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Effects of levosimendan on myocardial ischaemia–reperfusion injury

Published online by Cambridge University Press:  01 January 2008

D. Yapici ,
Z. Altunkan ,
M. Ozeren ,
E. Bilgin ,
E. Balli ,
L. Tamer ,
N. Doruk ,
H. Birbicer ,
D. Apa  and
U. Oral
D. Yapici*
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
Z. Altunkan
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
M. Ozeren
Affiliation:
University of Mersin, Department of Cardiovascular Surgery, Mersin, Turkey
E. Bilgin
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
E. Balli
Affiliation:
University of Mersin, Department of Histology, Mersin, Turkey
L. Tamer
Affiliation:
University of Mersin, Department of Biochemistry, Mersin, Turkey
N. Doruk
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
H. Birbicer
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
D. Apa
Affiliation:
University of Mersin, Department of Pathology, Mersin, Turkey
U. Oral
Affiliation:
University of Mersin, Department of Anaesthesiology and Intensive Care, Mersin, Turkey
*
Correspondence to: Davud Yapici, Department of Anaesthesiology and Intensive Care, Mersin University Medical Faculty, Zeytinlibahce C., 33079 Mersin, Turkey. E-mail: [email protected]; Tel: +90 324 3374300; Fax: +90 324 3374305
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Summary

Background and objective

Levosimendan has a cardioprotective action by inducing coronary vasodilatation and preconditioning by opening KATP channels. The aim of this study was to determine whether levosimendan enhances myocardial damage during hypothermic ischaemia and reperfusion in isolated rat hearts.

Methods

Twenty-one male Wistar rats were divided into three groups. After surgical preparation, coronary circulation was started by retrograde aortic perfusion using Krebs–Henseleit buffer solution and lasted 15 min. After perfusion Group 1 (control; n = 7) received no further treatment. In Group 2 (non-treated; n = 7), hearts were arrested with cold cardioplegic solution after perfusion and subjected to 60 min of hypothermic global ischaemia followed by 30 min reperfusion. In Group 3 (levosimendan treated; n = 7), levosimendan was added to the buffer solution during perfusion and the hearts were arrested with cold cardioplegic solution and subjected to 60 min of hypothermic global ischaemia followed by 30 min reperfusion. At the end of the reperfusion period, the hearts were prepared for biochemical assays and for histological analysis.

Results

Tissue malondialdehyde levels were significantly lower in the levosimendan-treated group than in the non-treated group (P = 0.019). The tissue Na+–K+ ATPase activity was significantly decreased in the non-treated group than in the levosimendan-treated group (P = 0.027). Tissue myeloperoxidase (MPO) enzyme activity was significantly higher in the non-treated group than in the levosimendan-treated group (P = 0.004). Electron microscopic examination of the hearts showed cardiomyocytic degeneration at the myofibril, mitochondria and sarcoplasmic reticulum in both non-treated and levosimendan-treated groups. The severity of these findings was more extensive in the non-treated group.

Conclusions

Treatment with levosimendan provided better cardioprotection with cold cardioplegic arrest followed by global hypothermic ischaemia in isolated rat hearts.

Keywords

HEARTDRUG, levosimendanISCHEMIC PRECONDITIONING, hypothermic, cardioplegicRAT
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 25 , Issue 1 , January 2008 , pp. 8 - 14
Copyright
Copyright © European Society of Anaesthesiology 2007

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References

1.Riess, ML, Camara, AKS, Kevin, LG et al. . Reduced reactive O2 species formation and preserved mitochondrial NADH and [Ca+2] levels during short-term 17°C ischemia in intact hearts. Cardiovasc Res 2004; 61: 580–590.Google Scholar
2.Stowe, DF, Fujita, S, An, J. Modulation of myocardial function and [Ca2] sensitivity by moderate hypothermia in guinea pig isolated hearts. Am J Physiol Heart Circ Physiol 1999; 277: H2321–H2332.Google Scholar
3.Bridge, JHB. Relationship between the sarcoplasmic reticulum and sarcolemmal calcium transport related by rapidly cooling rabbit ventricular muscle. J Gen Physiol 1986; 88: 437–473.Google Scholar
4.Remme, WJ, Swedberg, K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527–1560.Google Scholar
5.Haikala, H, Kaivola, J, Wall, P, Lavijoki, J, Linden, IB. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol 1995; 27: 1859–1866.Google Scholar
6.Yokoshiki, H, Katsube, Y, Sunagawa, M, Sperelakis, N. Levosimendan, a novel Ca+2 sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol 1997; 333: 249–259.Google Scholar
7.Pataricza, J, Krassoi, I, Hohn, J et al. . Functional role of potassium channels in the vasodilating mechanism of levosimendan in porcine isolated coronary artery. Cardiovasc Drugs Ther 2003; 17: 115–121.Google Scholar
8.Kopustinskiene, DM, Pollesello, P, Saris, NE. Levosimendan is a mitochondrial KATP channel opener. Eur J Pharmacol 2001; 428: 311–314.CrossRefGoogle Scholar
9.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.Google Scholar
10.Gross, GJ, Auchampach, JA. Blockade of ATP-sensitive potassium channels prevents myocardial preconditioning in dogs. Circ Res 1992; 70: 223–233.CrossRefGoogle ScholarPubMed
11.Kersten, JR, Montgomery, MW, Pagel, PS, Warltier, DC. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of KATP channels. Anesth Analg 2000; 90: 5–11.Google Scholar
12.Tritapepe, L, De Santis, V, Vitale, D et al. . Preconditioning effects of levosimendan in coronary artery bypass grafting-a pilot study. Br J Anaesth 2006; 96: 694–700.CrossRefGoogle ScholarPubMed
13.Loncher, A, Cloesky, F, Genade, S. Effect of a calcium-sensitizing agent, levosimendan, on the postcardioplegic inotropic response of myocardium. Cardiovasc Drugs Ther 2000 ; 14 (3): 271–281.Google Scholar
14.Juggi, JSAl-Awadi, F, Joseph, S et al. . Ischemic preconditioning is not additive to preservation with hypothermia or crystalloid cardioplegia in the globally ischemic rat heart. Mol Cell Biochem 1997; 176: 303–313.Google Scholar
15.Zhu, S-S, Zhang, ZM, Zhang, Y-C et al. . Myocardioprotective effects of combination of ischemic preconditioning with hypothermia and crystalloid cardioplegia in immature rabbits. Acta Physiol Sinica 2004; 56 (3): 389–396.Google Scholar
16.Yagi, K. Lipid peroxides and related radicals. Clinical medicine. In: Armstrong, D, ed. Free Radicals in Diagnostic Medicine. New York: Plenum Press, 1994: 1–15.Google Scholar
17.Reading, HW, Isbir, T. Action of lithium on ATPase in transmitter release from rat iris. Biochem Pharmacol 1979; 28: 3471–3474.CrossRefGoogle Scholar
18.Reading, HW, Isbir, T. The role of cation-activated ATPases in transmitter release from rat iris. Quart J Exp Physiol 1988; 65: 105–116.CrossRefGoogle Scholar
19.Lowry, OH, Roscbrough, NJ, Farr, AI, Randont, RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1954; 14: 157–167.Google Scholar
20.Golowich, SP, Kaplan, SD. Methods in Enzymology vol II. New York: Academic Press Inc, 1995: 769.Google Scholar
21.Weisel, RD, Mickle, DA, Finkle, CD et al. . Delayed myocardial metabolic recovery after blood cardioplegia. Ann Thorac Surg 1989; 48: 503–507.Google Scholar
22.Ning, X, Xu, C, Song, Y et al. . Hypothermia preserves function signalling for mitochondrial biogenesis during subsequent ischemia. Am J Physiol Heart Circ Physiol 1998; 274: H786–H793.Google Scholar
23.Tveita, T, Skandfer, M, Refsum, H, Ytrehus, K. Experimental hypothermia and rewarming: changes in mechanical function and metabolism of rat hearts. J Appl Physiol 1996; 80: 291–297.Google Scholar
24.Navas, JP, Anderson, W, Marsh, JD. Hypothermia increases calcium content of hypoxic myocytes. Am J Physiol 1990; 259 (2 Pt 2): H333–H339.Google Scholar
25.Steigen, TK, Aasum, E, Myrmel, T, Larsen, TS. Effects of fatty acids on myocardial calcium control during hypothermic perfusion. J Thorac Cardiovasc Surg 1994; 107: 233–241.Google Scholar
26.Knerr, SSM, Lieberman, M. Ion transport during hypothermia in cultured heart cell-implications for protection of the immature myocardium. J Mol Cell Cardiol 1993; 25: 277–288.Google Scholar
27.Kurihara, S, Sakai, T. Effect of rapid cooling on the mechanical and electrical responses in ventricular muscle of the guinea pig. J Physiol 1985; 361: 361–378.Google Scholar
28.Levijoki, J, Pollesello, P, Kaivola, J et al. . Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analyses with analogs of levosimendan. J Mol Cell Cardiol 2000; 32: 479–491.Google Scholar
29.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 myofibrils and sarcoplasmic reticulum in guinea pig heart. Circ Res 1995; 77: 107–113.Google Scholar
30.Gross, GJ, Fryer, RM. Sarcolemmal vs. mitochondrial ATP-sensitive K channels and myocardial preconditioning. Cric Res 2000; 84: 973–979.Google Scholar
31.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.CrossRefGoogle ScholarPubMed
32.Kopustinskiene, DM, Pollesello, P, Saris, NE. Potassium-specific effects of levosimendan on heart mitochondria. Biochem Pharmachol 2004; 68: 807–812.Google Scholar
33.Oldroyd, KG, Chopra, M, Rankin, AC, Bekh, JJ, Cobbe, SM. Lipid peroxidation during myocardial ischemia induced by pacing. Br Heart J 1990; 63: 88–92.Google Scholar
34.Werns, SW, Shea, MJ, Mitsos, SE et al. . Reduction of size of infarction by allopurinol in the ischemic-reperfused canine heart. Circulation 1986; 73: 518–524.Google Scholar
35.Tuna, M, Polat, S, Erman, T et al. . Effect of anti-rat interleukin-6 antibody after spinal cord injury in the rat: inducible nitric oxide synthase expression, sodium- and potassium-activated, magnesium-dependent adenosine-5′-triphosphatase and superoxide dismutase activation, and ultrastructural changes. J Neurosurg 2001; 95: 64–73.Google Scholar
36.Kim, M, Akera, T. Oxygen free radicals: cause of ischemia–reperfusion injury to cardiac Na–K ATPase. Am J Physiol 1987; 252 (2 Pt 2): H252–H257.Google Scholar
37.Mullane, KM, Kraemer, R, Smith, B et al. . Myeloperoxidase activity as a quantitative assessment of neutrophile infiltration into ischemic myocardium. J Pharmacol Methods 1985; 14: 157–167.CrossRefGoogle ScholarPubMed
38.Rydzynski, K, Dalen, H, Saetersdal, T, Engedal, H. Morphologic and morphometric analysis of the mast cells from human heart biopsies. Agents Actions 1987; 20 (3–4): 288–290.Google Scholar
39.Keller, AM, Clancy, RM, Barr, ML, Marboe, CC, Cannon, PJ. Acute reoxygenation injury in the isolated rat heart: role of resident cardiac mast cells. Circ Res 1988; 63 (6): 1044–1052.CrossRefGoogle ScholarPubMed