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Am J Physiol Heart Circ Physiol (July 8, 2004). doi:10.1152/ajpheart.00338.2004
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Submitted on April 8, 2004
Accepted on July 6, 2004

Opening of Mitochondrial KATP Channels Enhances Cardioprotection Through the Modulation of Mitochondrial Matrix Volume, Calcium Accumulation and Respiration

Anthony J. Rousou1, Maria Ericsson2, Micheline Federman3, Sidney Levitsky1, and James D. McCully1*

1 Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
2 Electron Microscopy Core Facility, Harvard Medical School, Boston, MA, USA
3 Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: james_mccully{at}hms.harvard.edu.

Previously, we have shown that the pharmacological opening of the mitochondrial ATPsensitive potassium channels with diazoxide (DZX) enhances the cardioprotection afforded by magnesium-supplemented potassium (K/Mg) cardioplegia. To determine the mechanisms involved in the cardioprotection afforded by K/Mg+DZX cardioplegia, rabbit hearts (n=24) were subjected to isolated Langendorff perfusion. Control hearts were perfused for 75 min. Global Ischemia (GI) hearts were subjected to 30 min. equilibrium, 30 min. global ischemia and 15 min. reperfusion. K/Mg and K/Mg+DZX cardioplegia hearts received either K/Mg or K/Mg+DZX for 5 minutes prior to global ischemia and reperfusion. Tissue was harvested for mitochondrial isolation and transmission electron microscopy (TEM). Mitochondrial structure, area, matrix volume, calcium and oxygen consumption were determined. TEM demonstrated that GI mitochondria were damaged and that K/Mg and K/Mg+DZX preserved mitochondrial structure. TEM and light scattering demonstrated separately that mitochondrial matrix and cristae area and matrix volume were significantly increased following global ischemia and reperfusion with GI > K/Mg+DZX > K/Mg hearts (p<0.05 vs. Control). Mitochondrial free calcium was significantly increased in GI and K/Mg hearts. K/Mg+DZX significantly decreased mitochondrial calcium accumulation (p<0.05 vs. GI and K/Mg). State 3 oxygen consumption and respiratory control index (RCI) in malate (complex I substrate) and succinate (complex II substrate) energized mitochondria were significantly decreased (p<0.05 vs. Control) in GI and K/Mg+DZX groups. These data indicate that the enhanced cardioprotection afforded by K/Mg+DZX cardioplegia occurs through the preservation of mitochondrial structure and the significant decrease in mitochondrial free calcium accumulation and mitochondrial state 3 oxygen consumption.




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