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Thorac Cardiovasc Surg 2008; 56(7): 379-385
DOI: 10.1055/s-2008-1038729
Original Basic Science

© Georg Thieme Verlag KG Stuttgart · New York

Inotropic, Vasodilating and Preconditioning Actions of Levosimendan in the Heart

K. Meyer1 , J. D. Schipke1 , R. C. Klocke2 , E. Gams3 , B. Korbmacher3
  • 1Research Group Experimental Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
  • 2Internal Medicine, Marienhospital, Vechta, Germany
  • 3Clinic of Thoracic and Cardiovascular Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
Further Information

Publication History

received March 25, 2008

Publication Date:
22 September 2008 (online)

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Abstract

Background: Levosimendan improves ventricular function, induces vasodilation and induces myocardial preconditioning. We determined the external efficiency and assessed the effects on arrhythmias. Methods: In isolated, blood-perfused rabbit hearts, levosimendan (0.75 µmol) or placebo was administered, while hemodynamics were recorded. After no-flow ischemia and reperfusion, data were recorded again. Results: Placebo in normoxic hearts did not affect measurements, while levosimendan increased heart rate (+ 18 %) and improved coronary output (+ 52 %), stroke volume (+ 28 %), maximal left ventricular pressure (+ 30 %), maximal rate of pressure increase (+ 36 %), work (+ 68 %), minimal rate of pressure increase (+ 53 %), coronary blood flow (+ 41 %), coronary resistance (− 19 %) and external efficiency (33 %; p < 0.05). During reperfusion, hemodynamics in the levosimendan group were significantly better preserved compared with the placebo group. Early reperfusion arrhythmias were decreased (levosimendan group: 7 ± 3 % vs. placebo group: 25 ± 17 %; p < 0.05). Conclusions: Levosimendan does not impair diastole, dilates coronary vessels, induces pharmacological preconditioning, improves external efficiency and exerts antiarrhythmic properties during reperfusion. As this drug protects the heart from reperfusion injury, it seems well suited for treating dysfunctional hearts after cardiac surgery.

Key words

myocardial protection - coronary bypass surgery - cardiovascular surgery

References

  • 1 Rooke G A, Feigl E O. Work as a correlate of canine left ventricular oxygen consumption, and the problem of catecholamine oxygen wasting.  Circ Res. 1982;  50 273-286
    PubMedSearch in Google Scholar
  • 2 Rehberg S, Ertmer C, Van A H, Lange M, Broking K, Morelli A, Westphal M. [Role of levosimendan in intensive care treatment of myocardial insufficiency].  Anaesthesist. 2007;  56 30-43
    CrossrefPubMedSearch in Google Scholar
  • 3 Arteaga G M, Kobayashi T, Solaro R J. Molecular actions of drugs that sensitize cardiac myofilaments to Ca2+.  Ann Med. 2002;  34 248-258
    PubMedSearch in Google Scholar
  • 4 Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells.  J Pharmacol Exp Ther. 1997;  283 375-383
    PubMedSearch in Google Scholar
  • 5 Light P E. Cardiac KATP channels and ischemic preconditioning: current perspectives.  Can J Cardiol. 1999;  15 1123-1130
    PubMedSearch in Google Scholar
  • 6 Das B, Sarkar C. Cardiomyocyte mitochondrial KATP channels participate in the antiarrhythmic and antiinfarct effects of KATP activators during ischemia and reperfusion in an intact anesthetized rabbit model.  Pol J Pharmacol. 2003;  55 771-786
    PubMedSearch in Google Scholar
  • 7 Schulz R, Rose J, Heusch G. Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine.  Am J Physiol. 1994;  267 H1341-H1352
    PubMedSearch in Google Scholar
  • 8 Busk M, Maeng M, Kristensen J, Berg J S, Mortensen U M, Nielsen T T, Nielsen-Kudsk J E. Effects of levosimendan on myocardial infarct size and hemodynamics in a closed-chest porcine ischemia-reperfusion model.  Cardiovasc Drugs Ther. 2006;  20 335-342
    CrossrefPubMedSearch in Google Scholar
  • 9 Lepran I, Pollesello P, Vajda S, Varro A, Papp J G. Preconditioning effects of levosimendan in a rabbit cardiac ischemia-reperfusion model.  J Cardiovasc Pharmacol. 2006;  48 148-152
    CrossrefPubMedSearch in Google Scholar
  • 10 Headrick J P. Aging impairs functional, metabolic and ionic recovery from ischemia-reperfusion and hypoxia-reoxygenation.  J Mol Cell Cardiol. 1998;  30 1415-1430
    CrossrefPubMedSearch in Google Scholar
  • 11 Rüegg J C. The vertebrate heart: modulation of calcium control. Rüegg JC Calcium in Muscle Contraction. Berlin, Heidelberg, New York; Springer 1992: 165-200
    Search in Google Scholar
  • 12 Rump A F, Acar D, Klaus W. A quantitative comparison of functional and anti-ischaemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts.  Br J Pharmacol. 1994;  112 757-762
    PubMedSearch in Google Scholar
  • 13 du Toit E F, Muller C A, McCarthy J, Opie L H. Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff-perfused guinea pig heart.  J Pharmacol Exp Ther. 1999;  290 505-514
    PubMedSearch in Google Scholar
  • 14 Todaka K, Wang J, Yi G H, Stennett R, Knecht M, Packer M, Burkhoff D. Effects of levosimendan on myocardial contractility and oxygen consumption.  J Pharmacol Exp Ther. 1996;  279 120-127
    PubMedSearch in Google Scholar
  • 15 Sato S, Talukder M A, Sugawara H, Sawada H, Endoh M. Effects of levosimendan on myocardial contractility and Ca2+ transients in aequorin-loaded right-ventricular papillary muscles and indo-1-loaded single ventricular cardiomyocytes of the rabbit.  J Mol Cell Cardiol. 1998;  30 1115-1128
    CrossrefPubMedSearch in Google Scholar
  • 16 Brixius K, Reicke S, Schwinger R H. Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium.  Am J Physiol Heart Circ Physiol. 2002;  282 H131-H137
    PubMedSearch in Google Scholar
  • 17 Palmer S, Kentish J C. Differential effects of the Ca2+ sensitizers caffeine and CGP 48506 on the relaxation rate of rat skinned cardiac trabeculae.  Circ Res. 1997;  80 682-687
    PubMedSearch in Google Scholar
  • 18 Hajjar R J, Schmidt U, Helm P, Gwathmey J K. Ca++ sensitizers impair cardiac relaxation in failing human myocardium.  J Pharmacol Exp Ther. 1997;  280 247-254
    PubMedSearch in Google Scholar
  • 19 Korbmacher B, Sunderdiek U, Selcan G, Arnold G, Schipke J D. Different responses on nonischemic and postischemic myocardium towards Ca++ sensitization – effect of Ca++ sensitization in stunned myocardium.  J Mol Cell Cardiol. 1997;  29 2053-2066
    CrossrefPubMedSearch in Google Scholar
  • 20 Hgashiyama A, Watkins M W, Chen Z, LeWinter M M. Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts.  Circulation. 1995;  92 3094-3104
    PubMedSearch in Google Scholar
  • 21 Tamargo J, Lopez-Sendon J. [Rationale and clinical evidence for the effects of new pharmacological treatments for heart failure].  Rev Esp Cardiol. 2004;  57 447-464
    PubMedSearch in Google Scholar
  • 22 Barraud D, Faivre V, Damy T, Welschbillig S, Gayat E, Heymes C, Payen D, Shah A M, Mebazaa A. Levosimendan restores both systolic and diastolic cardiac performance in lipopolysaccharide-treated rabbits: comparison with dobutamine and milrinone.  Crit Care Med. 2007;  35 1376-1382
    CrossrefPubMedSearch in Google Scholar
  • 23 Sonntag S, Sundberg S, Lehtonen L A, Kleber F X. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia.  J Am Coll Cardiol. 2004;  43 2177-2182
    CrossrefPubMedSearch in Google Scholar
  • 24 Lehtonen L A, Antila S, Pentikainen P J. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents.  Clin Pharmacokinet. 2004;  43 187-203
    CrossrefPubMedSearch in Google Scholar
  • 25 Michaels A D, McKeown B, Kostal M, Vakharia K T, Jordan M V, Gerber I L, Foster E, Chatterjee K. Effects of intravenous levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake.  Circulation. 2005;  111 1504-1509
    CrossrefPubMedSearch in Google Scholar
  • 26 Kaheinen P, Pollesello P, Levijoki J, Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels.  J Cardiovasc Pharmacol. 2001;  37 367-374
    CrossrefPubMedSearch in Google Scholar
  • 27 Erdei N, Papp Z, Pollesello P, Edes I, Bagi Z. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles.  Br J Pharmacol. 2006;  148 696-702
    CrossrefPubMedSearch in Google Scholar
  • 28 Sunderdiek U, Schmitz-Spanke S, Korbmacher B, Gams E, Schipke J D. Left ventricular dysfunction and disturbed O(2)-utilization in stunned myocardium: influence of ischemic preconditioning.  Eur J Cardiothorac Surg. 2001;  20 770-776
    CrossrefPubMedSearch in Google Scholar
  • 29 Trines S A, Slager C J, Onderwater T A, Lamers J M, Verdouw P D, Krams R. Oxygen wastage of stunned myocardium in vivo is due to an increased oxygen cost of contractility and a decreased myofibrillar efficiency.  Cardiovasc Res. 2001;  51 122-130
    CrossrefPubMedSearch in Google Scholar
  • 30 Cohen M V, Baines C P, Downey J M. Ischemic preconditioning: from adenosine receptor of KATP channel.  Annu Rev Physiol. 2000;  62 79-109
    CrossrefPubMedSearch in Google Scholar
  • 31 Post H, Heusch G. Ischemic preconditioning. Experimental facts and clinical perspective.  Minerva Cardioangiol. 2002;  50 569-605
    PubMedSearch in Google Scholar
  • 32 Kopustinskiene D M, Pollesello P, Saris N E. Levosimendan is a mitochondrial K(ATP) channel opener.  Eur J Pharmacol. 2001;  428 311-314
    CrossrefPubMedSearch in Google Scholar
  • 33 Gross G J, Fryer R M. Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning.  Circ Res. 1999;  84 (9) 973-979
    PubMedSearch in Google Scholar
  • 34 Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A, Nofroni I, Puddu P E, Singer M, Pietropaoli P. Preconditioning effects of levosimendan in coronary artery bypass grafting – a pilot study.  Br J Anaesth. 2006;  96 694-700
    PubMedSearch in Google Scholar
  • 35 Kersten J R, Montgomery M W, Pagel P S, Warltier D C. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels.  Anesth Analg. 2000;  90 5-11
    PubMedSearch in Google Scholar
  • 36 Maytin M, Leopold J, Loscalzo J. Oxidant stress in the vasculature.  Curr Atheroscler Rep. 1999;  1 156-164
    CrossrefPubMedSearch in Google Scholar
  • 37 Gasser R, Gasser S, Hammerl R, Hecking C. ATP-abhängige Kaliumkanäle im Herz-Kreislauf-System.  J Kardiol. 2003;  10 (Suppl C) 3-5
    PubMedSearch in Google Scholar
  • 38 Takahashi R, Endoh M. Effects of OR-1896, a metabolite of levosimendan, on force of contraction and Ca2+ transients under acidotic condition in aequorin-loaded canine ventricular myocardium.  Naunyn Schmiedebergs Arch Pharmacol. 2002;  366 440-448
    CrossrefPubMedSearch in Google Scholar
  • 39 Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier L S, Just H. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium.  Circulation. 1998;  98 2141-2147
    PubMedSearch in Google Scholar
  • 40 Vegh A, Szekeres L, Parratt J R. Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia-induced arrhythmias in anaesthetized dogs.  Br J Pharmacol. 1991;  104 294-295
    PubMedSearch in Google Scholar
  • 41 Sun W, Wainwright C L. The potential antiarrhythmic effects of exogenous and endogenous bradykinin in the ischaemic rat heart in vivo.  Coron Artery Dis. 1994;  5 541-550
    PubMedSearch in Google Scholar
  • 42 Murry C E, Jennings R B, Reimer K A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.  Circulation. 1986;  74 1124-1136
    CrossrefPubMedSearch in Google Scholar
  • 43 Marktanner R, Nacke P, Feindt P, Hohlfeld T, Schipke J D, Gams E. Delayed preconditioning via angiotensin-converting enzyme inhibition: pros and cons from an experimental study.  Clin Exp Pharmacol Physiol. 2006;  33 787-792
    CrossrefPubMedSearch in Google Scholar
  • 44 Tosaki A, Hearse D J. Protective effect of transient calcium reduction against reperfusion-induced arrhythmias.  Am J Physiol. 1987;  253 H225-H233
    PubMedSearch in Google Scholar
  • 45 Leesar M A, Stoddard M F, Dawn B, Jasti V G, Masden R, Bolli R. Delayed preconditioning-mimetic action of nitroglycerin in patients undergoing coronary angioplasty.  Circulation. 2001;  103 2935-2941
    PubMedSearch in Google Scholar
  • 46 Wang X, Wei M, Kuukasjarvi P, Laurikka J, Jarvinen O, Rinne T, Honkonen E L, Tarkka M. Novel pharmacological preconditioning with diazoxide attenuates myocardial stunning in coronary artery bypass grafting.  Eur J Cardiothorac Surg. 2003;  24 967-973
    CrossrefPubMedSearch in Google Scholar
  • 47 Kumar S, Kumar A, De Santis V. The preconditioning effects of levosimendan.  Br J Anaesth. 2006;  97 425
    PubMedSearch in Google Scholar

Prof. Jochen D. Schipke

Research Group Experimental Surgery
University Hospital Düsseldorf

Moorenstraße 5

40225 Düsseldorf

Germany

Phone: + 49 (0) 21 18 11 99 49

Fax: + 49 (0) 21 18 11 69 96

Email: schipke@med.uni-duesseldorf.de