Adenosine Receptors and the Heart: Role in Regulation of Coronary Blood Flow and Cardiac Electrophysiology

  • S. Jamal  MustafaEmail author
  • R. Ray  Morrison
  • Bunyen Teng
  • Amir Pelleg
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 193)


Adenosine is an autacoid that plays a critical role in regulating cardiac function, including heart rate, contractility, and coronary flow. In this chapter, current knowledge of the functions and mechanisms of action of coronary flow regulation and electrophysiology will be discussed. Currently, there are four known adenosine receptor (AR) subtypes, namely A1, A2A, A2B, and A3. All four subtypes are known to regulate coronary flow. In general, A2AAR is the predominant receptor subtype responsible for coronary blood flow regulation, which dilates coronary arteries in both an endothelial-dependent and -independent manner. The roles of other ARs and their mechanisms of action will also be discussed. The increasing popularity of gene-modified models with targeted deletion or overexpression of a single AR subtype has helped to elucidate the roles of each receptor subtype. Combining pharmacologic tools with targeted gene deletion of individual AR subtypes has proven invaluable for discriminating the vascular effects unique to the activation of each AR subtype. Adenosine exerts its cardiac electrophysiologic effects mainly through the activation of A1AR. This receptor mediates direct as well as indirect effects of adenosine (i.e., anti-β-adrenergic effects). In supraventricular tissues (atrial myocytes, sinuatrial node and atriovetricular node), adenosine exerts both direct and indirect effects, while it exerts only indirect effects in the ventricle. Adenosine exerts a negative chronotropic effect by suppressing the automaticity of cardiac pacemakers, and a negative dromotropic effect through inhibition of AV-nodal conduction. These effects of adenosine constitute the rationale for its use as a diagnostic and therapeutic agent. In recent years, efforts have been made to develop A1R-selective agonists as drug candidates that do not induce vasodilation, which is considered an undesirable effect in the clinical setting.


A1 adenosine receptor A2A adenosine receptor A2B adenosine receptor A3 adenosine receptor Endothelium Coronary artery Smooth muscle Adenosine receptor knockout Phospholipase C MAPK Adenosine receptor agonist Adenosine receptor antagonist Sinus node AV node Cardiac electrophysiology PSVT Anti-beta adrenergic action 



Adenylate cyclase


Atrial to His bundle activation time (representative of AV-nodalconduction time)


Adenosine receptor


Adenosine 5 -triphosphate






2-Chloro-N 6-cyclopentyl-adenosine


Coronary flow


2-[p-(2-carboxyethyl)]-phenylethyl-amino-5 -N-ethylcarboxamidoadenosine




Cyclooxygenase I


N 6-Cyclopentyladenosine


Delayed afterdepolarizations




N 6-[2-(3,5-Dimethoxyphenyl)-2-(2-methoxyphenyl] ethyladenosine




Extracellular regulated kinase


His bundle to ventricular activation time


Head-up tilt table test


Inward calcium current


Inward L-type Ca2 + current


Chloride current


Hyperpolarization-activated current (“funny” current)


Outward potassium current


ATP-dependent outward potassium current


Transient inward current


Jun N-terminal kinase




N G-Methyl-l-arginine


Left anterior descending artery


Long QT interval syndrome


Mitogen-activated protein kinase


Adenosine-5 -N-ethylcarboxamide


Nitric oxide


Phorbol 12,13-dibutyrate


Phosphatidylinositol 3-kinase


Phospholipase C


Protein kinase A

PKB (Akt)

Protein kinase B


Protein kinase C


P wave to R wave interval on the ECG


Paroxysmal supraventricular tachycardia


Q wave–T wave interval in the ECG


Corrected QT interval


R wave–R wave interval in the ECG


Sinus node


Sarcoplasmic reticulum


Sick sinus syndrome


Supraventricular tachycardia


Ventricular fibrillation


Ventricular tachycardia



We thank would like to Luiz Belardinelli, M.D. for critical reading of the manuscript and his helpful comments. Also, we would like to acknowledge the support of NIH (HL-027339-SJM; HL-074001-RRM).


  1. Abebe W, Makujina SR, Mustafa SJ (1994) Adenosine receptor-mediated relaxation of porcine coronary artery in presence and absence of endothelium. Am J Physiol 266:H2018–H2025PubMedGoogle Scholar
  2. Abebe W, Hussain T, Olanrewaju H, Mustafa SJ (1995) Role of nitric oxide in adenosine receptor-mediated relaxation of porcine coronary artery. Am J Physiol 269:H1672–H1678PubMedGoogle Scholar
  3. Ansari HR, Nadeem A, Tilley SL, Mustafa SJ (2007) Involvement of COX-1 in A3 adenosine receptor-mediated contraction through endothelium in mice aorta. Am J Physiol Heart Circ Physiol 293:H3448–H3455PubMedCrossRefGoogle Scholar
  4. Ansari H, Teng B, Nadeem A, Schnermann J, Mustafa S (2008) A1 adenosine receptor-activated protein kinase C signaling in A1 knock-out mice coronary artery smooth muscle cells. FASEB J 22:: 1152.11Google Scholar
  5. Ashton KJ, Nilsson U, Willems L, Holmgren K, Headrick JP (2003) Effects of aging and ischemia on adenosine receptor transcription in mouse myocardium. Biochem Biophys Res Commun 312:367–372PubMedCrossRefGoogle Scholar
  6. Ashton KJ, Peart JN, Morrison RR, Matherne GP, Blackburn MR, and Headrick JP (2007) Genetic modulation of adenosine receptor function and adenosine handling in murine hearts: insights and issues. J Mol Cell Cardiol 42:693–705PubMedCrossRefGoogle Scholar
  7. Belardinelli L, Isenberg G (1983) Actions of adenosine and isoproterenol on isolated mammalian ventricular myocytes. Circ Res 53:287–297PubMedGoogle Scholar
  8. Belardinelli L, Mattos EC, Berne RM (1981) Evidence for adenosine mediation of atrioventricular block in the ischemic canine myocardium. J Clin Invest 68:195–205PubMedCrossRefGoogle Scholar
  9. Belardinelli L, West GA, Clemo SHF (1987). Regulation of atrioventricular node function by adenosine. In: Gerlach E, Becker B (eds) Topics and perspectives of adenosine research. Springer, Berlin, pp 344–355Google Scholar
  10. Belardinelli L, Giles WR, West A (1988) Ionic mechanisms of adenosine actions in pacemaker cells from rabbit heart. J Physiol 405:615–633PubMedGoogle Scholar
  11. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M (1995) Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes. FASEB J 9:359–365PubMedGoogle Scholar
  12. Belardinelli L, Shryock JC, Snowdy S, Zhang Y, Monopoli A, Lozza G, Ongini E, Olsson RA, Dennis DM (1998) The A2A adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther 284:1066–1073PubMedGoogle Scholar
  13. Berne RM (1963) Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol 204:317–322PubMedGoogle Scholar
  14. Berne RM (1980) The role of adenosine in the regulation of coronary blood flow. Circ Res 47: 807–813PubMedGoogle Scholar
  15. Brignole M, Donateo P, Menozzi C (2003) The diagnostic value of ATP testing in patients with unexplained syncope. Europace 5:425–428PubMedCrossRefGoogle Scholar
  16. Bryan PT, Marshall JM (1999) Cellular mechanisms by which adenosine induces vasodilatation in rat skeletal muscle: significance for systemic hypoxia. J Physiol 514 (1): 163–175PubMedCrossRefGoogle Scholar
  17. Burnett D, Abi-Samra F, Vacek JL (1999) Use of intravenous adenosine as a noninvasive diagnostic test for sick sinus syndrome. Am Heart J 137:435–438PubMedCrossRefGoogle Scholar
  18. Carrega L, Saadjian AY, Mercier L, Zouher I, Berge-Lefranc JL, Gerolami V, Giaime P, Sbragia P, Paganelli F, Fenouillet E, Levy S, Guieu RP (2007) Increased expression of adenosine A2A receptors in patients with spontaneous and head-up-tilt-induced syncope. Heart Rhythm 4:870–876PubMedCrossRefGoogle Scholar
  19. Cerniway RJ, Yang Z, Jacobson MA, Linden J, Matherne GP (2001) Targeted deletion of A(3) adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium. Am J Physiol Heart Circ Physiol 281:H1751–H1758PubMedGoogle Scholar
  20. Cerqueira MD (2006) Advances in pharmacologic agents in imaging: new A2A receptor agonists. Curr Cardiol Rep 8:119–122PubMedCrossRefGoogle Scholar
  21. Cheung JW, Lerman BB (2003) CVT-510: a selective A1 adenosine receptor agonist. Cardiovasc Drug Rev 21:277–292PubMedGoogle Scholar
  22. Cheung JW, Stein KM, Markowitz SM, Iwai S, Guttigoli AB, Shah BK, Yarlagadda RK, Lerman BB, Mittal S (2004) Significance of adenosine-induced atrioventricular block in patients with unexplained syncope. Heart Rhythm 1:664–668PubMedCrossRefGoogle Scholar
  23. Chio CC, Chang YH, Hsu YW, Chi KH, Lin WW (2004) PKA-dependent activation of PKC, p38 MAPK and IKK in macrophage: implication in the induction of inducible nitric oxide synthase and interleukin-6 by dibutyryl cAMP. Cell Signal 16:565–575PubMedCrossRefGoogle Scholar
  24. Clemo HF, Belardinelli L (1986) Effect of adenosine on atrioventricular conduction. I: Site and characterization of adenosine action in the guinea pig atrioventricular node. Circ Res 59: 427–436Google Scholar
  25. Clemo HF, Bourassa A, Linden J, Belardinelli L (1987) Antagonism of the effects of adenosine and hypoxia on atrioventricular conduction time by two novel alkylxanthines: correlation with binding to adenosine A1 receptors. J Pharmacol Exp Ther 242:478–484PubMedGoogle Scholar
  26. Conti JB, Belardinelli L, Curtis AB (1995) Usefulness of adenosine in diagnosis of tachyarrhythmias. Am J Cardiol 75:952–955PubMedCrossRefGoogle Scholar
  27. Dana A, Skarli M, Papakrivopoulou J, Yellon DM (2000) Adenosine A(1) receptor induced delayed preconditioning in rabbits: induction of p38 mitogen-activated protein kinase activation and Hsp27 phosphorylation via a tyrosine kinase- and protein kinase C-dependent mechanism. Circ Res 86:989–997PubMedGoogle Scholar
  28. Dennis D, Jacobson K, Belardinelli L (1992) Evidence of spare A1-adenosine receptors in guinea pig atrioventricular node. Am J Physiol 262:H661–H671PubMedGoogle Scholar
  29. Denyer JC, Brown HF (1990) Pacemaking in rabbit isolated sino-atrial node cells during Cs + block of the hyperpolarization-activated current if. J Physiol 429:401–409PubMedGoogle Scholar
  30. Deussen A, Brand M, Pexa A, Weichsel J (2006) Metabolic coronary flow regulation—current concepts. Basic Res Cardiol 101:453–464PubMedCrossRefGoogle Scholar
  31. Dhalla AK, Shryock JC, Shreeniwas R, Belardinelli L (2003) Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 3:369–385PubMedCrossRefGoogle Scholar
  32. DiFrancesco D, Borer JS (2007) The funny current: cellular basis for the control of heart rate. Drugs 67(Suppl 2):15–24PubMedCrossRefGoogle Scholar
  33. DiMarco JP, Sellers TD, Berne RM, West GA, Belardinelli L (1983) Adenosine: electrophysiologic effects and therapeutic use for terminating paroxysmal supraventricular tachycardia. Circulation 68:1254–1263PubMedGoogle Scholar
  34. Dobson JG, Jr., Fenton RA, Romano FD (1987) The cardiac anti-adrenergic effect of adenosine. Prog Clin Biol Res 230:331–343PubMedGoogle Scholar
  35. Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K, Eltzschig HK (2007) Cardioprotection by ecto-5-nucleotidase (CD73)andA2B adenosine receptors. Circulation 115:1581–1590PubMedCrossRefGoogle Scholar
  36. Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK (2008) A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111:2024–2035PubMedCrossRefGoogle Scholar
  37. Fabritz L, Kirchhof P, Fortmuller L, Auchampach JA, Baba HA, Breithardt G, Neumann J, Boknik P, Schmitz W (2004) Gene dose-dependent atrial arrhythmias, heart block, and brady-cardiomyopathy in mice overexpressing A(3) adenosine receptors. Cardiovasc Res 62:: 500–508Google Scholar
  38. Feoktistov I, Biaggioni I (1997) Adenosine A2B receptors. Pharmacol Rev 49:381–402PubMedGoogle Scholar
  39. Flammang D, Pelleg A, Benditt DG (2005) The adenosine triphospate (ATP) test for evaluation of syncope of unknown origin. J Cardiovasc Electrophysiol 16:1388–1389PubMedGoogle Scholar
  40. Flammang D, AMS Investigators (2006) The ATP test: a useful test for identifying the cardio-inhibitory mechanism of syncope of unknown origin and for directing the therapy. Europace 8(Suppl 1):55Google Scholar
  41. Flood AJ, Willems L, Headrick JP (2002) Coronary function and adenosine receptor-mediated responses in ischemic-reperfused mouse heart. Cardiovasc Res 55:161–170PubMedCrossRefGoogle Scholar
  42. Fogaça RTH, Leal-Cardoso JH (1985) Effects of adenosine on digitalis induced arrhythmias. Braz J Med Biol Res 18:663AGoogle Scholar
  43. Fragakis N, Iliadis I, Sidopoulos E, Lambrou A, Tsaritsaniotis E, Katsaris G (2007) The value of adenosine test in the diagnosis of sick sinus syndrome: susceptibility of sinus and atrioventricular node to adenosine in patients with sick sinus syndrome and unexplained syncope. Europace 9:559–562PubMedCrossRefGoogle Scholar
  44. Francis JE, Webb RL, Ghai GR, Hutchison AJ, Moskal MA, deJesus R, Yokoyama R, Rovinski SL, Contardo N, Dotson R, Barclay B, Stone GA, Jarvis MF (1991) Highly selective adenosine A2 receptor agonists in a series of N-alkylated 2-aminoadenosines. J Med Chem 34:2570–2579PubMedCrossRefGoogle Scholar
  45. Fredholm BB, Arslan G, Halldner L, Kull B, Schulte G, Wasserman W (2000) Structure and function of adenosine receptors and their genes. Naunyn–Schmiedeberg’s Arch Pharmacol 362:364–374Google Scholar
  46. Frieden M, Sollini M, Beny J (1999) Substance P and bradykinin activate different types of KCa currents to hyperpolarize cultured porcine coronary artery endothelial cells. J Physiol 519(2):361–371PubMedCrossRefGoogle Scholar
  47. Frobert O, Haink G, Simonsen U, Gravholt CH, Levin M, Deussen A (2006) Adenosine concentration in the porcine coronary artery wall and A2A receptor involvement in hypoxia-induced vasodilatation. J Physiol 570:375–384PubMedGoogle Scholar
  48. Ge ZD, Peart JN, Kreckler LM, Wan TC, Jacobson MA, Gross GJ, Auchampach JA (2006) Cl-IB-MECA [2-chloro-N 6-(3-iodobenzyl)adenosine-5-N-methylcarboxamide] reduces ischemia/reperfusion injury in mice by activating the A3 adenosine receptor. J Pharmacol Exp Ther 319:1200–1210PubMedCrossRefGoogle Scholar
  49. Geraets D, Kienzle M (1992) Clinical use of adenosine. Iowa Med 82:25–28PubMedGoogle Scholar
  50. Gerlach E, Deuticke B (1966) Comparative studies on the formation of adenosine in the myocardium of different animal species in oxygen deficiency. Klin Wochenschr 44:1307–1310PubMedCrossRefGoogle Scholar
  51. Germack R, Dickenson JM (2004) Characterization of ERK1/2 signalling pathways induced by adenosine receptor subtypes in newborn rat cardiomyocytes. Br J Pharmacol 141:329–339PubMedCrossRefGoogle Scholar
  52. Glavind-Kristensen M, Matchkov V, Hansen VB, Forman A, Nilsson H, Aalkjaer C (2004) KATP-channel-induced vasodilation is modulated by the Na,K-pump activity in rabbit coronary small arteries. Br J Pharmacol 143:872–880PubMedCrossRefGoogle Scholar
  53. Hack SP, Christie MJ (2003) Adaptations in adenosine signaling in drug dependence: therapeutic implications. Crit Rev Neurobiol 15:235–274PubMedCrossRefGoogle Scholar
  54. Haq SE, Clerk A, Sugden PH (1998) Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by adenosine in the perfused rat heart. FEBS Lett 434:305–308PubMedCrossRefGoogle Scholar
  55. Harrison GJ, Cerniway RJ, Peart J, Berr SS, Ashton K, Regan S, Paul Matherne G, Headrick JP (2002) Effects of A(3) adenosine receptor activation and gene knock-out in ischemic-reperfused mouse heart. Cardiovasc Res 53:147–155PubMedCrossRefGoogle Scholar
  56. Hasan AZ, Abebe W, Mustafa SJ (2000) Antagonism of coronary artery relaxation by adenosine A2A-receptor antagonist ZM241385. J Cardiovasc Pharmacol 35:322–325CrossRefGoogle Scholar
  57. Hayward E, Showler L, Soar J (2007) Aminophylline in bradyasystolic cardiac arrest. Emerg Med J 24:582–583PubMedCrossRefGoogle Scholar
  58. Headrick JP, Gauthier NS, Morrison RR, Matherne GP (2000) Chronotropic and vasodilatory responses to adenosine and isoproterenol in mouse heart: effects of adenosine A1 receptor overexpression. Clin Exp Pharmacol Physiol 27:185–190PubMedCrossRefGoogle Scholar
  59. Hein TW, Wang W, Zoghi B, Muthuchamy M, Kuo L (2001) Functional and molecular characterization of receptor subtypes mediating coronary microvascular dilation to adenosine. J Mol Cell Cardiol 33:271–282PubMedCrossRefGoogle Scholar
  60. Hodgson JM, Dib N, Kern MJ, Bach RG, Barrett RJ (2007) Coronary circulation responses to binodenoson, a selective adenosine A2A receptor agonist. Am J Cardiol 99:1507–1512PubMedCrossRefGoogle Scholar
  61. Hori M, Kitakaze M (1991) Adenosine, the heart, and coronary circulation. Hypertension 18: 565–574PubMedGoogle Scholar
  62. Hove-Madsen L, Prat-Vidal C, Llach A, Ciruela F, Casado V, Lluis C, Bayes-Genis A, Cinca J, Franco R (2006) Adenosine A2A receptors are expressed in human atrial myocytes and modulate spontaneous sarcoplasmic reticulum calcium release. Cardiovasc Res 72:292–302PubMedCrossRefGoogle Scholar
  63. Hua X, Kovarova M, Chason KD, Nguyen M, Koller BH, Tilley SL (2007) Enhanced mast cell activation in mice deficient in the A2b adenosine receptor. J Exp Med 204:117–128PubMedCrossRefGoogle Scholar
  64. Hussain T, Mustafa SJ (1993) Regulation of adenosine receptor system in coronary artery: functional studies and cAMP. Am J Physiol 264:H441–H447PubMedGoogle Scholar
  65. Hussain T, Mustafa SJ (1995) Binding of A1 adenosine receptor ligand [3H]8-cyclopentyl-1,3-dipropylxanthine in coronary smooth muscle. Circ Res 77:194–198PubMedGoogle Scholar
  66. Hutchinson SA, Scammells PJ (2004) A(1) adenosine receptor agonists: medicinal chemistry and therapeutic potential. Curr Pharm Des 10:2021–2039PubMedCrossRefGoogle Scholar
  67. Hutchison AJ, Webb RL, Oei HH, Ghai GR, Zimmerman MB, Williams M (1989) CGS 21680C, an A2 selective adenosine receptor agonist with preferential hypotensive activity. J Pharmacol Exp Ther 251:47–55PubMedGoogle Scholar
  68. Ingwall JS (2007) On substrate selection for ATP synthesis in the failing human myocardium. Am J Physiol Heart Circ Physiol 293:H3225–H3226PubMedCrossRefGoogle Scholar
  69. Ingwall JS, Weiss RG (2004) Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ Res 95:135–145PubMedCrossRefGoogle Scholar
  70. Iwai S, Markowitz SM, Stein KM, Mittal S, Slotwiner DJ, Das MK, Cohen JD, Hao SC, Lerman BB (2002) Response to adenosine differentiates focal from macroreentrant atrial tachycardia: validation using three-dimensional electroanatomic mapping. Circulation 106:2793–2799PubMedCrossRefGoogle Scholar
  71. Iwai S, Cantillon DJ, Kim RJ, Markowitz SM, Mittal S, Stein KM, Shah BK, Yarlagadda RK, Cheung JW, Tan VR, Lerman BB (2006) Right and left ventricular outflow tract tachycardias: evidence for a common electrophysiologic mechanism. J Cardiovasc Electrophysiol 17: 1052–1058PubMedCrossRefGoogle Scholar
  72. Kalyankrishna S, Malik KU (2003) Norepinephrine-induced stimulation of p38 mitogen-activated protein kinase is mediated by arachidonic acid metabolites generated by activation of cytosolic phospholipase A(2) in vascular smooth muscle cells. J Pharmacol Exp Ther 304:761–772PubMedCrossRefGoogle Scholar
  73. Keim S, Curtis AB, Belardinelli L, Epstein ML, Staples ED, Lerman BB (1992) Adenosine-induced atrioventricular block: a rapid and reliable method to assess surgical and radiofrequency catheter ablation of accessory atrioventricular pathways. J Am Coll Cardiol 19: 1005–1012PubMedGoogle Scholar
  74. Kemp BK, Cocks TM (1999) Adenosine mediates relaxation of human small resistance-like coronary arteries via A2B receptors. Br J Pharmacol 126:1796–1800PubMedCrossRefGoogle Scholar
  75. Kim N, Chung J, Kim E, Han J (2003) Changes in the Ca2 + -activated K + channels of the coronary artery during left ventricular hypertrophy. Circ Res 93:541–547PubMedCrossRefGoogle Scholar
  76. Kirchhof P, Fabritz L, Fortmuller L, Matherne GP, Lankford A, Baba HA, Schmitz W, Breithardt G, Neumann J, Boknik P (2003) Altered sinus nodal and atrioventricular nodal function in freely moving mice overexpressing the A1 adenosine receptor. Am J Physiol Heart Circ Physiol 285:H145–H153PubMedGoogle Scholar
  77. Kirsch GE, Codina J, Birnbaumer L, Brown AM (1990) Coupling of ATP-sensitive K + channels to A1 receptors by G proteins in rat ventricular myocytes. Am J Physiol 259:H820–H826PubMedGoogle Scholar
  78. Knaapen P, Germans T, Knuuti J, Paulus WJ, Dijkmans PA, Allaart CP, Lammertsma AA, Visser FC (2007) Myocardial energetics and efficiency: current status of the noninvasive approach. Circulation 115:918–927PubMedCrossRefGoogle Scholar
  79. Komalavilas P, Mehta S, Wingard CJ, Dransfield DT, Bhalla J, Woodrum JE, Molinaro JR, Brophy CM (2001) PI3-kinase/Akt modulates vascular smooth muscle tone via cAMP signaling pathways. J Appl Physiol 91:1819–1827PubMedGoogle Scholar
  80. Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor. Nature 388:674–678PubMedCrossRefGoogle Scholar
  81. Lerman BB (1993) Response of nonreentrant catecholamine-mediated ventricular tachycardia to endogenous adenosine and acetylcholine. Evidence for myocardial receptor-mediated effects. Circulation 87:382–390Google Scholar
  82. Lerman BB, Belardinelli L, West GA, Berne RM, DiMarco JP (1986) Adenosine-sensitive ventricular tachycardia: evidence suggesting cyclic AMP-mediated triggered activity. Circulation 74:270–280PubMedGoogle Scholar
  83. Lerman BB, Wesley RC, Jr., DiMarco JP, Haines DE, Belardinelli L (1988) Antiadrenergic effects of adenosine on His-Purkinje automaticity. Evidence for accentuated antagonism. J Clin Invest 82:2127–2135CrossRefGoogle Scholar
  84. Lerman BB, Stein K, Engelstein ED, Battleman DS, Lippman N, Bei D, Catanzaro D (1995) Mechanism of repetitive monomorphic ventricular tachycardia. Circulation 92:421–429PubMedGoogle Scholar
  85. Lerman BB, Stein KM, Markowitz SM (1997) Mechanisms of idiopathic left ventricular tachycardia. J Cardiovasc Electrophysiol 8:571–583PubMedCrossRefGoogle Scholar
  86. Lerman BB, Stein KM, Markowitz SM, Mittal S, Slotwiner DJ (2000) Ventricular arrhythmias in normal hearts. Cardiol Clin 18:265–291PubMedCrossRefGoogle Scholar
  87. Li J, Fenton RA, Wheeler HB, Powell CC, Peyton BD, Cutler BS, Dobson JG, Jr. (1998) Adenosine A2a receptors increase arterial endothelial cell nitric oxide. J Surg Res 80:357–364PubMedCrossRefGoogle Scholar
  88. Li PL, Zhang DX, Zou AP, Campbell WB (1999) Effect of ceramide on KCa channel activity and vascular tone in coronary arteries. Hypertension 33:1441–1446PubMedGoogle Scholar
  89. Lindsay BD (2007) Focal and macroreentrant atrial tachycardia: from bench to bedside and back to the bench again. Heart Rhythm 4:1361–1363PubMedCrossRefGoogle Scholar
  90. Liu Y, Terata K, Rusch NJ, Gutterman DD (2001) High glucose impairs voltage-gated K( + ) channel current in rat small coronary arteries. Circ Res 89:146–152PubMedCrossRefGoogle Scholar
  91. Lowes VL, Ip NY, Wong YH (2002) Integration of signals from receptor tyrosine kinases and G protein-coupled receptors. Neurosignals 11:5–19PubMedCrossRefGoogle Scholar
  92. Mader TJ, Menegazzi JJ, Betz AE, Logue ES, Callaway CW, Sherman LD (2006) Adenosine A1 receptor antagonism hastens the decay in ventricular fibrillation waveform morphology during porcine cardiac arrest. Resuscitation 71:254–259PubMedCrossRefGoogle Scholar
  93. Makujina SR, Sabouni MH, Bhatia S, Douglas FL, Mustafa SJ (1992) Vasodilatory effects of adenosine A2 receptor agonists CGS 21680 and CGS 22492 in human vasculature. Eur J Pharmacol 221:243–247.PubMedCrossRefGoogle Scholar
  94. Marala RB, Mustafa SJ (1995a) Adenosine A1 receptor-induced upregulation of protein kinase C: role of pertussis toxin-sensitive G protein(s). Am J Physiol 269:H1619–H1624PubMedGoogle Scholar
  95. Marala RB, Mustafa SJ (1995b) Adenosine analogues prevent phorbol ester-induced PKC depletion in porcine coronary artery via A1 receptor. Am J Physiol 268:H271–H277PubMedGoogle Scholar
  96. Marala RB, Mustafa SJ (1995c) Modulation of protein kinase C by adenosine: involvement of adenosine A1 receptor-pertussis toxin sensitive nucleotide binding protein system. Mol Cell Biochem 149–150:51–58PubMedCrossRefGoogle Scholar
  97. Markowitz SM, Nemirovksy D, Stein KM, Mittal S, Iwai S, Shah BK, Dobesh DP, Lerman BB (2007) Adenosine-insensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium. J Am Coll Cardiol 49:1324–1333PubMedCrossRefGoogle Scholar
  98. Markowitz SM, Stein KM, Mittal S, Slotwiner DJ, Lerman BB (1999) Differential effects of adenosine on focal and macroreentrant atrial tachycardia. J Cardiovasc Electrophysiol 10:489–502PubMedCrossRefGoogle Scholar
  99. Meloche S, Landry J, Huot J, Houle F, Marceau F, Giasson E (2000) p38 MAP kinase pathway regulates angiotensin II-induced contraction of rat vascular smooth muscle. Am J Physiol Heart Circ Physiol 279:H741–H751PubMedGoogle Scholar
  100. Mittal S, Stein KM, Markowitz SM, Iwai S, Guttigoli A, Lerman BB (2004) Single-stage adenosine tilt testing in patients with unexplained syncope. J Cardiovasc Electrophysiol 15:637–640PubMedCrossRefGoogle Scholar
  101. Morrison RR, Talukder MA, Ledent C, Mustafa SJ (2002) Cardiac effects of adenosine in A(2A) receptor knockout hearts: uncovering A(2B) receptors. Am J Physiol Heart Circ Physiol 282:H437–H444PubMedGoogle Scholar
  102. Morrison RR, Teng B, Oldenburg PJ, Katwa LC, Schnermann JB, Mustafa SJ (2006) Effects of targeted deletion of A1 adenosine receptors on postischemic cardiac function and expression of adenosine receptor subtypes. Am J Physiol Heart Circ Physiol 291:H1875–H1882PubMedCrossRefGoogle Scholar
  103. Morrison RR, Tan XL, Ledent C, Mustafa SJ, Hofmann PA (2007) Targeted deletion of A2A adenosine receptors attenuates the protective effects of myocardial postconditioning. Am J Physiol Heart Circ Physiol 293:H2523–H2529PubMedCrossRefGoogle Scholar
  104. Mustafa SJ, Abebe W (1996) Coronary vasodilation by adenosine: receptor subtypes and mechanisms of action. Drug Dev Res 39:308–313CrossRefGoogle Scholar
  105. Mustafa SJ, Askar AO (1985) Evidence suggesting an Ra-type adenosine receptor in bovine coronary arteries. J Pharmacol Exp Ther 232:49–56PubMedGoogle Scholar
  106. Mutafova-Yambolieva VN, Keef KD (1997) Adenosine-induced hyperpolarization in guinea pig coronary artery involves A2b receptors and KATP channels. Am J Physiol 273:H2687–H2695PubMedGoogle Scholar
  107. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151PubMedCrossRefGoogle Scholar
  108. Niiya K, Uchida S, Tsuji T, Olsson RA (1994) Glibenclamide reduces the coronary vasoactivity of adenosine receptor agonists. J Pharmacol Exp Ther 271:14–19PubMedGoogle Scholar
  109. Nitenberg A, Durand E, Delatour B, Sdiri W, Raha S, Lafont A (2007) Postocclusion hyperemia provides a better estimate of coronary reserve than intracoronary adenosine in patients with coronary artery stenosis. J Invasive Cardiol 19:390–394PubMedGoogle Scholar
  110. Nogami A (2002) Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev 6:448–457PubMedCrossRefGoogle Scholar
  111. Olanrewaju HA, Mustafa SJ (2000) Adenosine A(2A) and A(2B) receptors mediated nitric oxide production in coronary artery endothelial cells. Gen Pharmacol 35:171–177PubMedGoogle Scholar
  112. Olanrewaju HA, Qin W, Feoktistov I, Scemama JL, Mustafa SJ (2000) Adenosine A(2A) and A(2B) receptors in cultured human and porcine coronary artery endothelial cells. Am J Physiol Heart Circ Physiol 279:H650–H656PubMedGoogle Scholar
  113. Olanrewaju HA, Gafurov BS, Lieberman EM (2002) Involvement of K + channels in adenosine A2A and A2B receptor-mediated hyperpolarization of porcine coronary artery endothelial cells. J Cardiovasc Pharmacol 40:43–49PubMedCrossRefGoogle Scholar
  114. Olsson RA (1970) Changes in content of purine nucleoside in canine myocardium during coronary occlusion. Circ Res 26:301–306PubMedGoogle Scholar
  115. Ono K, Han J (2000) The p38 signal transduction pathway: activation and function. Cell Signal 12:1–13PubMedCrossRefGoogle Scholar
  116. Parry SW, Nath S, Bourke JP, Bexton RS, Kenny RA (2006) Adenosine test in the diagnosis of unexplained syncope: marker of conducting tissue disease or neurally mediated syncope? Eur Heart J 27:1396–1400PubMedCrossRefGoogle Scholar
  117. Peart JN, Headrick JP (2007) Adenosinergic cardioprotection: multiple receptors, multiple pathways. Pharmacol Ther 114:208–221PubMedCrossRefGoogle Scholar
  118. Pelleg A, Belardinelli L (1993) Cardiac electrophysiology and pharmacology of adenosine: basic and clinical aspects. Cardiovasc Res 27:54–61PubMedCrossRefGoogle Scholar
  119. Pelleg A, Kutalek SP (1997) Adenosine in the mammalian heart: nothing to get excited about. Trends Pharmacol Sci 18:236–238PubMedGoogle Scholar
  120. Peterman C, Sanoski CA (2005) Tecadenoson: a novel, selective A1 adenosine receptor agonist. Cardiol Rev 13:315–321PubMedCrossRefGoogle Scholar
  121. Pelleg A, Mitamura H, Mitsuoka T, Michelson EL, Dreifus LS (1986) Effects of adenosine and adenosine 5-triphosphate on ventricular escape rhythm in the canine heart. J Am Coll Cardiol 8:1145–1151PubMedCrossRefGoogle Scholar
  122. Pelleg A, Hurt C, Miyagawa A, Michelson EL, Dreifus LS (1990a) Differential sensitivity of cardiac pacemakers to exogenous adenosine in vivo. Am J Physiol 258:H1815–H1822PubMedGoogle Scholar
  123. Pelleg A, Hurt CM, Michelson EL (1990b) Cardiac effects of adenosine and ATP. Ann N Y Acad Sci 603:19–30PubMedCrossRefGoogle Scholar
  124. Pelleg A, Hurt CM, Hewlett EL (1996) ATP shortens atrial action potential duration in the dog: role of adenosine, the vagus nerve, and G protein. Can J Physiol Pharmacol 74:15–22PubMedCrossRefGoogle Scholar
  125. Pelleg A, Katchanov G, Xu J (1997) Autonomic neural control of cardiac function: modulation by adenosine and adenosine 5-triphosphate. Am J Cardiol 79:11–14PubMedCrossRefGoogle Scholar
  126. Pelleg A, Pennock RS, Kutalek SP (2002) Proarrhythmic effects of adenosine: one decade of clinical data. Am J Ther 9:141–147PubMedCrossRefGoogle Scholar
  127. Quayle JM, Nelson MT, Standen NB (1997) ATP-sensitive and inwardly rectifying potassium channels in smooth muscle. Physiol Rev 77:1165–1232PubMedGoogle Scholar
  128. Rahman A, Anwar KN, Minhajuddin M, Bijli KM, Javaid K, True AL, Malik AB (2004) cAMP Targeting of p38 MAP kinase Inhibits thrombin-induced NF-{kappa}B activation and ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol 287:L1017–L1024PubMedCrossRefGoogle Scholar
  129. Ramagopal MV, Chitwood RW Jr, Mustafa SJ (1988) Evidence for an A2 adenosine receptor in human coronary arteries. Eur J Pharmacol 151:483–486PubMedCrossRefGoogle Scholar
  130. Ray CJ, Marshall JM (2006) The cellular mechanisms by which adenosine evokes release of nitric oxide from rat aortic endothelium. J Physiol 570:85–96PubMedCrossRefGoogle Scholar
  131. Reichelt ME, Willems L, Molina JG, Sun CX, Noble JC, Ashton KJ, Schnermann J, Blackburn MR, Headrick JP (2005) Genetic deletion of the A1 adenosine receptor limits myocardial ischemic tolerance. Circ Res 96:363–367PubMedCrossRefGoogle Scholar
  132. Rekik M, Mustafa JS (2003) Modulation of A2A adenosine receptors and associated Galphas proteins by ZM 241385 treatment of porcine coronary artery. J Cardiovasc Pharmacol 42:736–744PubMedCrossRefGoogle Scholar
  133. Resh W, Feuer J, Wesley RC, Jr. (1992) Intravenous adenosine: a noninvasive diagnostic test for sick sinus syndrome. Pacing Clin Electrophysiol 15:2068–2073PubMedCrossRefGoogle Scholar
  134. Robinson AJ, Dickenson JM (2001) Regulation of p42/p44 MAPK and p38 MAPK by the adenosine A(1) receptor in DDT(1)MF-2 cells. Eur J Pharmacol 413:151–161PubMedCrossRefGoogle Scholar
  135. Rogers PA, Chilian WM, Bratz IN, Bryan RM, Jr., Dick GM (2007) H2O2 activates redox- and 4-aminopyridine-sensitive Kv channels in coronary vascular smooth muscle. Am J Physiol Heart Circ Physiol 292:H1404–H1411PubMedCrossRefGoogle Scholar
  136. Rubio R, Wiedmeier VT, Berne RM (1974) Relationship between coronary flow and adenosine production and release. J Mol Cell Cardiol 6:561–566PubMedCrossRefGoogle Scholar
  137. Saadjian AY, Levy S, Franceschi F, Zouher I, Paganelli F, Guieu RP (2002) Role of endogenous adenosine as a modulator of syncope induced during tilt testing. Circulation 106:569–574PubMedCrossRefGoogle Scholar
  138. Salloum FN, Das A, Thomas CS, Yin C, Kukreja RC (2007) Adenosine A(1) receptor mediates delayed cardioprotective effect of sildenafil in mouse. J Mol Cell Cardiol 43:545–551PubMedCrossRefGoogle Scholar
  139. Sanders L, Rakovic S, Lowe M, Mattick PA, Terrar DA (2006) Fundamental importance of \({\mathrm{Na}}^{+}\mbox{ -}{\mathrm{Ca}}^{2+}\) exchange for the pacemaking mechanism in guinea-pig sino-atrial node. J Physiol 571:639–649PubMedCrossRefGoogle Scholar
  140. Schrader J, Baumann G, Gerlach E (1977) Adenosine as inhibitor of myocardial effects of catecholamines. Pflugers Arch 372:29–35PubMedCrossRefGoogle Scholar
  141. Schulte G, Fredholm BB (2002) Adenosine A2B receptors activate extracellular signal-regulated kinase ERK 1/2 and stress-activated protein kinase p38. In: XIVth World Congress of Pharmacology, San Francisco, CA, 7–12 July 2002, 44(2):A262Google Scholar
  142. Schulte G, Fredholm BB (2003) Signalling from adenosine receptors to mitogen-activated protein kinases. Cell Signal 15:813–827PubMedCrossRefGoogle Scholar
  143. Shen WK, Kurachi Y (1995) Mechanisms of adenosine-mediated actions on cellular and clinical cardiac electrophysiology. Mayo Clin Proc 70:274–291PubMedCrossRefGoogle Scholar
  144. Shen WK, Hammill SC, Munger TM, Stanton MS, Packer DL, Osborn MJ, Wood DL, Bailey KR, Low PA, Gersh BJ (1996) Adenosine: potential modulator for vasovagal syncope. J Am Coll Cardiol 28:146–154PubMedCrossRefGoogle Scholar
  145. Shryock JC, Snowdy S, Baraldi PG, Cacciari B, Spalluto G, Monopoli A, Ongini E, Baker SP, Belardinelli L (1998) A2A-adenosine receptor reserve for coronary vasodilation. Circulation 98:711–718PubMedGoogle Scholar
  146. 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 286:611–618PubMedGoogle Scholar
  147. Song Y, Thedford S, Lerman BB, Belardinelli L (1992) Adenosine-sensitive afterdepolarizations and triggered activity in guinea pig ventricular myocytes. Circ Res 70:743–753PubMedGoogle Scholar
  148. Song Y, Wu L, Shryock JC, Belardinelli L (2002) Selective attenuation of isoproterenol-stimulated arrhythmic activity by a partial agonist of adenosine A1 receptor. Circulation 105:118–123PubMedCrossRefGoogle Scholar
  149. Sun Park W, Kyoung Son Y, Kim N, Boum Youm J, Joo H, Warda M, Ko JH, Earm YE, Han J (2006) The protein kinase A inhibitor, H-89, directly inhibits KATP and Kir channels in rabbit coronary arterial smooth muscle cells. Biochem Biophys Res Commun 340:1104–1110PubMedCrossRefGoogle Scholar
  150. Taegtmeyer H, Wilson CR, Razeghi P, Sharma S (2005) Metabolic energetics and genetics in the heart. Ann N Y Acad Sci 1047:208–218PubMedCrossRefGoogle Scholar
  151. Talukder MA, Morrison RR, Jacobson MA, Jacobson KA, Ledent C, Mustafa SJ (2002a) Targeted deletion of adenosine A(3) receptors augments adenosine-induced coronary flow in isolated mouse heart. Am J Physiol Heart Circ Physiol 282:H2183–H2189PubMedGoogle Scholar
  152. Talukder MA, Morrison RR, Mustafa SJ (2002b) Comparison of the vascular effects of adenosine in isolated mouse heart and aorta. Am J Physiol Heart Circ Physiol 282:H49–H57PubMedGoogle Scholar
  153. Talukder MA, Morrison RR, Ledent C, Mustafa SJ (2003) Endogenous adenosine increases coronary flow by activation of both A2A and A2B receptors in mice. J Cardiovasc Pharmacol 41:562–570PubMedCrossRefGoogle Scholar
  154. Tang L, Parker M, Fei Q, Loutzenhiser R (1999) Afferent arteriolar adenosine A2a receptors are coupled to KATP in in vitro perfused hydronephrotic rat kidney. Am J Physiol 277:F926–F933PubMedGoogle Scholar
  155. Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (2005) Role of A1 adenosine receptors in regulation of vascular tone. Am J Physiol Heart Circ Physiol 288:H1411–H1416PubMedCrossRefGoogle Scholar
  156. Tawfik HE, Teng B, Morrison RR, Schnermann J, Mustafa SJ (2006) Role of A1 adenosine receptor in the regulation of coronary flow. Am J Physiol Heart Circ Physiol 291:H467–H472PubMedCrossRefGoogle Scholar
  157. Teng B, Qin W, Ansari HR, Mustafa SJ (2005) Involvement of p38-mitogen-activated protein kinase in adenosine receptor-mediated relaxation of coronary artery. Am J Physiol Heart Circ Physiol 288:H2574–H2580PubMedCrossRefGoogle Scholar
  158. Teng B, Ledent C, Mustafa SJ (2008) Up-regulation of A(2B) adenosine receptor in A(2A) adenosine receptor knockout mouse coronary artery. J Mol Cell Cardiol 44:905–914PubMedCrossRefGoogle Scholar
  159. Tune JD, Gorman MW, Feigl EO (2004) Matching coronary blood flow to myocardial oxygen consumption. J Appl Physiol 97:404–415PubMedCrossRefGoogle Scholar
  160. Viskin S, Belhassen B, Roth A, Reicher M, Averbuch M, Sheps D, Shalabye E, Laniado S (1993) Aminophylline for bradyasystolic cardiac arrest refractory to atropine and epinephrine. Ann Intern Med 118:279–281PubMedGoogle Scholar
  161. Viskin S, Rosso R, Rogowski O, Belhassen B, Levitas A, Wagshal A, Katz A, Fourey D, Zeltser D, Oliva A, Pollevick GD, Antzelevitch C, Rozovski U (2006) Provocation of sudden heart rate oscillation with adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside test for diagnosing long QT syndrome. Eur Heart J 27:469–475PubMedCrossRefGoogle Scholar
  162. Wang J, Whitt SP, Rubin LJ, Huxley VH (2005) Differential coronary microvascular exchange responses to adenosine: roles of receptor and microvessel subtypes. Microcirculation 12: 313–326PubMedCrossRefGoogle Scholar
  163. Watts SW, Florian JA, Monroe KM (1998) Dissociation of angiotensin II-stimulated activation of mitogen-activated protein kinase kinase from vascular contraction. J Pharmacol Exp Ther 286:1431–1438PubMedGoogle Scholar
  164. Wilden PA, Agazie YM, Kaufman R, Halenda SP (1998) ATP-stimulated smooth muscle cell proliferation requires independent ERK and PI3K signaling pathways. Am J Physiol 275: H1209–H1215PubMedGoogle Scholar
  165. Xu J, Tong H, Wang L, Hurt CM, Pelleg A (1993) Endogenous adenosine, A1 adenosine receptor, and pertussis toxin sensitive guanine nucleotide binding protein mediate hypoxia induced AV nodal conduction block in guinea pig heart in vivo. Cardiovasc Res 27:134–140PubMedCrossRefGoogle Scholar
  166. Xu J, Wang L, Hurt CM, Pelleg A (1994) Endogenous adenosine does not activate ATP-sensitive potassium channels in the hypoxic guinea pig ventricle in vivo. Circulation 89:1209–1216PubMedGoogle Scholar
  167. Xu J, Hurt CM, Pelleg A (1995) Digoxin-induced ventricular arrhythmias in the guinea pig heart in vivo: evidence for a role of endogenous catecholamines in the genesis of delayed afterdepolarizations and triggered activity. Heart Vessels 10:119–127PubMedCrossRefGoogle Scholar
  168. Xu J, Kussmaul W, Kurnik PB, Al-Ahdav M, Pelleg A (2005) Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in the dog. V. Role of purinergic receptors. Am J Physiol Regul Integr Comp Physiol 288:R651–R655Google Scholar
  169. Yang ZW, Wang J, Zheng T, Altura BT, Altura BM (2000) Low [Mg2 + ]o induces contraction of cerebral arteries: roles of tyrosine and mitogen-activated protein kinases. Am J Physiol Heart Circ Physiol 279:H185–H194PubMedGoogle Scholar
  170. Yang D, Zhang Y, Nguyen HG, Koupenova M, Chauhan AK, Makitalo M, Jones MR, St Hilaire C, Seldin DC, Toselli P, Lamperti E, Schreiber BM, Gavras H, Wagner DD, Ravid K (2006) The A2B adenosine receptor protects against inflammation and excessive vascular adhesion. J Clin Invest 116:1913–1923PubMedCrossRefGoogle Scholar
  171. Yang D, Koupenova M, McCrann DJ, Kopeikina KJ, Kagan HM, Schreiber BM, Ravid K (2008) The A2b adenosine receptor protects against vascular injury. Proc Natl Acad Sci USA 105: 792–796PubMedCrossRefGoogle Scholar
  172. Zablocki JA, Wu L, Shryock J, Belardinelli L (2004) Partial A(1) adenosine receptor agonists from a molecular perspective and their potential use as chronic ventricular rate control agents during atrial fibrillation (AF). Curr Top Med Chem 4:839–854PubMedCrossRefGoogle Scholar
  173. Zatta AJ, Headrick JP (2005) Mediators of coronary reactive hyperaemia in isolated mouse heart. Br J Pharmacol 144:576–587PubMedCrossRefGoogle Scholar
  174. Zaza A, Rocchetti M, DiFrancesco D (1996) Modulation of the hyperpolarization-activated current (I(f)) by adenosine in rabbit sinoatrial myocytes. Circulation 94:734–741PubMedGoogle Scholar
  175. Zhao Z, Makaritsis K, Francis CE, Gavras H, Ravid K (2000) A role for the A3 adenosine receptor in determining tissue levels of cAMP and blood pressure: studies in knock-out mice. Biochim Biophys Acta 1500:280–290PubMedGoogle Scholar
  176. Zhao TC, Hines DS, Kukreja RC (2001) Adenosine-induced late preconditioning in mouse hearts: role of p38 MAP kinase and mitochondrial K(ATP) channels. Am J Physiol Heart Circ Physiol 280:H1278–H1285PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • S. Jamal  Mustafa
    • 1
    Email author
  • R. Ray  Morrison
    • 2
  • Bunyen Teng
    • 1
  • Amir Pelleg
    • 3
  1. 1.Department of Physiology and Pharmacology, School of MedicineWest Virginia UniversityMorgantownUSA
  2. 2.Division of Critical Care MedicineSt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of Medicine, College of MedicineDrexel UniversityPhiladelphiaUSA

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