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1 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA; Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: dfstowe{at}mcw.edu.
ATP -sensitive K+ (KATP) channel opening in inner mitochondrial membranes (IMM) protects hearts from ischemia reperfusion (IR) injury. Opening of the big conductance Ca2+ -sensitive K+ channel, BKCa, is now also known to elicit cardiac preconditioning. We investigated the role of pharmacologic opening of the BKCa channel on inducing mitochondrial preconditioning during ischemia and reperfusion and the role of O2 derived free radicals in modulating protection by putative mBKCa channel opening. Left ventricular pressure (LVP) was measured with a balloon and transducer in guinea pig hearts isolated and perfused at constant pressure. NADH, reactive O2 species (ROS), principally superoxide (O2.-), and mitochondrial m[Ca2+] were measured spectrophotofluorometrically at the LV free wall using autofluorescence and fluorescent dyes dihydroethidium and indo 1, respectively. BKCa channel opener NS1619 (NS) was given for 15 min ending 25 min before 30 min of global IR. Either MnTBAP (TB), a synthetic dismutator of O2.-, or an antagonist of the BKCa 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 1) NS induces a mitochondrial -preconditioned state evident during early ischemia, presumably on BKCa channels, 2) NS effects are blocked by BKCa antagonist PX, and 3) NS -induced preconditioning is dependent on production of ROS. Thus, NS may induce mitochondrial ROS release to initiate preconditioning
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