Abstract
We previously demonstrated, in contrast to pure ischemic injury, that inhibition of BKCa channels improves cardiac contractile recovery following CP. We now investigate the mechanism via which BKCa blockade may be protective during CP. Isolated rat hearts and myocytes were subjected to either in vitro ischemia (30 mins) or hyperkalemic CP (2hrs) followed by reperfusion (30 min). Mitochondrial membrane potential (mMP), ROS generation (n=12), and BKCa‐mediated signaling (n=3) were measured in H9c2 cells with or without CP and the BKCa blocker paxilline (pax). CP and ischemia reduced cardiac contractile function in hearts (n>;6) and myocytes (n>;=15). BKCa blockade increased whole heart recovery and myocyte shortening in CP, but not in ischemic groups. Pax did not affect Ca++ transients in myocytes, or indicators of Ca++ signaling and survival in hearts and H9c2 cells (phospho‐PKA, p‐cTnI, PKA, pAkt, pPLB, p‐sHSP). In H9c2 cells, CP reduced mMP and increased ROS, which was partially blocked by pax. Pax increased phosphorylation of GSK3B in both hearts and cells, independent of changes in Akt phosphorylation. In contrast to protective effects of BKCa openers in the setting of ischemic injury, BKCa channel blockers may improve cardiac recovery in the context of hyperkalemic CP. Cardioprotective mechanisms associated with BKCa blockade include normalized ROS and mMP, and increased GSK3B phosphorylation.
Published Version
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