Department of Clinical and Experimental Medicine, University of East Piedmont "A. Avogadro", Novara, Italy.
Cardiovasc Drugs Ther. 2010 Feb;24(1):5-15. doi: 10.1007/s10557-010-6217-0.
Powerful mediators of programmed cell death, such as apoptosis and autophagy, can contribute to myocyte cell loss during pathological cardiac conditions. Levosimendan has been shown to exert beneficial hemodynamic effects in presence of global myocardial ischemia and heart failure through vasodilatation and increase of cardiac contractility. Recently, the intracoronary administration of a bolus levosimendan was found to exert favourable cardiac anti-stunning effects without lowering arterial pressure, which limits the use of levosimendan mainly in coronary artery disease. Here we tested whether the intracoronary administration of levosimendan can beneficially modulate programmed cell death in acute regional myocardial ischemia.
Acute regional myocardial ischemia was induced in 20 anaesthetized pigs and intracoronary levosimendan 15 min bolus administration was started 4 h afterwards. The effects of levosimendan on coronary blood flow and cardiac function were evaluated and myocardial biopsies were examined for criteria of autophagy and apoptosis.
The administration of levosimendan caused a significant increase of coronary blood flow (p < 0.05) in absence of changes in cardiac function. Moreover, levosimendan prevented the down-regulation of the anti-apoptotic gene, Bcl-2, and the up-regulation of the apoptotic markers Bax and cytochrome c, which resulted in a reduced expression of TUNEL fragmented nuclei (p < 0.05). Furthermore, levosimendan maintained Beclin 1 at 4 h and potentiated LC3 II expression, these results being consistent with autophagy activation.
Such effects of intracoronary levosimendan bolus administration during regional myocardial ischemia indicate the occurrence of cardio-protection by modulation of programmed form of cell death.
程序性细胞死亡的强大介质，如细胞凋亡和自噬，可以导致病理性心脏条件下的心肌细胞丢失。左西孟旦已被证明在存在全心缺血和心力衰竭时通过血管扩张和增加心肌收缩力发挥有益的血液动力学效应。最近，冠状动脉内给予左西孟旦推注被发现具有有利的心脏抗顿抑作用，而不降低动脉压，这限制了左西孟旦主要在冠状动脉疾病中的应用。在这里，我们测试了冠状动脉内给予左西孟旦是否可以有益地调节急性区域性心肌缺血中的程序性细胞死亡。
在 20 只麻醉猪中诱导急性区域性心肌缺血，并在 4 小时后开始冠状动脉内给予左西孟旦 15 分钟推注。评估左西孟旦对冠状动脉血流和心功能的影响，并检查心肌活检以评估自噬和凋亡标准。
左西孟旦的给药导致冠状动脉血流显著增加（p < 0.05），而心功能没有变化。此外，左西孟旦防止了抗凋亡基因 Bcl-2 的下调和凋亡标志物 Bax 和细胞色素 c 的上调，导致 TUNEL 片段化核的表达减少（p < 0.05）。此外，左西孟旦在 4 小时时维持 Beclin 1 并增强 LC3 II 的表达，这些结果与自噬激活一致。
在区域性心肌缺血期间冠状动脉内给予左西孟旦推注的这种作用表明通过调节程序性细胞死亡的形式发生了心脏保护。
