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Impact of Ca2+-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning

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Abstract

Purpose

Small and big conductance Ca2+-sensitive potassium (KCa) channels are involved in cardioprotective measures aiming at reducing myocardial reperfusion injury. For levosimendan, infarct size–reducing effects were shown. Whether activation of these channels is involved in levosimendan-induced postconditioning is unknown. We hypothesized that levosimendan exerts a concentration-dependent cardioprotective effect and that both types of Ca2+-sensitive potassium channels are involved.

Methods

In a prospective blinded experimental laboratory investigation, hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. At the onset of reperfusion, hearts were perfused with various concentrations of levosimendan (0.03–1 μM) in order to determine a concentration-response relationship. To elucidate the involvement of KCa-channels for the observed cardioprotection, in the second set of experiments, 0.3 μM levosimendan was administered in combination with the subtype-specific KCa-channel inhibitors paxilline (1 μM, big KCa-channel) and NS8593 (0.1 μM, small KCa-channel) respectively. Infarct size was determined by tetrazolium chloride (TTC) staining.

Results

Infarct size in controls was 60 ± 7% and 59 ± 6% respectively. Levosimendan at a concentration of 0.3 μM reduced infarct size to 30 ± 5% (P < 0.0001 vs. control). Higher concentrations of levosimendan did not induce a stronger effect. Paxilline but not NS8593 completely abolished levosimendan-induced cardioprotection while both substances alone had no effect on infarct size.

Conclusions

Cardioprotection by levosimendan-induced postconditioning shows a binary phenomenon, either ineffective or with maximal effect. The cardioprotective effect requires activation of big but not small KCa channels.

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References

  1. Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003;285(2):H579–88.

    Article  CAS  Google Scholar 

  2. Steurer MP, Steurer MA, Baulig W, Piegeler T, Schlapfer M, Spahn DR, et al. Late pharmacologic conditioning with volatile anesthetics after cardiac surgery. Crit Care. 2012;16(5):R191.

    Article  Google Scholar 

  3. Huhn R, Heinen A, Weber NC, Schlack W, Preckel B, Hollmann MW. Ischaemic and morphine-induced post-conditioning: impact of mK (Ca) channels. Br J Anaesth. 2010;105(5):589–95.

    Article  CAS  Google Scholar 

  4. Honisch A, Theuring N, Ebner B, Wagner C, Strasser RH, Weinbrenner C. Postconditioning with levosimendan reduces the infarct size involving the PI3K pathway and KATP-channel activation but is independent of PDE-III inhibition. Basic Res Cardiol. 2010;105(2):155–67.

    Article  Google Scholar 

  5. du Toit EF, Genis A, Opie LH, Pollesello P, Lochner A. A role for the RISK pathway and K (ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea pig heart. Br J Pharmacol. 2008;154(1):41–50.

    Article  Google Scholar 

  6. Matsumoto S, Cho S, Tosaka S, Higashijima U, Maekawa T, Hara T, et al. Hyperglycemia raises the threshold of levosimendan- but not milrinone-induced postconditioning in rat hearts. Cardiovasc Diabetol. 2012;11:4.

    Article  CAS  Google Scholar 

  7. Papp Z, Edes I, Fruhwald S, De Hert SG, Salmenpera M, Leppikangas H, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159(2):82–7.

    Article  Google Scholar 

  8. Kinoshita M, Tsutsumi YM, Fukuta K, Kasai A, Tanaka K. Isoflurane-induced postconditioning via mitochondrial calcium-activated potassium channels. J Med Investig. 2016;63(1–2):80–4.

    Article  Google Scholar 

  9. Stefani E, Ottolia M, Noceti F, Olcese R, Wallner M, Latorre R, et al. Voltage-controlled gating in a large conductance Ca2+−sensitive K+channel (hslo). Proc Natl Acad Sci U S A. 1997;94(10):5427–31.

    Article  CAS  Google Scholar 

  10. Jenkins DP, Strobaek D, Hougaard C, Jensen ML, Hummel R, Sorensen US, et al. Negative gating modulation by (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) depends on residues in the inner pore vestibule: pharmacological evidence of deep-pore gating of K (Ca)2 channels. Mol Pharmacol. 2011;79(6):899–909.

    Article  CAS  Google Scholar 

  11. Stowe DF, Yang M, Heisner JS, Camara AKS. Endogenous and agonist-induced opening of mitochondrial big versus small Ca2+−sensitive K+ channels on cardiac cell and mitochondrial protection. J Cardiovasc Pharmacol. 2017;70(5):314–28.

    Article  CAS  Google Scholar 

  12. Behmenburg F, Dorsch M, Huhn R, Mally D, Heinen A, Hollmann MW, et al. Impact of mitochondrial Ca2+-sensitive potassium (mBKCa) channels in sildenafil-induced cardioprotection in rats. PLoS One. 2015;10(12):e0144737.

    Article  Google Scholar 

  13. Behmenburg F, Trefz L, Dorsch M, Strothoff M, Mathes A, Raupach A, et al. Milrinone-induced postconditioning requires activation of mitochondrial Ca(2+)-sensitive potassium (mBKCa) channels. J Cardiothorac Vasc Anesth. 2018;32(5):2142–8.

    Article  CAS  Google Scholar 

  14. Pasdois P, Quinlan CL, Rissa A, Tariosse L, Vinassa B, Costa AD, et al. Ouabain protects rat hearts against ischemia-reperfusion injury via pathway involving src kinase, mitoKATP, and ROS. Am J Physiol Heart Circ Physiol. 2007;292(3):H1470–8.

    Article  CAS  Google Scholar 

  15. Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012;17(3):125–30.

    PubMed  PubMed Central  Google Scholar 

  16. Shintani Y, Node K, Asanuma H, Sanada S, Takashima S, Asano Y, et al. Opening of Ca2+−activated K+ channels is involved in ischemic preconditioning in canine hearts. J Mol Cell Cardiol. 2004;37(6):1213–8.

    CAS  PubMed  Google Scholar 

  17. Bell RM, Mocanu MM, Yellon DM. Retrograde heart perfusion: the Langendorff technique of isolated heart perfusion. J Mol Cell Cardiol. 2011;50(6):940–50.

    Article  CAS  Google Scholar 

  18. Najafi M, Noroozi E, Javadi A, Badalzadeh R. Anti-arrhythmogenic and anti-inflammatory effects of troxerutin in ischemia/reperfusion injury of diabetic myocardium. Biomed Pharmacother. 2018;102:385–91.

    Article  CAS  Google Scholar 

  19. Leistner M, Sommer S, Kanofsky P, Leyh R, Sommer SP. Ischemia time impacts on respiratory chain functions and Ca(2+)-handling of cardiac subsarcolemmal mitochondria subjected to ischemia reperfusion injury. J Cardiothorac Surg. 2019;14(1):92.

    Article  Google Scholar 

  20. Kim JH, Kim J, Park YH, Chun KJ, Kim JS, Jang YH, et al. Cardiodynamics and infarct size in regional and global ischemic isolated heart model: comparison of 1 hour and 2 hours reperfusion. Korean Circ J. 2012;42(9):600–5.

    Article  Google Scholar 

  21. Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, et al. Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol. 2018;314(4):H812–H38.

    Article  CAS  Google Scholar 

  22. Hu H, Shao LR, Chavoshy S, Gu N, Trieb M, Behrens R, et al. Presynaptic Ca2+−activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J Neurosci. 2001;21(24):9585–97.

    Article  CAS  Google Scholar 

  23. Sanchez M, McManus OB. Paxilline inhibition of the alpha-subunit of the high-conductance calcium-activated potassium channel. Neuropharmacology. 1996;35(7):963–8.

    Article  CAS  Google Scholar 

  24. Wang X, Fisher PW, Xi L, Kukreja RC. Essential role of mitochondrial Ca2+−activated and ATP-sensitive K+ channels in sildenafil-induced late cardioprotection. J Mol Cell Cardiol. 2008;44(1):105–13.

    Article  Google Scholar 

  25. Zhou Y, Lingle CJ. Paxilline inhibits BK channels by an almost exclusively closed-channel block mechanism. J Gen Physiol. 2014;144(5):415–40.

    Article  CAS  Google Scholar 

  26. Lange M, Redel A, Smul TM, Lotz C, Nefzger T, Stumpner J, et al. Desflurane-induced preconditioning has a threshold that is lowered by repetitive application and is mediated by beta 2-adrenergic receptors. J Cardiothorac Vasc Anesth. 2009;23(5):607–13.

    Article  CAS  Google Scholar 

  27. Thornton JD, Thornton CS, Sterling DL, Downey JM. Blockade of ATP-sensitive potassium channels increases infarct size but does not prevent preconditioning in rabbit hearts. Circ Res. 1993;72(1):44–9.

    Article  CAS  Google Scholar 

  28. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2001;281(4):H1630–6.

    Article  CAS  Google Scholar 

  29. Wojtovich AP, Nadtochiy SM, Brookes PS, Nehrke K. Ischemic preconditioning: the role of mitochondria and aging. Exp Gerontol. 2012;47(1):1–7.

    Article  CAS  Google Scholar 

  30. Huhn R, Weber NC, Preckel B, Schlack W, Bauer I, Hollmann MW, et al. Age-related loss of cardiac preconditioning: impact of protein kinase A. Exp Gerontol. 2012;47(1):116–21.

    Article  CAS  Google Scholar 

  31. Huhn R, Heinen A, Hollmann MW, Schlack W, Preckel B, Weber NC. Cyclosporine A administered during reperfusion fails to restore cardioprotection in prediabetic Zucker obese rats in vivo. Nutr Metab Cardiovasc Dis. 2010;20(10):706–12.

    Article  CAS  Google Scholar 

  32. Huhn R, Heinen A, Weber NC, Hollmann MW, Schlack W, Preckel B. Hyperglycaemia blocks sevoflurane-induced postconditioning in the rat heart in vivo: cardioprotection can be restored by blocking the mitochondrial permeability transition pore. Br J Anaesth. 2008;100(4):465–71.

    Article  CAS  Google Scholar 

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Acknowledgments

In partial fulfillment of the requirements for an MD thesis (M. van de Snepscheut). We thank J. Reinle and L. Goetze for their practical support.

Funding

This study was supported by institutional and departmental sources.

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Authors and Affiliations

  1. Department of Anesthesiology, University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany

    Martin Stroethoff, Sebastian Bunte, Annika Raupach, Margit van de Snepscheut, Carolin Torregroza, Ragnar Huhn & Stephan U. Sixt

  2. Institute of Cardiovascular Physiology, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225, Duesseldorf, Germany

    André Heinen

  3. Department of Anesthesiology and Intensive Care Medicine, University Hospital Cologne, Kerpener Str. 62, 50937, Cologne, Germany

    Alexander Mathes

  4. Department of Anesthesiology, Amsterdam University Medical Center (AUMC), Location AMC, Meiberdreef 9, 1100 DD, Amsterdam, Netherlands

    Markus W. Hollmann

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  1. Martin Stroethoff
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  2. Sebastian Bunte
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  3. Annika Raupach
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  4. Margit van de Snepscheut
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  8. Markus W. Hollmann
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Corresponding author

Correspondence to Ragnar Huhn.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Informed consent was obtained from all individual participants included in the study.

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Stroethoff, M., Bunte, S., Raupach, A. et al. Impact of Ca2+-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning. Cardiovasc Drugs Ther 33, 581–588 (2019). https://doi.org/10.1007/s10557-019-06908-7

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