Abstract 16926: Inhibition of Large Conductance K+ Channels (BKCa) Improves Cardiac Functional Recovery Following Cold Hyperkalemic Cardioplegic (CP) Arrest in Isolated Hearts
Introduction: Cardioplegia during heart surgery subjects myocardium to reversible ischemic injury that impairs cardiac function (a.k.a - “myocardial stunning”). BKCa blockers have established the protective role of BKCa activators for ischemic injury and preconditioning. However, the effect of BKCa blockers alone in the setting of ischemic injury associated with hyperkalemic CP is unknown. Surprisingly, we found that inhibition of BKCa channels, with two distinct BKCa blockers, greatly increased functional recovery following CP.
Methods: Isolated perfused rat hearts were subjected to 2 hours intermittent cold cardioplegia (St Thomas II) followed by 30 minutes normothermic reperfusion. CP was delivered every 30 min, for 1 min. During CP, hearts were maintained at 10 deg C. Hearts were treated with or without (CP, n=10) the BKCa channel inhibitors paxilline (CP + Pax, 1uM (n=4) and 100 nM (n=4)) or iberiotoxin (10 nM (n=2)) supplied in the cardioplegia. Hearts constantly perfused with KHB served as controls.
Results: Baseline parameters of cardiac function were similar between groups (mean values: LVDP: 120±5.1 mmHg, ±dP/dt:3298±132, 2465±126). CP reduced cardiac function 30 min post reperfusion (LVDP:61±3.8%,±dP/dt: 67±4.4%, 59±5.1% recovery compared to baseline). Treatment with 100 nM paxilline significantly improved CP-induced reductions in cardiac function (LVDP: 92±4.3%., ±dP/dt: 108±5.6%, 104 ± 6.0% compared to baseline, (p<.01 for LVDP and ±dP/dt, CP+Pax 100 nM vs CP)). Similar results were obtained with both 1 uM paxilline treatment and iberiotoxin. There were no significant changes in heart rate or coronary flow associated with BKCa channel blockade. Paxilline blocked CP-induced phosphorylation of the akt signaling cascade, activation of which is associated with depressed cardiac contractility.
Conclusions: In contrast to known protective effects of BKCa openers in the setting of ischemic injury, BKCa channel blockers (as a CP additive) profoundly improve cardiac recovery in the context of hyperkalemic cardioplegic arrest.
- © 2011 by American Heart Association, Inc.