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Cardiac mitochondrial preconditioning by Big Ca²⁺-sensitive K⁺ channel opening requires superoxide radical generation

Departments of ¹Anesthesiology and ²Physiology, Anesthesiology Research Laboratories, ³Cardiovascular Research Center, The Medical College of Wisconsin, Milwaukee; ⁴Veterans Affairs Medical Center Research Service, Milwaukee; and ⁵Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin

Submitted 19 July 2005 ; accepted in final form 19 August 2005

ATP-sensitive K⁺ channel opening in inner mitochondrial membranes protects hearts from ischemia-reperfusion (I/R) injury. Opening of the Big conductance Ca²⁺-sensitive K⁺ channel (BK_Ca) is now also known to elicit cardiac preconditioning. We investigated the role of the pharmacological opening of the BK_Ca channel on inducing mitochondrial preconditioning during I/R and the role of O₂-derived free radicals in modulating protection by putative mitochondrial (m)BK_Ca channel opening. Left ventricular (LV) pressure (LVP) was measured with a balloon and transducer in guinea pig hearts isolated and perfused at constant pressure. NADH, reactive oxygen species (ROS), principally superoxide (O₂^–·), and m[Ca²⁺] were measured spectrophotofluorometrically at the LV free wall using autofluorescence and fluorescent dyes dihydroethidium and indo 1, respectively. BK_Ca channel opener 1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3H)benzimid-axolone (NS; NS-1619) was given for 15 min, ending 25 min before 30 min of global I/R. Either Mn(III)tetrakis(4-benzoic acid)porphyrin (TB; MnTBAP), a synthetic dismutator of O₂^–·, or an antagonist of the BK_Ca channel paxilline (PX) was given alone or for 5 min before, during, and 5 min after NS. NS pretreatment resulted in a 2.5-fold increase in developed LVP and a 2.5-fold decrease in infarct size. This was accompanied by less O₂^–· generation, decreased m[Ca²⁺], and more normalized NADH during early ischemia and throughout reperfusion. Both TB and PX antagonized each preconditioning effect. This indicates that 1) NS induces a mitochondrial-preconditioned state, evident during early ischemia, presumably on mBK_Ca channels; 2) NS effects are blocked by BK_Ca antagonist PX; and 3) NS-induced preconditioning is dependent on the production of ROS. Thus NS may induce mitochondrial ROS release to initiate preconditioning.

cell signaling; ischemic biology; oxidant stress; energy metabolism; heart; mitochondria; reactive oxygen species; redox balance

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