Department of Anesthesiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Duesseldorf, Heinrich-Heine-University Duesseldorf, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
Int J Mol Sci. 2021 Apr 26;22(9):4517. doi: 10.3390/ijms22094517.
Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3-10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration-response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.
心肌梗死患者的预后因合并症（如糖尿病）而受到不利影响。在实验环境中，不仅糖尿病，而且急性高血糖也被证明会通过多种药理学制剂阻碍心脏保护特性。对于左西孟旦诱导的后处理，在健康心肌中显示出强烈的梗死面积缩小作用。然而，急性高血糖被认为会阻断这种保护作用。在本研究中，我们研究了（1）左西孟旦诱导的后处理在高血糖条件下是否具有浓度依赖性效应，以及（2）与线粒体通透性转换孔（mPTP）阻滞剂环孢素 A（CsA）联合是否可以恢复高血糖下左西孟旦的心脏保护特性。为了进行这项实验研究，雄性 Wistar 大鼠的心脏被随机分组并安装到 Langendorff 系统上，用恒压 80mmHg 的 Krebs-Henseleit 缓冲液灌注。所有分离的心脏均在高血糖条件下经历 33 分钟的整体缺血和 60 分钟的再灌注。（1）在再灌注开始时，用不同浓度的左西孟旦（Lev）（0.3-10μM）灌注心脏 10 分钟，以研究浓度反应关系。在第二组实验（2）中，给予 0.3μM 左西孟旦与 mPTP 阻滞剂 CsA 联合使用，以阐明高血糖下心脏保护作用受阻的潜在机制。梗死面积通过氯化四唑（TTC）染色确定。（1）对照（Con）心脏的梗死面积为 52±12%。没有任何给予的左西孟旦浓度降低梗死面积（Lev0.3：49±9%；Lev1：57±9%；Lev3：47±11%；Lev10：50±7%；均与 Con 相比无统计学差异）。（2）Con 和 Lev0.3 心脏的梗死面积分别为 53±4%和 56±2%。CsA 单独使用对梗死面积没有影响（CsA：50±10%；与 Con 相比无统计学差异）。与单独使用 Lev0.3 相比，Lev0.3 和 CsA 的联合使用（Lev0.3+CsA）显著降低了梗死面积（Lev0.3+CsA：35±4%；<0.05 与 Lev0.3 相比）。我们证明了（1）高血糖阻断了左西孟旦诱导的后处理的梗死面积缩小作用，并且不能通过增加浓度来克服。（2）此外，通过联合使用左西孟旦和 mPTP 阻滞剂 CsA，可以恢复高血糖下的心脏保护作用。
