Department of Physiology, University of Melbourne, Victoria, Australia.
Int J Cardiol. 2012 Aug 23;159(2):112-8. doi: 10.1016/j.ijcard.2011.02.038. Epub 2011 Mar 9.
Ca(2+)/calmodulin-dependent protein kinase (CaMKII) activation is known to be associated with conditions where the incidence of arrhythmias is increased, and where cardiomyocyte Ca(2+)-overload occurs. The goal of this study was to determine whether CaMKII inhibition in the intact heart may be linked to the suppression of ventricular arrhythmias occurring during reperfusion after an ischemic insult.
Non-paced male rat hearts (n = 8-11) were treated with a CaMKII inhibitor (KN93, 2.5 μmol/L) 10 min prior to global ischemia (20 min) and for the initial 10 min of reperfusion. Cardiac mechanical and arrhythmic responses were evaluated under constant pressure perfusion conditions and myocyte damage assessed by measurement of coronary effluent lactate dehydrogenase (LDH).
Under basal conditions, KN93 increased coronary flow (41 ± 8% increase, p<0.05) and was negatively inotropic (29 ± 7% decrease, p<0.05), but did not affect heart rate. Ischemic contracture was significantly diminished in KN93-treated hearts (onset, min: 11.48 ± 0.50 vs 16.27 ± 1.23, p<0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular tachycardia/fibrillation in reperfusion (11/11 control vs 1/8 KN93). In the absence of ventricular arrhythmias, heart rate was substantially reduced (% basal; 100 ± 3% vs 46 ± 8%, p<0.05) throughout reperfusion. Left ventricular developed pressure was initially low in KN93 hearts post-ischemia, but recovered to control levels by the end of 60 min reperfusion (68 ± 5% vs 56 ± 5%, p = ns). LDH was significantly reduced in KN93-treated hearts.
Although CaMKII inhibition diminishes contractile performance of the intact heart in the initial post-ischemic period, it provides crucial benefits through protection against potentially lethal reperfusion-induced arrhythmias and cardiomyocyte sarcolemmal rupture.
已知钙/钙调蛋白依赖性蛋白激酶 (CaMKII) 的激活与心律失常发生率增加和心肌细胞钙超载的情况有关。本研究的目的是确定在缺血性损伤后再灌注期间发生的心室性心律失常是否与完整心脏中的 CaMKII 抑制有关。
在整体缺血（20 分钟）前 10 分钟和再灌注的最初 10 分钟内，用 CaMKII 抑制剂（KN93，2.5 μmol/L）处理非起搏雄性大鼠心脏（n = 8-11）。在恒压灌注条件下评估心脏机械和心律失常反应，并通过测量冠状流出液乳酸脱氢酶 (LDH) 评估心肌细胞损伤。
在基础条件下，KN93 增加了冠脉流量（增加 41 ± 8%，p<0.05），并具有负性肌力作用（减少 29 ± 7%，p<0.05），但不影响心率。在 KN93 处理的心脏中，缺血性挛缩显著减少（发作时间，分钟：11.48 ± 0.50 与 16.27 ± 1.23，p<0.05）。再灌注早期的 CaMKII 抑制几乎完全消除了再灌注时室性心动过速/颤动的发生率（对照组 11/11，KN93 组 1/8）。在没有室性心律失常的情况下，心率在整个再灌注期间显著降低（相对于基础的%；100 ± 3%与 46 ± 8%，p<0.05）。在 KN93 心脏中，缺血后左心室发展压最初较低，但在 60 分钟再灌注结束时恢复到对照水平（68 ± 5%与 56 ± 5%，p = ns）。KN93 处理的心脏中 LDH 显著降低。
尽管 CaMKII 抑制在缺血后早期会降低完整心脏的收缩性能，但它通过防止潜在致命的再灌注诱导性心律失常和心肌细胞膜破裂提供了至关重要的益处。
