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Effect of the Calcium Sensitizer Levosimendan on the Performance of Ischaemic Myocardium in Anaesthetised Pigs

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Abstract

The calcium sensitizer levosimendan (LEV) improves the function of stunned myocardium, cardiac performance in heart failure, and possibly the efficiency of myocardial work. The present experiments investigated the effect of LEV on myocardial contraction and metabolism of acutely ischaemic myocardium distal to a functionally effective coronary artery stenosis. Anaesthetised open chest pigs (n = 14) were instrumented to assess heart rate (HR), aortic pressure (AoP), cardiac output (CO), blood flow in the left descending (QLAD) and circumflex (QLCX) coronary artery, myocardial end-diastolic segment length and systolic shortening (edL, MSS by sonomicrometry) in the LAD- and LCX-territory. Systemic vascular resistance (SVR), and a myocardial power index (PowI) for the LAD- and LCX-region were calculated. Following obstruction of QLAD by an external snare proximal to the first diagonal branch LEV was given intravenously (10 + 20 + 30 μg/kg 15 min apart, n = 8) or the vehicle of LEV (n = 6). Following LEV haemodynamics and regional myocardial performance changed significantly: HR +22 min−1, AoP −6 mmHg, CO +17%, SVR −21%; intact myocardium: QLCX +15%, RLCX −24%, PowILCX + 39%; ischaemic myocardium: QLAD −7%, MSSLAD −42%, PowILAD −27%. The data confirm the pharmacological profile of LEV: positive chronotropy, positive inotropy, and vasodilatation. The pump function of acutely ischaemic myocardium worsened following LEV. The efficiency of myocardial performance did not improve. A beneficial effect of LEV on the function of ischaemic myocardium was possibly outmanoeuvred by the increase in heart rate.

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References

  1. Lancaster MK, Cook SJ. The effects of levosimendan on [Ca2+]i in guinea-pig isolated ventricular myocytes. Eur JPharmacol 1997;339:97–100.

    Google Scholar 

  2. Edes I, Kiss E, Kitada Y, et al. Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 1995;77:107–113.

    Google Scholar 

  3. Udvary E, Papp JG, Vegh A. Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction. Br J Pharmacol 1995;114:656–661.

    Google Scholar 

  4. Pagel PS, Hettrick DA, Warltier DC. Comparison of the effects of levosimendan, pimobendan, and milrinone on canine left ventricular-arterial coupling and mechanical efficiency. Basic Res Cardiol 1996;91:296–307.

    Google Scholar 

  5. Haikala H, Kaheinen P, Levijoki J, Linden IB. The role of cAMP-and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. Cardiovasc Res 1997;34:536–546.

    Google Scholar 

  6. Hasenfuss G, Pieske B, Castell M, Kretschmann B, Maier LS, Just H. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998;98:2141–2147.

    Google Scholar 

  7. Jamali IN, Kersten JR, Pagel PS, Hettrick DA, Warltier DC. Intracoronary levosimendan enhances contractile function of stunned myocardium. Anesth Analg 1997;85:23–29.

    Google Scholar 

  8. Sonntag S, Opitz C, Wellnhofer E, et al. Effects of the calcium sensitizer levosimendan on stunned myocardium after percutaneous transluminal coronary angioplasty. Eur Heart J 2000;21(Suppl):40.

    Google Scholar 

  9. Follath F, Cleland JGF, Just H, et al. Efficacy and safety of intravenous levosimendan in severe low-output heart failure. Circulation 1999;100(Suppl I):I–646.

    Google Scholar 

  10. Sunderdiek U, Korbmacher B, Gams E, Schipke JD. Myocardial efficiency in stunned myocardium. Comparison of Ca2+ sensitization and PDEIII-inhibition on energy consumption. Europ J Cardiothor Surg 2000;18:83–89.

    Google Scholar 

  11. Heimisch W, Hagl S, Gebhardt K, Meisner H, Mendler N, Sebening F. Direct measurement of cyclic changes in regional wall geometry in the left ventricle of the dog. Innov Tech Biol Med 1981;2:487–501.

    Google Scholar 

  12. Schad H, Heimisch W, Haas F, Mendler N. Effect of the 'specific bradycardic agent' alinidine on the function of ischemic myocardium. Thorac Cardiovasc Surg 1991;39(Suppl 3):211–216.

    Google Scholar 

  13. Schad H, Heimisch W, Mendler N. Models of coronary artery disease: “critical” versus “functional” coronary artery stenosis. Thorac Cardiovasc Surg 1991;39:13–18.

    Google Scholar 

  14. Schad H, Heimisch W, Barankay A, Hesse S, Mendler N. Effects of the serotonin-antagonist ketanserin on the function of ischaemic and normally perfused myocardium and modification by beta-1-blockade in anaesthetized normotensive dogs. Res Exp Med Berl 1992;192:355–365.

    Google Scholar 

  15. Hacker TA, Renstrom B, Paulson D, Liedtke AJ, Stanley WC. Ischemia produces an increase in ammonia output in swine myocardium. Cardioscience 1994;5:255–260.

    Google Scholar 

  16. McFalls EO, Baldwin DR, Marx D, Maxwell K, Ward HB. Glucose uptake increases relative to oxygen consumption during short-term hibernation. Basic Res Cardiol 2000;95:39–46.

    Google Scholar 

  17. Schulz R, Guth BD, Pieper K, Martin C, Heusch G. Recruitment of an inotropic reserve in moderately ischemic myocardium at the expense of metabolic recovery. A model of short-term hibernation. Circ Res 1992;70:1282–1295.

    Google Scholar 

  18. Figgitt DP, Gillies PS, Goa KL. Levosimendan. Drugs 2001;61:613–627;discussion 628-629.

    Google Scholar 

  19. McGough MF, Pagel PS, Lowe D, Hettrick DA, Kersten JR, Warltier DC. Effects of levosimendan on left ventricular function: Correlation with plasma concentrations in conscious dogs. J Cardiothorac Vasc Anesth 1997;11:49–53.

    Google Scholar 

  20. Lilleberg J, Nieminen MS, Akkila J, et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 1998;19:660–668.

    Google Scholar 

  21. Harkin CP, Pagel PS, Tessmer JP, Warltier DC. Systemic and coronary hemodynamic actions and left ventricular functional effects of levosimendan in conscious dogs. J Cardiovasc Pharmacol 1995;26:179–188.

    Google Scholar 

  22. Pataricza J, Hohn J, Petri A, Balogh A, Papp JG. Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol 2000;52:213–217.

    Google Scholar 

  23. Lilleberg J, Sundberg S, Nieminen MS. Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. J Cardiovasc Pharmacol 1995;26(Suppl 1):S63–S69.

    Google Scholar 

  24. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J AmColl Cardiol 2000;36:1903–1912.

    Google Scholar 

  25. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study investigators. Circulation 2000;102:2222–2227.

    Google Scholar 

  26. Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS, Warltier DC. Levosimendan enhances cardiac performance after cardiopulmonary bypass: A prospective, randomized placebo-controlled trial. J Cardiovasc Pharmacol 1999;34:219–228.

    Google Scholar 

  27. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M. Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 2001;29:2185–2193.

    Google Scholar 

  28. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther 2000;68:522–531.

    Google Scholar 

  29. du Toit E, Hofmann D, McCarthy J, Pineda C. Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model. Heart 2001;86:81–87.

    Google Scholar 

  30. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. The novel calcium sensitizer levosimendan activates the ATPsensitive K+ channel in rat ventricular cells. J Pharmacol Exp Ther 1997;283:375–383.

    Google Scholar 

  31. Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg 2000;90:5–11.

    Google Scholar 

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Authors and Affiliations

  1. Department of Anaesthesiology, German Heart Centre Munich, Lazarettstr 36, D-80636, München, Germany

    Peter Tassani

  2. Department of Cardiovascular Surgery, German Heart Centre Munich, Lazarettstr 36, D-80636, München, Germany

    Hubert Schad, Werner Heimisch, Angelika Bernhard-Abt, Ursula Ettner, Nikolaus Mendler & Rüdiger Lange

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  1. Peter Tassani
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  2. Hubert Schad
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  7. Rüdiger Lange
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Tassani, P., Schad, H., Heimisch, W. et al. Effect of the Calcium Sensitizer Levosimendan on the Performance of Ischaemic Myocardium in Anaesthetised Pigs. Cardiovasc Drugs Ther 16, 435–441 (2002). https://doi.org/10.1023/A:1022190503351

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