp S, Cohen MV, Downey JM (2007) Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A2b-dependent signaling during early reperfusion. J Mol Cell Cardiol 43:262–271

    PubMed  CAS  Google Scholar 

  47. Lankford AR, Yang J-N, Rose’Meyer R, French BA, Matherne GP, Fredholm BB, Yang Z (2006) Effect of modulating cardiac A1 adenosine receptor expression on protection with ischemic preconditioning. Am J Physiol 290:H1469–H1473

    CAS  Google Scholar 

  48. Lee JE, Bokoch G, Liang BT (2001) A novel cardioprotective role of RhoA: new signaling mechanism for adenosine. FASEB J 15:1886–1894

    PubMed  CAS  Google Scholar 

  49. Linden J, Thai T, Figler H, Jin X, Robeva AS (1999) Characterization of human A2B adenosine receptors: radioligand binding, western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol 56:705–713

    PubMed  CAS  Google Scholar 

  50. Liu GS, Richards SC, Olsson RA, Mullane K, Walsh RS, Downey JM (1994) Evidence that the adenosine A3 receptor may mediate the protection afforded by preconditioning in the isolated rabbit heart. Cardiovasc Res 28:1057–1061

    PubMed  CAS  Google Scholar 

  51. Liu GS, Thornton J, Van Winkle DM, Stanley AWH, Olsson RA, Downey JM (1991) Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 84:350–356

    PubMed  CAS  Google Scholar 

  52. Liu Y, Downey JM (1992) Ischemic preconditioning protects against infarction in rat heart. Am J Physiol 263:H1107–H1112

    PubMed  CAS  Google Scholar 

  53. Mackay K, Mochly-Rosen D (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J Biol Chem 274:6272–6279

    PubMed  CAS  Google Scholar 

  54. Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB (1999) Adenosine as an adjunct to thrombolytic therapy for actue myocardial infarction. Results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) Trial. J Am Coll Cardiol 34:1711–1720

    PubMed  CAS  Google Scholar 

  55. Maulik N, Watanabe M, Zu Y-L, Huang C-K, Cordis GA, Schley JA, Das DK (1996) Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat hearts. FEBS Lett 396:233–237

    PubMed  CAS  Google Scholar 

  56. McVey MJ, Smits GJ, Cox BF, Kitzen JM, Clark KL, Perrone MH (1999) Cardiovascular pharmacology of the adenosine A1/A2-receptor agonist AMP 579: coronary hemodynamic and cardioprotective effects in the canine myocardium. J Cardiovasc Pharmacol 33:703–710

    PubMed  CAS  Google Scholar 

  57. Miki T, Cohen MV, Downey JM (1998) Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. Mol Cell Biochem 186:3–12

    PubMed  CAS  Google Scholar 

  58. Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM (2000) The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. Basic Res Cardiol 95:472–478

    PubMed  CAS  Google Scholar 

  59. Mubagwa K, Flameng W (2001) Adenosine, adenosine receptors and myocardial protection: an updated overview. Cardiovasc Res 52:25–39

    PubMed  CAS  Google Scholar 

  60. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    PubMed  CAS  Google Scholar 

  61. Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ, Jiang R, Guyton RA, Vinten-Johansen J, Zhao Z-Q (2007) Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol 102:90–100

    PubMed  CAS  Google Scholar 

  62. Nakano A, Cohen MV, Critz S, Downey JM (2000) SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts. Basic Res Cardiol 95:466–471

    PubMed  CAS  Google Scholar 

  63. Napoli C, Liguori A, Chiariello M, Di Ieso N, Condorelli M, Ambrosio G (1998) New-onset angina preceding acute myocardial infarction is associated with improved contractile recovery after thrombolysis. Eur Heart J 19:411–419

    PubMed  CAS  Google Scholar 

  64. Natarajan V, Taher MM, Roehm B, Parinandi NL, Schmid HHO, Kiss Z, Garcia JGN (1993) Activation of endothelial cell phospholipase D by hydrogen peroxide and fatty acid hydroperoxide. J Biol Chem 268:930–937

    PubMed  CAS  Google Scholar 

  65. Norton ED, Jackson EK, Turner MB, Virmani R, Forman MB (1992) The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury. Am Heart J 123:332–338

    PubMed  CAS  Google Scholar 

  66. Norton ED, Jackson EK, Virmani R, Forman MB (1991) Effect of intravenous adenosine on myocardial reperfusion injury in a model with low myocardial collateral blood flow. Am Heart J 122:1283–1291

    PubMed  CAS  Google Scholar 

  67. Olafsson B, Forman MB, Puett DW, Pou A, Cates CU, Friesinger GC, Virmani R (1987) Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation 76:1135–1145

    PubMed  CAS  Google Scholar 

  68. Oldenburg O, Qin Q, Krieg T, Yang X-M, Philipp S, Critz SD, Cohen MV, Downey JM (2004) Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. Am J Physiol 286:H468–H476

    CAS  Google Scholar 

  69. Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliaro P (2006) Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol 101:180–189

    PubMed  CAS  Google Scholar 

  70. Philipp S, Yang X-M, Cui L, Davis AM, Downey JM, Cohen MV (2006) Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade. Cardiovasc Res 70:308–314

    PubMed  CAS  Google Scholar 

  71. Ping P, Zhang J, Qiu Y, Tang X-L, Manchikalapudi S, Cao X, Bolli R (1997) Ischemic preconditioning induces selective translocation of protein kinase C isoforms ε and η in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res 81:404–414

    PubMed  CAS  Google Scholar 

  72. Pitarys CJ II, Virmani R, Vildibill HD Jr, Jackson EK, Forman MB (1991) Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period. Circulation 83:237–247

    PubMed  Google Scholar 

  73. Qin Q, Yang X-M, Cui L, Critz SD, Cohen MV, Browner NC, Lincoln TM, Downey JM (2004) Exogenous NO triggers preconditioning via a cGMP- and mitoKATP-dependent mechanism. Am J Physiol 287:H712–H718

    CAS  Google Scholar 

  74. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (2005) A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol 45:1775–1780

    PubMed  CAS  Google Scholar 

  75. Schneider S, Chen W, Hou J, Steenbergen C, Murphy E (2001) Inhibition of p38 MAPK α/β reduces ischemic injury and does not block protective effects of preconditioning. Am J Physiol 280:H499–H508

    CAS  Google Scholar 

  76. Schulte G, Fredholm BB (2003) Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 15:813–827

    PubMed  CAS  Google Scholar 

  77. Schultz JEJ, Hsu AK, Gross GJ (1998) Ischemic preconditioning in the intact rat heart is mediated by δ1- but not μ- or κ-opioid receptors. Circulation 97:1282–1289

    PubMed  CAS  Google Scholar 

  78. Schultz JEJ, Rose E, Yao Z, Gross GJ (1995) Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol 268:H2157–H2161

    PubMed  CAS  Google Scholar 

  79. Schulz R, Belosjorow S, Gres P, Jansen J, Michel MC, Heusch G (2002) p38 MAP kinase is a mediator of ischemic preconditioning in pigs. Cardiovasc Res 55:690–700

    PubMed  CAS  Google Scholar 

  80. Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, Heusch G (2003) Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J 17:1355–1357

    PubMed  CAS  Google Scholar 

  81. Schulz R, Post H, Vahlhaus C, Heusch G (1998) Ischemic preconditioning in pigs: a graded phenomenon. Its relation to adenosine and bradykinin. Circulation 98:1022–1029

    PubMed  CAS  Google Scholar 

  82. Schulz R, Rose J, Post H, Heusch G (1995) Involvement of endogenous adenosine in ischaemic preconditioning in swine. Pflugers Arch 430:273–282

    PubMed  CAS  Google Scholar 

  83. Schwiebert EH, Karlson KH, Friedman PA, Dietl P, Spielman WS, Stanton BA (1992) Adenosine regulates a chloride channel via protein kinase C and a G protein in a rabbit cortical collecting duct cell line. J Clin Invest 89:834–841

    PubMed  CAS  Google Scholar 

  84. Smits GJ, McVey M, Cox BF, Perrone MH, Clark KL (1998) Cardioprotective effects of the novel adenosine A1/A2 receptor agonist AMP 579 in a porcine model of myocardial infarction. J Pharmacol Exp Ther 286:611–618

    PubMed  CAS  Google Scholar 

  85. Solenkova NV, Solodushko V, Cohen MV, Downey JM (2006) Endogenous adenosine protects preconditioned heart during early minutes of reperfusion by activating Akt. Am J Physiol 290:H441–H449

    CAS  Google Scholar 

  86. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit J-F, Bonnefoy E, Finet G, André-Fouët X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148

    PubMed  Google Scholar 

  87. Thornton JD, Liu GS, Olsson RA, Downey JM (1992) Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation 85:659–665

    PubMed  CAS  Google Scholar 

  88. Tissier R, Cohen MV, Downey JM (2007) Protecting the acutely ischemic myocardium beyond reperfusion therapies: are we any closer to realizing the dream of infarct size elimination? Arch Mal Coeur Vaiss (in press)

  89. Todd J, Zhao Z-Q, Williams MW, Sato H, Van Wylen DGL, Vinten-Johansen J (1996) Intravascular adenosine at reperfusion reduces infarct size and neutrophil adherence. Ann Thorac Surg 62:1364–1372

    PubMed  CAS  Google Scholar 

  90. Tsuchida A, Miura T, Miki T, Shimamoto K, Iimura O (1992) Role of adenosine receptor activation in myocardial infarct size limitation by ischaemic preconditioning. Cardiovasc Res 26:456–461

    Article  PubMed  CAS  Google Scholar 

  91. Turcato S, Turnbull L, Wang G-Y, Honbo N, Simpson PC, Karliner JS, Baker AJ (2006) Ischemic preconditioning depends on age and gender. Basic Res Cardiol 101:235–243

    PubMed  CAS  Google Scholar 

  92. Vander Heide RS, Reimer KA (1996) Effect of adenosine therapy at reperfusion on myocardial infarct size in dogs. Cardiovasc Res 31:711–718

    PubMed  CAS  Google Scholar 

  93. VanWinkle DM, Chien GL, Wolff RA, Soifer BE, Kuzume K, Davis RF (1994) Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel. Am J Physiol 266:H829–H839

    CAS  Google Scholar 

  94. Velasco CE, Turner M, Cobb MA, Virmani R, Forman MB (1991) Myocardial reperfusion injury in the canine model after 40 minutes of ischemia: effect of intracoronary adenosine. Am Heart J 122:1561–1570

    PubMed  CAS  Google Scholar 

  95. Walker DM, Walker JM, Pugsley WB, Pattison CW, Yellon DM (1995) Preconditioning in isolated superfused human muscle. J Mol Cell Cardiol 27:1349–1357

    PubMed  CAS  Google Scholar 

  96. Wall TM, Sheehy R, Hartman JC (1994) Role of bradykinin in myocardial preconditioning. J Pharmacol Exp Ther 270:681–689

    PubMed  CAS  Google Scholar 

  97. Wang Y, Ashraf M (1998) Activation of α1-adrenergic receptor during Ca2+ pre-conditioning elicits strong protection against Ca2+ overload injury via protein kinase C signaling pathway. J Mol Cell Cardiol 30:2423–2435

    PubMed  CAS  Google Scholar 

  98. Weinbrenner C, Liu G-S, Cohen MV, Downey JM (1997) Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. J Mol Cell Cardiol 29:2383–2391

    PubMed  CAS  Google Scholar 

  99. Wright DT, Fischer BM, Li C, Rochelle LG, Akley NJ, Adler KB (1996) Oxidant stress stimulates mucin secretion and PLC in airway epithelium via a nitric oxide-dependent mechanism. Am J Physiol 271:L854–L861

    PubMed  CAS  Google Scholar 

  100. Xu Z, Cohen MV, Downey JM, Vanden Hoek TL, Yao Z (2001) Attenuation of oxidant stress during reoxygenation by AMP 579 in cardiomyocytes. Am J Physiol 281:H2585–H2589

    CAS  Google Scholar 

  101. Xu Z, Downey JM, Cohen MV (2001) AMP 579 reduces contracture and limits infarction in rabbit heart by activating adenosine A2 receptors. J Cardiovasc Pharmacol 38:474–481

    PubMed  CAS  Google Scholar 

  102. Xu Z, Downey JM, Cohen MV (2003) Timing and duration of administration are crucial for antiinfarct effect of AMP 579 infused at reperfusion in rabbit heart. Heart Dis 5:368–371

    PubMed  CAS  Google Scholar 

  103. Xu Z, Yang X-M, Cohen MV, Neumann T, Heusch G, Downey JM (2000) Limitation of infarct size in rabbit hearts by the novel adenosine receptor agonist AMP 579 administered at reperfusion. J Mol Cell Cardiol 32:2339–2347

    PubMed  CAS  Google Scholar 

  104. Yang X-M, Krieg T, Cui L, Downey JM, Cohen MV (2004) NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by signaling through PI3K, ERK, and NO. J Mol Cell Cardiol 36:411–421

    PubMed  CAS  Google Scholar 

  105. Yang X-M, Philipp S, Downey JM, Cohen MV (2005) Postconditioning’s protection is not dependent on circulating blood factors or cells but involves adenosine receptors and requires PI3-kinase and guanylyl cyclase activation. Basic Res Cardiol 100:57–63

    PubMed  CAS  Google Scholar 

  106. Yang X-M, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV (2004) Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol 44:1103–1110

    PubMed  Google Scholar 

  107. Yang X-M, Sato H, Downey JM, Cohen MV (1997) Protection of ischemic preconditioning is dependent upon a critical timing sequence of protein kinase C activation. J Mol Cell Cardiol 29:991–999

    PubMed  CAS  Google Scholar 

  108. Yang Z, Day Y-J, Toufektsian M-C, Ramos SI, Marshall M, Wang X-Q, French BA, Linden J (2005) Infarct-sparing effect of A2A-adenosine receptor activation is due primarily to its action on lymphocytes. Circulation 111:2190–2197

    PubMed  CAS  Google Scholar 

  109. Ytrehus K, Liu Y, Downey JM (1994) Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol 266:H1145–H1152

    PubMed  CAS  Google Scholar 

  110. Ytrehus K, Liu Y, Tsuchida A, Miura T, Liu GS, Yang X-M, Herbert D, Cohen MV, Downey JM (1994) Rat and rabbit heart infarction: effects of anesthesia, perfusate, risk zone, and method of infarct sizing. Am J Physiol 267:H2383–H2390

    PubMed  CAS  Google Scholar 

  111. Zhao J, Renner O, Wightman L, Sugden PH, Stewart L, Miller AD, Latchman DS, Marber MS (1998) The expression of constitutively active isotopes of protein kinase C to investigate preconditioning. J Biol Chem 273:23072–23079

    PubMed  CAS  Google Scholar 

  112. Zhao Z-Q, Budde JM, Morris C, Wang N-P, Velez DA, Muraki S, Guyton RA, Vinten-Johansen J (2001) Adenosine attenuates reperfusion-induced apoptotic cell death by modulating expression of Bcl-2 and Bax proteins. J Mol Cell Cardiol 33:57–68

    PubMed  CAS  Google Scholar 

  113. Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285:H579–H588

    CAS  Google Scholar 

  114. Zhao Z-Q, Nakamura M, Wang N-P, Velez DA, Hewan-Lowe KO, Guyton RA, Vinten-Johansen J (2000) Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res 94:133–144

    PubMed  CAS  Google Scholar 

  115. Zhao Z-Q, Nakamura M, Wang N-P, Wilcox JN, Shearer S, Guyton RA, Vinten-Johansen J (1999) Administration of adenosine during reperfusion reduces injury of vascular endothelium and death of myocytes. Coron Artery Dis 10:617–628

    Article  PubMed  CAS  Google Scholar 

  116. Zhao Z-Q, Todd JC, Sato H, Ma X-L, Vinten-Johansen J (1997) Adenosine inhibition of neutrophil damage during reperfusion does not involve KATP-channel activation. Am J Physiol 273:H1677–H1687

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Physiology, MSB 3050, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA

    Michael V. Cohen MD & James M. Downey

  2. Dept. of Medicine, University of South Alabama, Mobile, AL, USA

    Michael V. Cohen MD

Authors
  1. Michael V. Cohen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James M. Downey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael V. Cohen MD.

Additional information

Returned for 1. revision: 17 September 2007 1. Revision received: 4 October 2007

Returned for 2. revision: 11 October 2007 2. Revision received: 16 October 2007

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cohen, M.V., Downey, J.M. Adenosine: trigger and mediator of cardioprotection. Basic Res Cardiol 103, 203–215 (2008). https://doi.org/10.1007/s00395-007-0687-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-007-0687-7

Key words

Search

Navigation