Skip to main content
SpringerLink
Log in

The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Objective

Sepsis-evoked myocardial dysfunction is possibly due to decreased myofilament calcium sensitivity, and a calcium sensitizer may thus specifically improve contractility in sepsis by enhancing myofilament calcium sensitivity. We examined whether the calcium sensitizer levosimendan mitigates myocardial dysfunction and improves contractility in hearts isolated from endotoxin-treated guinea pigs.

Design and setting

Prospective, controlled, randomized animal study in a university research laboratory.

Subjects

Guinea pig hearts isolated 4 h (n=10) or 18 h (n=8) following E. coli LPS (4 mg/kg i.p.) and hearts from sham-treated controls (n=11 and n=6).

Interventions

Isolated hearts were perfused at constant aortic pressure [Krebs-Henseleit buffer, heart rate: 300/min, left ventricular (LV) diastolic pressure: 6–8 mmHg], and LV developed pressure (LVdP) and LVdP/dt were continuously assessed. Levosimendan was added to the perfusate in incremental concentrations (0.03, 0.1, 0.3 µM).

Measurements and results

Endotoxin resulted in a significant decrease in LVdP by 20±6% and 43±8%, in +LVdP/dt by 16±5% and 44±7%, and in −LVdP/dt by 27±8% and 47±8% after 4 and 18 h, respectively. In septic hearts levosimendan increased LV function concentration-dependently by 32±4% (LVdP), 33±5% (+LVdP/dt), and 37±7% (−LVdP/dt) 4 h and by 31±6% (LVdP), 33±6% (+LVdP/dt), and 32±7% (−LVdP/dt) 18 h after LPS. However, levosimendan increased myocardial function similarly in control hearts.

Conclusions

While the calcium sensitizer levosimendan markedly improved LV contractility in hearts from both endotoxic and sham animals, it failed to specifically abolish endotoxin-evoked myocardial dysfunction. Thus, decreased calcium sensitivity either does not play a major role in endotoxin-evoked cardiomyopathy or the location of its pathomechanism differs from levosimendan's site of action.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE (1984) Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med 100:483–490

    CAS  PubMed  Google Scholar 

  2. Parrillo JE (1989) The cardiovascular pathophysiology of sepsis. Annu Rev Med 40:469–485

    Article  CAS  PubMed  Google Scholar 

  3. Kumar A, Krieger A, Symeoneides S, Parrillo JE (2001) Myocardial dysfunction in septic shock. II. Role of cytokines and nitric oxide. J Cardiothorac Vasc Anesth 15:485–511

    Article  CAS  PubMed  Google Scholar 

  4. Rigby SL, Hofmann PA, Zhong J, Adams HR, Rubin LJ (1998) Endotoxemia-induced myocardial dysfunction is not associated with changes in myofilament Ca2+ responsiveness. Am J Physiol 274:H580–H590

    CAS  PubMed  Google Scholar 

  5. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL (1993) Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest 92:2303–2312

    CAS  PubMed  Google Scholar 

  6. Yasuda S, Lew WY (1997) Lipopolysaccharide depresses cardiac contractility and beta-adrenergic contractile response by decreasing myofilament response to Ca2+ in cardiac myocytes. Circ Res 81:1011–1020

    CAS  PubMed  Google Scholar 

  7. Goldhaber JI, Kim KH, Natterson PD, Lawrence T, Yang P, Weiss JN (1996) Effects of TNF-alpha on [Ca2+]i and contractility in isolated adult rabbit ventricular myocytes. Am J Physiol 271:H1449–H1455

    CAS  PubMed  Google Scholar 

  8. Powers FM, Farias S, Minami H, Martin AF, Solaro RJ, Law WR (1998) Cardiac myofilament protein function is altered during sepsis. J Mol Cell Cardiol 30:967–978

    Article  CAS  PubMed  Google Scholar 

  9. Tavernier B, Garrigue D, Boulle C, Vallet B, Adnet P (1998) Myofilament calcium sensitivity is decreased in skinned cardiac fibres of endotoxin-treated rabbits. Cardiovasc Res 38:472–479

    Article  CAS  PubMed  Google Scholar 

  10. Takeuchi K, del Nido PJ, Ibrahim AE, Poutias DN, Glynn P, Cao-Danh H, Cowan DB, McGowan FX Jr (1999) Increased myocardial calcium cycling and reduced myofilament calcium sensitivity in early endotoxemia. Surgery 126:231–238

    Article  CAS  PubMed  Google Scholar 

  11. Tavernier B, Mebazaa A, Mateo P, Sys S, Ventura-Clapier R, Veksler V (2001) Phosphorylation-dependent alteration in myofilament Ca2+ sensitivity but normal mitochondrial function in septic heart. Am J Respir Crit Care Med 163:362–367

    CAS  PubMed  Google Scholar 

  12. Tavernier B, Li JM, El-Omar MM, Lanone S, Yang ZK, Trayer IP, Mebazaa A, Shah AM (2001) Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 15:294–296

    CAS  PubMed  Google Scholar 

  13. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207–214

    CAS  PubMed  Google Scholar 

  14. Silverman HJ, Penaranda R, Orens JB, Lee NH (1993) Impaired beta-adrenergic receptor stimulation of cyclic adenosine monophosphate in human septic shock: association with myocardial hyporesponsiveness to catecholamines. Crit Care Med 21:31–39

    CAS  PubMed  Google Scholar 

  15. Hotchkiss RS, Karl IE (1996) Calcium: a regulator of the inflammatory response in endotoxemia and sepsis. New Horiz 4:58–71

    CAS  PubMed  Google Scholar 

  16. Ming MJ, Hu DY, Chen HS, Liu LM, Nan X, Lu RQ (2000) Effects of MCI-154, a calcium sensitizer, on cardiac dysfunction in endotoxic shock in rabbits. Shock 13:459–463

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Sandell EP, Hayha M, Antila S, Heikkinen P, Ottoila P, Lehtonen LA, Pentikainen PJ (1995) Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure. J Cardiovasc Pharmacol 26:S57–S62

    CAS  PubMed  Google Scholar 

  19. Parker JL, Adams HR (1985) Development of myocardial dysfunction in endotoxin shock. Am J Physiol 248:H818–H826

    CAS  PubMed  Google Scholar 

  20. Parker JL, Adams HR (1979) Myocardial effects of endotoxin shock: characterization of an isolated heart muscle model. Adv Shock Res 2:163–175

    CAS  PubMed  Google Scholar 

  21. Thompson M, Kliewer A, Maass D, Becker L, White DJ, Bryant D, Arteaga G, Horton J, Giroir BP (2000) Increased cardiomyocyte intracellular calcium during endotoxin-induced cardiac dysfunction in guinea pigs. Pediatr Res 47:669–676

    CAS  PubMed  Google Scholar 

  22. Follath F, Cleland JG, Just H, Papp JG, Scholz H, Peuhkurinen K, Harjola VP, Mitrovic V, Abdalla M, Sandell EP, Lehtonen L (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 360:196–202

    CAS  PubMed  Google Scholar 

  23. Ming MJ, Hu D, Chen HS, Liu LM, Nan X, Hua CH, Lu RQ (2000) Effect of MCI-154, a calcium sensitizer, on calcium sensitivity of myocardial fibers in endotoxic shock rats. Shock 14:652–656

    CAS  PubMed  Google Scholar 

  24. Sellin LC, Alajoutsijarvi A, Tornquist K, Fraser M, Pippuri A, Ojala I (1988) Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl) aminophenyl]-4:5-dihydro-3 (2H)-pyridazinone hydrochloride. Arzneimittelforschung 38:1787–1789

    CAS  PubMed  Google Scholar 

  25. Haikala H, Levijoki J, Linden IB (1995) Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. J Mol Cell Cardiol 27:2155–2165

    CAS  PubMed  Google Scholar 

  26. Barton P, Garcia J, Kouatli A, Kitchen L, Zorka A, Lindsay C, Lawless S, Giroir B (1996) Hemodynamic effects of i.v. milrinone lactate in pediatric patients with septic shock. A prospective, double-blinded, randomized, placebo-controlled, interventional study. Chest 109:1302–1312

    CAS  PubMed  Google Scholar 

  27. Heinz G, Geppert A, Delle Karth G, Reinelt P, Gschwandtner ME, Neunteufl T, Zauner C, Frossard M, Siostrzonek P (1999) IV milrinone for cardiac output increase and maintenance: comparison in nonhyperdynamic SIRS/sepsis and congestive heart failure. Intensive Care Med 25:620–624

    Article  CAS  PubMed  Google Scholar 

  28. Kumar A, Kosuri R, Kandula P, Dimou C, Allen J, Parrillo JE (1999) Effects of epinephrine and amrinone on contractility and cyclic adenosine monophosphate generation of tumor necrosis factor alpha-exposed cardiac myocytes. Crit Care Med 27:286–292

    CAS  PubMed  Google Scholar 

  29. Edes I, Kiss E, Kitada Y, Powers FM, Papp JG, Kranias EG, Solaro RJ (1995) 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 77:107–113

    CAS  PubMed  Google Scholar 

  30. Hasenfuss G, Pieske B, Kretschmann B, Holubarsch C, Alpert NR, Just H (1995) Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. J Cardiovasc Pharmacol 26:S45–S51

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE (1986) The coronary circulation in human septic shock. Circulation 73:637–644

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Matthias Behrends & Jürgen Peters

Authors
  1. Matthias Behrends
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jürgen Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Behrends.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Behrends, M., Peters, J. The calcium sensitizer levosimendan attenuates endotoxin-evoked myocardial dysfunction in isolated guinea pig hearts. Intensive Care Med 29, 1802–1807 (2003). https://doi.org/10.1007/s00134-003-1879-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-003-1879-8

Keywords

Search

Navigation