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Thorac Cardiovasc Surg 2010; 58(2): 86-92
DOI: 10.1055/s-0029-1186271
Original Cardiovascular

© Georg Thieme Verlag KG Stuttgart · New York

Efficacy of the Non-Adenosine Analogue A1 Adenosine Receptor Agonist (BR-4935) on Cardiovascular Function after Cardiopulmonary Bypass

G. Veres1 , 4 [*] , T. Radovits1 [*] , G. Otila1 , K. Hirschberg1 , 4 , H. Haider1 , N. Krieger1 , A. Knoll2 , E. Weigang3 , Z. Szabolcs4 , M. Karck1 , G. Szabó1
  • 1Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany
  • 2Bayer HealthCare, Wuppertal, Germany
  • 3Department of Cardiovascular Surgery, University of Freiburg, Freiburg, Germany
  • 4Department of Cardiovascular Surgery, Semmelweis University, Budapest, Hungary
Further Information

Publication History

received February 1, 2009

Publication Date:
23 March 2010 (online)

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Abstract

Background: We tested the hypothesis that pharmacological preconditioning with a newly developed, potent non-adenosine analogue A1AdoR agonist (BR-4935) improves biventricular cardiac and endothelial function after cardiopulmonary bypass. Methods: Twelve anesthetized dogs underwent cardiopulmonary bypass. Dogs were divided into two groups: group 1 (n = 6) received saline vehicle, group 2 (n = 6) received BR-4935 before cardiopulmonary bypass. Biventricular hemodynamic variables were measured using a combined pressure-volume conductance catheter. Coronary blood flow, ATP content, malondialdehyde and myeloperoxidase levels and vasodilatative responses to acetylcholine and sodium nitroprusside were also determined. Results: Administration of the A1AdoR agonist led to a significantly better recovery of left and right ventricular systolic function after 60 minutes of reperfusion. Although the vasodilatative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary blood flow in the BR-4935 group. In addition, the ATP content was significantly higher in the same group. Furthermore, malondialdehyde and myeloperoxidase levels significantly decreased in the A1AdoR group. Conclusion: Pharmacological preconditioning with a new, potent non-adenosine analogue A1AdoR agonist improves biventricular function recovery and endothelial function after hypothermic cardiac arrest.

Key words

myocardial protection - cardiovascular surgery - coronary bypass surgery

References

  • 1 Wallace A, Lam H W, Nosé P S, Bellows W, Mangano D T. Changes in systolic and diastolic ventricular function with cold cardioplegic arrest in man. The Multicenter Study of Perioperative Ischemia (McSPI) Research Group.  J Card Surg. 1994;  9 (Suppl. 3) 497-502
    PubMedGoogle Scholar
  • 2 Forman M B, Velasco C E. Role of adenosine in the treatment of myocardial stunning.  Cardiovasc Drugs Ther. 1991;  5 (5) 901-908
    CrossrefPubMedGoogle Scholar
  • 3 Ely S W, Berne R M. Protective effects of adenosine in myocardial ischemia.  Circulation. 1992;  85 (3) 893-904
    PubMedGoogle Scholar
  • 4 Shryock J C, Belardinelli L. Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology.  Am J Cardiol. 1997;  79 (12) 2-10
    PubMedGoogle Scholar
  • 5 Yaar R, Jones M R, Chen J F, Ravid K. Animal models for the study of adenosine receptor function.  J Cell Physiol. 2005;  202 (1) 9-20
    CrossrefPubMedGoogle Scholar
  • 6 Thornton J D, Liu G S, Olsson R A, Downey J M. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction.  Circulation. 1992;  85 (2) 659-665
    PubMedGoogle Scholar
  • 7 Toombs C F, McGee S, Johnston W E, Vinten-Johansen J. Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia.  Circulation. 1992;  86 (3) 986-994
    PubMedGoogle Scholar
  • 8 Lasley R D, Rhee J W, Van Wylen D G, Mentzer Jr R M. Adenosine A1 receptor mediated protection of the globally ischemic isolated rat heart.  J Mol Cell Cardiol. 1990;  22 (1) 39-47
    PubMedGoogle Scholar
  • 9 Liu G S, Thornton J, Van Winkle D M, Stanley A W, Olsson R A, Downey J M. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart.  Circulation. 1991;  84 (1) 350-356
    PubMedGoogle Scholar
  • 10 Van Winkle D M, Chein G L, Wolff R A, Soifer B E, Kuzume K, Davis R F. Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel.  Am J Physiol. 1994;  266 (2 Pt 2) H829-H839
    PubMedGoogle Scholar
  • 11 Auchampach J A, Gross G J. Adenosine A1 receptors, KATP channels, and ischemic preconditioning in dogs.  Am J Physiol. 1993;  264 (5 Pt 2) H1327-H1336
    PubMedGoogle Scholar
  • 12 Rosentreter U, Kraemer T, Shimada M et al. Substituted 2-thio-3,5-dicyano-4-phenyl-6-aminopyridines and the use of the same. Patent Pub No. WO/2003/053441. 
    PubMedGoogle Scholar
  • 13 Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L M. Apoptosis in human acute myocardial infarction.  Circulation. 1997;  95 (2) 320-323
    PubMedGoogle Scholar
  • 14 Murry C E, Jennings R B, Reimer K A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.  Circulation. 1986;  74 (5) 1124-1136
    CrossrefPubMedGoogle Scholar
  • 15 Yellon D M, Downey J M. Preconditioning the myocardium: from cellular physiology to clinical cardiology.  Physiol Rev. 2003;  83 (4) 1113-1151
    PubMedGoogle Scholar
  • 16 Baines C P, Cohen M V, Downey J M. Signal transduction in ischemic preconditioning: the role of kinases and mitochondrial K(ATP) channels.  J Cardiovasc Electrophysiol. 1999;  10 (5) 741-754
    CrossrefPubMedGoogle Scholar
  • 17 Miura T, Liu Y, Kita H, Ogawa T, Shimamoto K. Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation.  J Am Coll Cardiol. 2000;  35 (1) 238-245
    CrossrefPubMedGoogle Scholar
  • 18 Louttit J B, Hunt A A, Maxwell M P, Drew G M. The time course of cardioprotection induced by GR79236, a selective adenosine A1-receptor agonist, in myocardial ischaemia-reperfusion injury in the pig.  J Cardiovasc Pharmacol. 1999;  33 (2) 285-291
    CrossrefPubMedGoogle Scholar
  • 19 Finegan B A, Lopaschuk G D, Gandhi M, Clanachan A S. Inhibition of glycolysis and enhanced mechanical function of working rat hearts as a result of adenosine A1 receptor stimulation during reperfusion following ischaemia.  Br J Pharmacol. 1996;  118 (2) 355-363
    PubMedGoogle Scholar
  • 20 Bolling S F, Bies L E, Gallagher K P, Bove E L. Enhanced myocardial protection with adenosine.  Ann Thorac Surg. 1989;  47 (6) 809-815
    CrossrefPubMedGoogle Scholar
  • 21 Parker P E, Bashour F A, Downey H F, Boutros I S. Coronary reperfusion: effects of vasodilators (papaverine and adenosine).  Am Heart J. 1977;  93 (1) 66-72
    CrossrefPubMedGoogle Scholar
  • 22 Cox B F, Greenland B D, Perrone M H, Merkel L A. Ischaemia/reperfusion selectively attenuates coronary vasodilatation to an adenosine A2- but not to an A1-agonist in the dog.  Br J Pharmacol. 1994;  111 (4) 1233-1239
    PubMedGoogle Scholar
  • 23 Vanden Hoek T, Becker L B, Shao Z H, Li C Q, Schumacker P T. Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion.  Circ Res. 2000;  86 (5) 541-548
    PubMedGoogle Scholar
  • 24 Narayan P, Mentzer Jr R M, Lasley R D. Adenosine A1 receptor activation reduces reactive oxygen species and attenuates stunning in ventricular myocytes.  J Mol Cell Cardiol. 2001;  33 (1) 121-129
    CrossrefPubMedGoogle Scholar
  • 25 Jordan J E, Zhao Z Q, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury.  Cardiovasc Res. 1999;  43 (4) 860-878
    CrossrefPubMedGoogle Scholar
  • 26 Loria V, Dato I, Graziani F, Biasucci L M. Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes.  Mediators Inflamm. 2008;  DOI: 10.1155/2008/135625 , published online March 11, 2008
    PubMedGoogle Scholar
  • 27 Budde J M, Morris C D, Velez D A et al. Reduction of infarct size and preservation of endothelial function by multidose intravenous adenosine during extended reperfusion.  J Surg Res. 2004;  116 (1) 104-115
    CrossrefPubMedGoogle Scholar
  • 28 Schmitt J P, Schröder J, Schunkert H, Birnbaum D E, Aebert H. Role of apoptosis in myocardial stunning after open heart surgery.  Ann Thorac Surg. 2002;  73 (4) 1229-1235
    CrossrefPubMedGoogle Scholar
  • 29 Shalaby A, Rinne T, Järvinen O et al. Initial results of a clinical study: adenosine enhanced cardioprotection and its effect on cardiomyocytes apoptosis during coronary artery bypass grafting.  Eur J Cardiothorac Surg. 2008;  33 (4) 639-644
    CrossrefPubMedGoogle Scholar
  • 30 Lee H T, LaFaro R J, Reed G E. Pretreatment of human myocardium with adenosine during open heart surgery.  J Card Surg. 1995;  10 (6) 665-676
    CrossrefPubMedGoogle Scholar
  • 31 Mentzer Jr R M, Birjiniuk V, Khuri S et al. Adenosine myocardial protection: preliminary results of a phase II clinical trial.  Ann Surg. 1999;  229 (5) 643-649 discussion 649-650
    CrossrefPubMedGoogle Scholar
  • 32 Cohen G, Feder-Elituv R, Iazetta J et al. Phase 2 studies of adenosine cardioplegia.  Circulation. 1998;  98 (Suppl. 19) II225-II233
    PubMedGoogle Scholar
  • 33 Teoh L K, Grant R, Hulf J A, Pugsley W B, Yellon D M. The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery.  Cardiovasc Res. 2002;  53 (1) 175-180
    CrossrefPubMedGoogle Scholar

1 These authors contributed equally to this work.

Gábor Veres, MD

Department of Cardiac Surgery
University of Heidelberg

INF 326

69120 Heidelberg

Germany

Phone: + 49 62 21 56 62 46

Fax: + 49 62 21 56 45 71

Email: gaborveres@yahoo.com

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