Cardiovascular Drugs and Therapy

, Volume 26, Issue 3, pp 257–263

Pleiotropic Effects of Dronedarone on Ischemia/Reperfusion Injury in Heart and Brain

Article

Abstract

In the present manuscript we critically review the available evidence for pleiotropic effects of dronedarone in settings of myocardial and cerebral ischemia/reperfusion, both from experimental and clinical data.

Key words

Cerebral ischemia Dronedarone Myocardial ischemia Reperfusion Stroke 

References

  1. 1.
    Dobrev D, Nattel S. New antiarrhythmic drugs for treatment of atrial fibrillation. Lancet. 2010;375:1212–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Watanabe Y, Kimura J. Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol. 2008;377:371–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Bogdan R, Goegelein H, Ruetten H. Effect of dronedarone on Na+, Ca2+ and HCN channels. Naunyn Schmiedebergs Arch Pharmacol. 2011;383:347–56.PubMedCrossRefGoogle Scholar
  4. 4.
    Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360:668–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol. 2008;153:1589–601.PubMedCrossRefGoogle Scholar
  6. 6.
    Heusch G, Yoshimoto N, Müller-Ruchholtz ER. Effects of heart rate on hemodynamic severity of coronary artery stenosis in the dog. Basic Res Cardiol. 1982;77:562–73.PubMedCrossRefGoogle Scholar
  7. 7.
    Heusch G, Yoshimoto N. Effects of heart rate and perfusion pressure on segmental coronary resistances and collateral perfusion. Pflugers Arch. 1983;397:284–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010;56:1973–83.PubMedCrossRefGoogle Scholar
  9. 9.
    Neill WA, Phelps NC, Oxendine JM, Mahler DJ, Sim DN. Effect of heart rate on coronary blood flow distribution in dogs. Am J Cardiol. 1973;32:306–12.PubMedCrossRefGoogle Scholar
  10. 10.
    Guth BD, Heusch G, Seitelberger R, Ross Jr J. Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res. 1987;60:738–46.PubMedGoogle Scholar
  11. 11.
    Guth BD, Heusch G, Seitelberger R, Ross Jr J. Elimination of exercise-induced regional myocardial dysfunction by a bradycardic agent in dogs with chronic coronary stenosis. Circulation. 1987;75:661–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Heusch G, Skyschally A, Gres P, van Caster P, Schilawa D, Schulz R. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine—protection beyond heart rate reduction. Eur Heart J. 2008;29:2265–75.PubMedCrossRefGoogle Scholar
  13. 13.
    Manning A, Thisse V, Hodeige D, Richard J, Heyndrickx JP, Chatelain P. SR 33589, a new amiodarone-like antiarrhythmic agent—electrophysiological effects in anesthetized dogs. J Cardiovasc Pharmacol. 1995;25:252–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987–99.PubMedCrossRefGoogle Scholar
  15. 15.
    Davy JM, Herold M, Hoglund C, Timmermans A, Alings A, Radzik D, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the efficacy and safety of dronedarone for the control of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156:Google Scholar
  16. 16.
    Herrmann S, Layh B, Ludwig A. Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol. 2011;51:997–1006.PubMedCrossRefGoogle Scholar
  17. 17.
    Hodeige D, Heyndrickx JP, Chatelain P, Manning A. SR 33589, a new amiodarone-like antiarrhythmic agent: anti-adrenoceptor activity in anaesthetized and conscious dogs. Eur J Pharmacol. 1995;279:25–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Heusch G. A BEAUTIFUL lesson—ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more? Eur Heart J. 2009;30:2300–1.PubMedCrossRefGoogle Scholar
  20. 20.
    Wichmann J, Ertl G, Hohne W, Schweisfurth H, Wernze H, Kochsiek K. Alpha-receptor restriction of coronary blood flow during atrial fibrillation. Am J Cardiol. 1983;52:887–92.PubMedCrossRefGoogle Scholar
  21. 21.
    Wichmann J, Ertl G, Rudolph G, Kochsiek K. Effect of experimentally induced atrial fibrillation on coronary circulation in dogs. Basic Res Cardiol. 1983;78:473–91.PubMedCrossRefGoogle Scholar
  22. 22.
    Ertl G, Wichmann J, Kaufmann M, Kochsiek K. Alpha-receptor constriction induced by atrial fibrillation during maximal coronary dilatation. Basic Res Cardiol. 1986;81:29–39.PubMedCrossRefGoogle Scholar
  23. 23.
    Heusch G, Deussen A, Schipke J, Thämer V. α1- and α2-Adrenoceptor-mediated vasoconstriction of large and small canine coronary arteries in vivo. J Cardiovasc Pharmacol. 1984;6:961–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Baumgart D, Haude M, Goerge G, Liu F, Ge J, Große-Eggebrecht C, et al. Augmented α-adrenergic constriction of atherosclerotic human coronary arteries. Circulation. 1999;99:2090–7.PubMedGoogle Scholar
  25. 25.
    Heusch G, Deussen A. The effects of cardiac sympathetic nerve stimulation on the perfusion of stenotic coronary arteries in the dog. Circ Res. 1983;53:8–15.PubMedGoogle Scholar
  26. 26.
    Seitelberger R, Guth BD, Heusch G, Lee JD, Katayama K, Ross Jr J. Intracoronary alpha 2-adrenergic receptor blockade attenuates ischemia in conscious dogs during exercise. Circ Res. 1988;62:436–42.PubMedGoogle Scholar
  27. 27.
    Heusch G. α -Adrenergic mechanisms in myocardial ischemia. Circulation. 1990;81:1–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Gregorini L, Marco J, Kozàkovà M, Palombo C, Anguissola GB, Marco I, et al. α-Adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction. Circulation. 1999;99:482–90.PubMedGoogle Scholar
  29. 29.
    Gregorini L, Marco J, Farah B, Bernies M, Palombo C, Kozakova M, et al. Effects of selective α1- and α2-adrenergic blockade on coronary flow reserve after coronary stenting. Circulation. 2002;106:2901–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Heusch G, Baumgart D, Camici P, Chilian W, Gregorini L, Hess O, et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation. 2000;101:689–94.PubMedGoogle Scholar
  31. 31.
    Bukowska A, Hammwohner M, Sixdorf A, Schild L, Wiswedel I, Rohl FW, et al. Dronedarone prevents microcirculatory abnormalities in the left ventricle during atrial tachypacing. Br J Pharmacol. 2011. doi:10.1111/j.1476-5381.2011.01784.x.
  32. 32.
    Himmel HM, Dobrev D, Grossmann M, Ravens U. N-desethylamiodarone modulates intracellular calcium concentration in endothelial cells. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:489–96.PubMedCrossRefGoogle Scholar
  33. 33.
    Grossman M, Dobrev D, Kirch W. Amiodarone causes endothelium-dependent vasodilation in human hand veins in vivo. Clin Pharmacol Ther. 1998;64:302–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Skyschally A, Heusch G. Reduction of myocardial infarct size by dronedarone in pigs-a pleiotropic action? Cardiovasc Drugs Ther. 2011;25:197–201.PubMedCrossRefGoogle Scholar
  35. 35.
    Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 1999;18:2323–9.PubMedCrossRefGoogle Scholar
  36. 36.
    El Chemaly A, Magaud C, Patri S, Jayle C, Guinamard R, Bois P. The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes. J Cardiovasc Electrophysiol. 2007;18:1190–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Suffredini S, Stillitano F, Comini L, Bouly M, Brogioni S, Ceconi C, et al. Long term treatment with ivabradine in post-myocardial infarcted rats counteracts f-channel overexpression. Br J Pharmacol. 2012;165:1457–66.Google Scholar
  38. 38.
    Yu X, Chen XW, Zhou P, Yao LJ, Liu T, Zhang B, et al. Calcium influx through I-f channels in rat ventricular myocytes. Am J Physiol-Cell Physiology. 2007;292:C1147–55.CrossRefGoogle Scholar
  39. 39.
    Heusch G. Pleiotropic action(s) of the bradycardic agent ivabradine: cardiovascular protection beyond heart rate reduction. Br J Pharmacol. 2008;155:970–1.PubMedCrossRefGoogle Scholar
  40. 40.
    Inserte J, Garcia-Dorado A, Ruiz-Meana M, Padilla F, Barrabés JA, Pina P, et al. Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death. Cardiovasc Res. 2002;55:739–48.PubMedCrossRefGoogle Scholar
  41. 41.
    Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM, Downey J, et al. Translating novel strategies for cardioprotection: the hatter workshop recommendations. Basic Res Cardiol. 2010;105:677–86.PubMedCrossRefGoogle Scholar
  42. 42.
    Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, et al. Postconditioning and protection from reperfusion injury: where do we stand? Cardiovasc Res. 2010;87:406–23.PubMedCrossRefGoogle Scholar
  43. 43.
    Schwartz Longacre L, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, et al. New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation. 2011;124:1172–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Connolly SJ, Crijns HJ, Torp-Pedersen C, van Eickels M, Gaudin C, Page RL, et al. Analysis of stroke in Athena: a placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg BID for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Circulation. 2009;120:1174–80.PubMedCrossRefGoogle Scholar
  45. 45.
    Christiansen CB, Torp-Pedersen C, Kober L. Impact of dronedarone in atrial fibrillation and flutter on stroke reduction. Clin Interv Aging. 2010;5:63–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Dagres N, Varounis C, Iliodromitis EK, Lekakis JP, Rallidis LS, nastasiou-Nana M. Dronedarone and the incidence of stroke in patients with paroxysmal or persistent atrial fibrillation: a systematic review and meta-analysis of randomized trials. Am J Cardiovasc Drugs. 2011;Epub ahead of print.Google Scholar
  47. 47.
    Kober L, Torp-Pedersen C, McMurray JJ, Gotzsche O, Levy S, Crijns H, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678–87.PubMedCrossRefGoogle Scholar
  48. 48.
    Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011;365:2268–76.PubMedCrossRefGoogle Scholar
  49. 49.
    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Tatlisumak T, Carano RA, Takano K, Meiler MR, Li F, Sotak CH, et al. Broad-spectrum cation channel inhibition by LOE 908 MS reduces infarct volume in vivo and postmortem in focal cerebral ischemia in the rat. J Neurol Sci. 2000;178:107–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Park HS, Lee BK, Park S, Kim SU, Lee SH, Baik EJ, et al. Effects of sabiporide, a specific Na+/H+exchanger inhibitor, on neuronal cell death and brain ischemia. Brain Res. 2005;1061:67–71.PubMedCrossRefGoogle Scholar
  52. 52.
    Aoki Y, Tamura M, Itoh Y, Seto T, Nonaka K, Mukai H, et al. Effective plasma concentration of a novel Na+/Ca2+ channel blocker NS-7 for its cerebroprotective actions in rats with a transient middle cerebral artery occlusion. J Pharmacol Exp Ther. 2001;296:306–11.PubMedGoogle Scholar
  53. 53.
    Chen CM, Liu SH, Lin-Shiau SY. Honokiol, a neuroprotectant against mouse cerebral ischaemia, mediated by preserving Na+, K+−ATPase activity and mitochondrial functions. Basic Clin Pharmacol Toxicol. 2007;101:108–16.PubMedCrossRefGoogle Scholar
  54. 54.
    Candelario-Jalil E. Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs. 2009;10:644–54.PubMedGoogle Scholar
  55. 55.
    Shi H. Hypoxia inducible factor 1 as a therapeutic target in ischemic stroke. Curr Med Chem. 2009;16:4593–600.PubMedCrossRefGoogle Scholar
  56. 56.
    Adluri RS, Thirunavukkarasu M, Dunna NR, Zhan L, Oriowo B, Takeda K, et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1−/−) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1alpha transcription factor and its target genes in mice. Antioxid Redox Signal. 2011;15:1789–97.PubMedCrossRefGoogle Scholar
  57. 57.
    Ogle ME, Gu X, Espinera AR, Wei L. Inhibition of prolyl hydroxylases by dimethyloxaloylglycine after stroke reduces ischemic brain injury and requires hypoxia inducible factor-1alpha. Neurobiol Dis. 2012;45:733–42.Google Scholar
  58. 58.
    Yeh SH, Ou LC, Gean PW, Hung JJ, Chang WC. Selective inhibition of early–but not late–expressed HIF-1alpha is neuroprotective in rats after focal ischemic brain damage. Brain Pathol. 2011;21:249–62.PubMedCrossRefGoogle Scholar
  59. 59.
    Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis. 2004;19:151–67.PubMedCrossRefGoogle Scholar
  60. 60.
    Engelhorn T, Schwarz MA, Heusch G, Doerfler A, Schulz R. Reduction of cerebral infarct size by dronedarone. Cardiovasc Drugs Ther. 2011;25:523–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Naccarelli GV, Wolbrette DL, Levin V, Samii S, Banchs JE, Penny-Peterson E, et al. Safety and efficacy of dronedarone in the treatment of atrial fibrillation/flutter. Clin Med Insights Cardiol. 2011;5:103–19.PubMedCrossRefGoogle Scholar
  62. 62.
    Sherman DG, Kim SG, Boop BS, Corley SD, DiMarco JP, Hart RG, et al. Occurrence and characteristics of stroke events in the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) study. Arch Intern Med. 2005;165:1185–91.PubMedCrossRefGoogle Scholar
  63. 63.
    Le Heuzey JY, De Ferrari GM, Radzik D, Santini M, Zhu J, Davy JM. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: the DIONYSOS study. J Cardiovasc Electrophysiol. 2010;21:597–605.PubMedCrossRefGoogle Scholar
  64. 64.
    Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm cohort of atrial fibrillation. Eur Heart J. 2010;31:967–75.PubMedCrossRefGoogle Scholar
  65. 65.
    Nieuwlaat R, Hohnloser SH, Connolly SJ. Effect of dronedarone in patients with permanent atrial fibrillation during the ATHENA study. Eur Heart J. 2011;32:618.CrossRefGoogle Scholar
  66. 66.
    Das RR, Seshadri S, Beiser AS, Kelly-Hayes M, Au R, Himali JJ, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke. 2008;39:2929–35.PubMedCrossRefGoogle Scholar
  67. 67.
    Lip GYH, Frison L, Grind M, On behalf of the SPORTIF Investigators. Effect of hypertension on anticoagulated patients with atrial fibrillation. Eur Heart J. 2007;28:752–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Lees AD, Wilson J, Orchard CH, Orchard MA. Ouabain enhances basal and stimulus-induced cytoplasmic calcium concentrations in platelets. Thromb Haemost. 1989;62:1000–5.PubMedGoogle Scholar
  69. 69.
    Chirinos JA, Castrellon A, Zambrano JP, Jimenez JJ, Jy W, Horstman LL, et al. Digoxin use is associated with increased platelet and endothelial cell activation in patients with nonvalvular atrial fibrillation. Heart Rhythm. 2005;2:525–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, et al. Inaugural article: digoxin and other cardiac glycosides inhibit HIF-1{alpha} synthesis and block tumor growth. Proc Natl Acad Sci USA. 2008;105:19579–86.PubMedCrossRefGoogle Scholar
  71. 71.
    Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, Campochiaro PA. Digoxin inhibits retinal ischemia-induced HIF-1alpha expression and ocular neovascularization. FASEB J. 2010;24:1759–67.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institut für Pathophysiologie, Zentrum für Innere MedizinUniversitätsklinikum EssenEssenGermany
  2. 2.Institut für PhysiologieJustus Liebig-Universität GiessenGiessenGermany

Personalised recommendations