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Activation of big conductance Ca2+-activated K+ channels (BK) protects the heart against ischemia–reperfusion injury

  • Bo Hjorth Bentzen
  • Oleg Osadchii
  • Thomas Jespersen
  • Rie Schultz Hansen
  • Søren-Peter Olesen
  • Morten GrunnetEmail author
Cardiovascular Physiology

Abstract

Activation of the large-conductance Ca2+-activated K+ channel (BK) in the cardiac inner mitochondrial membrane has been suggested to protect the heart against ischemic injury. However, these findings are limited by the low selectivity profile and potency of the BK channel activator (NS1619) used. In the present study, we address the cardioprotective role of BK channels using a novel, potent, selective, and chemically unrelated BK channel activator, NS11021. Using electrophysiological recordings of heterologously expressed channels, NS11021 was found to activate BK α + β1 channel complexes, while producing no effect on cardiac KATP channels. The cardioprotective effects of NS11021-induced BK channel activation were studied in isolated, perfused rat hearts subjected to 35 min of global ischemia followed by 120 min of reperfusion. 3 μM NS11021 applied prior to ischemia or at the onset of reperfusion significantly reduced the infarct size [control: 44.6 ± 2.0%; NS11021: 11.4 ± 2.0%; NS11021 at reperfusion: 19.8 ± 3.3% (p < 0.001 for both treatments compared to control)] and promoted recovery of myocardial performance. Co-administration of the BK-channel inhibitor paxilline (3 μM) antagonized the protective effect. These findings suggest that tissue damage induced by ischemia and reperfusion can be reduced by activation of cardiac BK channels.

Keywords

Potassium channels BK channels Ischemia–reperfusion injury Cardioprotection Mitochondria 

Notes

Acknowledgments

The work was supported by The Danish National Research Foundation Centre for Cardiac Arrhythmia, and The Danish Medical Research Council.

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Bo Hjorth Bentzen
    • 1
  • Oleg Osadchii
    • 1
  • Thomas Jespersen
    • 1
  • Rie Schultz Hansen
    • 2
  • Søren-Peter Olesen
    • 1
    • 2
  • Morten Grunnet
    • 1
    • 2
    • 3
    Email author
  1. 1.Danish National Research Foundation Centre for Cardiac ArrhythmiaUniversity of CopenhagenCopenhagenDenmark
  2. 2.NeuroSearch A/SBallerupDenmark
  3. 3.Department of Biomedical Sciences, The Panum Institute 12.5., Faculty of Health SciencesUniversity of CopenhagenCopenhagen NDenmark

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