恩格列净对大鼠缺血再灌注后的心脏保护作用

Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats

Keywords：Heart failure, Myocardial infarction, Experimental models of disease, Cardiology

关键词：心力衰竭，心肌梗塞，疾病的实验模型，心脏病学
作者：Seefeldt JM, Lassen TR, Vognstoft Hjortbak M, Jespersen NR, Kvist F, Hansen J, Boetker HE
出版期刊：《Scientific Reports》 2021/5/5

Abstract：

The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of β-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 ± 7% vs. 46 ± 8%, p < 0.0001 while administration 1.5 h before IR, at onset of reperfusion or ex-vivo did not. EMPA alleviated LV dysfunction irrespective of the reduction in IS. EMPA improved mitochondrial respiration and modulated myocardial interstitial metabolism while the concentration of β-hydroxybutyric acid was only transiently increased without any association with IS reduction. EMPA reduces infarct size and yields cardioprotection in non-diabetic rats with ischemic LV dysfunction by an indirect, delayed intrinsic mechanism that also improves systolic function beyond infarct size reduction. The mechanism involves enhanced mitochondrial respiratory capacity and modulated myocardial metabolism but not hyperketonemia.

文章简介：

Sodium Glucose Co-Transporter-2 抑制剂 empagliflozin (EMPA) 可降低心肌梗塞后心力衰竭的死亡率和住院率，而与糖尿病状态无关。虽然研究结果表明其具有内在的心脏保护能力，但其机制仍然未知。我们研究了暴露于整体 IR 损伤的离体心脏的梗塞大小 (IS) 离体和遭受局部心肌缺血再灌注 (IR) 损伤的大鼠体内的梗塞大小 (IS)，我们对这些大鼠的左心室功能障碍进行了 28 天的随访。我们比较了 7 天前口服 EMPA、IR 损伤前 1.5 小时和再灌注开始时给予 EMPA 并在随访期间继续口服给药的大鼠。我们使用超声心动图、高分辨率呼​​吸测定法、微透析和血浆β-羟基丁酸水平分别评估心肌功能、线粒体呼吸和中间代谢。用 EMPA 预处理 7 天可降低体内 IS（65 ± 7% vs. 46 ± 8%，p < 0.0001，而在 IR 前 1.5 小时给药，再灌注开始或离体没有。EMPA 减轻了 LV 功能障碍，无论IS 降低。EMPA 改善线粒体呼吸并调节心肌间质代谢，而 β-羟基丁酸的浓度仅短暂增加，与 IS 降低没有任何关联。EMPA 可减少缺血性 LV 功能障碍的非糖尿病大鼠的梗死面积并产生心脏保护作用一种间接的、延迟的内在机制，除了缩小梗塞面积外，还可以改善收缩功能。该机制涉及增强线粒体呼吸能力和调节心肌代谢，但不包括高酮血症。

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