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Acta Physiologica 2012; Volume 204, Supplement 689
91st Annual Meeting of The German Physiological Society
3/22/2012-3/25/2012
Dresden, Germany
CARDIOPROTECTION BY CYCLOSPORINE A IS MEDIATED BY THE INHIBITION OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE AND NOT BY AN IMPROVEMENT OF MITOCHONDRIAL RESPIRATION
Abstract number: P027
Gedik1 *N., Skyschally1 A., Walter1 B., Heusch1 G.
1University of Essen, Medical School, Institute of Pathophysiology, Essen, Germany
The preservation of mitochondrial function during myocardial ischemia/reperfusion is decisive for survival of cardiomyocytes and thus salvage of myocardium. Ischemic postconditioning (PoCo), short repetitive re-occlusions at the onset of reperfusion, reduces infarct size. Better preservation of mitochondrial complex I respiration and inhibition of mitochondrial permeability transition pore (mPTP), as measured by calcium retention capacity (CRC), are responsible for such protection. Cyclosporine A (CsA) binds to cyclophilin D and inhibits mPTP opening. CsA infusion prior to reperfusion reduces infarct size. Apart from inhibiting mPTP opening, CsA inhibits the phosphatase calcineurin and thus possibly preserves the phosphorylation/activation of cardioprotective proteins which ultimately improve mitochondrial respiration.
Therefore, we compared the impact of CsA and PoCo on both, mitochondrial respiration and CRC in a clinically relevant pig model.
Anesthetized pigs underwent 90 min ischemia followed by 10 min reperfusion initiated as immediate full reperfusion (IFR; n=8), with CsA (5 mg/kg i.v.; 5 min before reperfusion; n=4), or with PoCo (6 cycles of 20 s reperfusion/re-occlusion; n=8). Mitrochondria were isolated from the area at risk. Mitochondrial respiration and CRC were measured at 37 °C in the presence of complex I substrates and ADP.
ADP-stimulated complex I respiration (nmol O2/min/mg protein) was similar between IFR (122±6) and CsA (116±11), but better preserved with PoCo (164±12; p<0.05 vs. IFR and CsA). CRC (nmol Ca2+/mg protein) was greater with both, CsA (1287±128; p<0.05 vs. IFR) and PoCo (1096±45; p<0.05 vs. IFR) than with IFR (756±103).
Conclusion: Protection against infarction after ischemia/reperfusion by CsA can not be attributed to better preservation of mitochondrial respiration, but is indeed secondary to mPTP inhibition.
To cite this abstract, please use the following information:
Acta Physiologica 2012; Volume 204, Supplement 689 :P027