Cardiovascular Drugs and Therapy

, Volume 28, Issue 1, pp 7–17 | Cite as

Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation

  • Chung Ho Leung
  • Lixing Wang
  • Jan M. Nielsen
  • Michael B. Tropak
  • Yana Y. Fu
  • Hideyuki Kato
  • John Callahan
  • Andrew N. Redington
  • Christopher A. Caldarone



Coronary effluent from an isolated perfused heart undergoing ischemic preconditioning can be transferred to precondition another naïve isolated heart. We investigated the effects of this effluent on mitochondrial integrity and function following a global infarct model of ischemia/reperfusion and the role of adenosine in this model of remote preconditioning.

Methods and Results

Coronary effluent from isolated perfused rabbit hearts was collected prior to (control effluent) and during three cycles of 5-min ischemia and 10-min reperfusion (IPC effluent). Adenosine concentration was significantly increased in IPC effluent (2.6 ± 1.1 μM) versus control effluent (0.21 ± 0.06 μM, P < 0.01). Infarct size (% necrotic LV mass) after 30-min global ischemia and 90-min reperfusion was significantly reduced in hearts preconditioned with IPC effluent (IPCeff, 23 ± 7 %) and control effluent supplemented with 2.5 μM exogenous adenosine (Ceff + 2.5 μM ADO, 25 ± 10 %) when compared to control effluent perfused hearts (Ceff, 41 ± 8 %, P < 0.05). Compared to Ceff mitochondria, IPCeff mitochondria had preserved complex I/State3 and complex IV/State 3 respiration and outer membrane integrity, and reduced cytochrome c release. In contrast, Ceff + 2.5 μM ADO mitochondria had improved state 2 respiration and coupling to oxidative phosphorylation, reduced reactive oxygen species production and preserved outer membrane integrity. Administration of adenosine receptor blocker 8-(p-sulfophenyl)theophylline abolished the infarct limiting effect (46 ± 7 %) and the mitochondrial integrity and function preservation of IPC effluent.


Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.


Ischemia-reperfusion injury Adenosine Mitochondria Cardioprotection Ischemic preconditioning Remote ischemic preconditioning 



This study was supported by The Leducq Foundation (grant number 06/CVD) and the Heart and Stroke Foundation of Ontario.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10557_2013_6489_Fig6_ESM.jpg (12 kb)
Supplementary Figure 1

Ions detected in the effluent by reverse phase liquid chromatography mass spectrometry. Intensity of select ions in IPC effluent (n = 2) relative to Control effluent (n = 2) is shown on the y-axis. Mass to charge (m/z) ratio for detected ions are shown on the x-axis. This ratio is a reflection of the molecular weight of the individual ions detected by the mass spectrometer (LTQ Orbitrap). (JPEG 12 kb)

10557_2013_6489_MOESM1_ESM.tif (918 kb)
High resolution (TIFF 917 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chung Ho Leung
    • 1
  • Lixing Wang
    • 1
  • Jan M. Nielsen
    • 2
  • Michael B. Tropak
    • 3
  • Yana Y. Fu
    • 1
  • Hideyuki Kato
    • 1
  • John Callahan
    • 3
  • Andrew N. Redington
    • 4
  • Christopher A. Caldarone
    • 1
  1. 1.Division of Cardiovascular SurgeryHospital for Sick Children/University of TorontoTorontoCanada
  2. 2.Department of CardiologyAarhus University HospitalAarhusDenmark
  3. 3.Division of Genetics and Genome BiologyHospital for Sick ChildrenTorontoCanada
  4. 4.Division of CardiologyHospital for Sick ChildrenTorontoCanada

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