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Preconditioning by Levosimendan is Mediated by Activation of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels

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Abstract

Purpose

Activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa)-channels is a crucial step for cardioprotection by preconditioning. Whether activation of these channels is involved in levosimendan-induced preconditioning is unknown. We investigated if cardioprotection by levosimendan requires activation of mBKCa-channels in the rat heart in vitro.

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. Before ischemia, hearts were perfused with different concentrations of levosimendan (0.03–1 μM) for determination of a dose-effect curve. In a second set of experiments, 0.3 μM levosimendan was administered in combination with the mBKCa-channel inhibitor paxilline (1 μM). Infarct size was determined by TTC staining.

Results

In control, animal’s infarct size was 58 ± 7%. Levosimendan at a concentration of 0.3 μM reduced infarct size to 30 ± 7% (P < 0.05 vs. control). Higher concentrations with 1 μM levosimendan did not confer stronger protection. Paxilline completely blocked levosimendan-induced cardioprotection while paxilline alone had no effect on infarct size.

Conclusions

This study shows that activation of mBKCa-channels plays a pivotal role in levosimendan-induced preconditioning.

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Funding

This study was supported by institutional and departmental sources.

Author information

Authors and Affiliations

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

    Sebastian Bunte, Friederike Behmenburg, Anton Bongartz, Martin Stroethoff, Annika Raupach, Ragnar Huhn & Stephan U. Sixt

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

    André Heinen

  3. Department of Cardiovascular Surgery, University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany

    Jan-Philipp Minol

  4. Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, AZ, Netherlands

    Markus W. Hollmann

Authors
  1. Sebastian Bunte
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  2. Friederike Behmenburg
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  4. Martin Stroethoff
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Corresponding author

Correspondence to Ragnar Huhn.

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The authors declare that they have no conflict of interest.

Ethical Approval

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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Bunte, S., Behmenburg, F., Bongartz, A. et al. Preconditioning by Levosimendan is Mediated by Activation of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels. Cardiovasc Drugs Ther 32, 427–434 (2018). https://doi.org/10.1007/s10557-018-6819-5

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  • DOI: https://doi.org/10.1007/s10557-018-6819-5

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