Ischemic post-conditioning (iPoCo) by coronary re-occlusion/reperfusion during immediate reperfusion after prolonged myocardial ischemia reduces infarct size. Mechanical manipulation of culprit lesions, however, carries the risk of coronary microembolization which may obscure iPoCo’s cardioprotection. Pharmacological post-conditioning with exogenous triiodothyronine (T3) could serve as an alternative conditioning strategy. Similar to iPoCo, T3 may activate cardioprotective prosurvival pathways. We aimed to study T3’s impact on infarct size and its underlying signal transduction. Hearts were isolated from male Lewis rats (200–380 g), buffer-perfused and subjected to 30 min/120 min global zero-flow ischemia/reperfusion (I/R). In additional hearts, either iPoCo (2 × 30 s/30 s I/R) was performed or T3 (100–500 µg/L) infused at reperfusion. Infarct size was demarcated with triphenyl tetrazolium chloride staining and calculated as percent of ventricular mass. Infarct size was reduced with iPoCo to 16 ± 7% vs. 36 ± 4% with I/R only. The maximum infarct size reduction was observed with 300 µg/L T3 (14 ± 2%). T3 increased the phosphorylation of protein kinase B and mitogen extracellular-regulated-kinase 1/2, both key enzymes of the reperfusion injury salvage kinase (RISK) pathway. Pharmacological RISK blockade (RISK-BL) during reperfusion abrogated T3’s cardioprotection (35 ± 10%). Adult ventricular cardiomyocytes were isolated from buffer-perfused rat hearts and exposed to 30 min/5 min hypoxia/reoxygenation (H/R); reoxygenation was initiated without or with T3, respectively, and without or with RISK-BL, respectively. Maximal preservation of viability was observed with 500 µg/L T3 after H/R (27 ± 4% of all cells vs. 5 ± 3% in time-matched controls). Again, RISK-BL abrogated protection (11 ± 3%). Mitochondria were isolated at early reperfusion from buffer-perfused rat hearts without or with iPoCo or 300 µg/L T3, respectively, at reperfusion. T3 improved mitochondrial function (i.e.: increased respiration, adenosine triphosphate production, calcium retention capacity, and decreased reactive oxygen species formation) to a similar extent as iPoCo. T3 at reperfusion reduces infarct size by activation of the RISK pathway. T3’s protection is a cardiomyocyte phenomenon and targets mitochondria.

长时间心肌缺血后立即再灌注期间通过冠状动脉再闭塞/再灌注进行的缺血后处理（iPoCo）可减少梗塞面积。然而，对罪魁祸首病变进行机械操作会带来冠状动脉微栓塞的风险，这可能会掩盖 iPoCo 的心脏保护作用。使用外源性三碘甲状腺原氨酸（T3）进行药理学后调理可以作为替代调理策略。与 iPoCo 类似，T3 可能激活心脏保护性促生存途径。我们的目的是研究 T3 对梗塞面积的影响及其潜在的信号转导。从雄性 Lewis 大鼠 (200-380 g) 中分离心脏，灌注缓冲液并进行 30 分钟/120 分钟整体零流量缺血/再灌注 (I/R)。在另外的心脏中，进行 iPoCo (2 × 30 s/30 s I/R) 或在再灌注时输注 T3 (100–500 µg/L)。梗塞面积用氯化三苯基四唑染色划分，并计算为心室质量的百分比。使用 iPoCo 时，梗塞面积减少至 16 ± 7%，而仅使用 I/R 时，梗塞面积减少至 36 ± 4%。使用 300 µg/L T3 观察到梗塞面积最大减少 (14 ± 2%)。 T3 增加了蛋白激酶 B 和丝裂原细胞外调节激酶 1/2 的磷酸化，这两种酶都是再灌注损伤挽救激酶 (RISK) 途径的关键酶。再灌注期间的药理学RISK阻断(RISK-BL)消除了T3的心脏保护作用(35±10%)。从缓冲液灌注的大鼠心脏中分离出成年心室心肌细胞，并暴露于 30 分钟/5 分钟缺氧/复氧 (H/R)；分别在不使用或使用 T3 的情况下以及分别不使用或使用 RISK-BL 的情况下启动复氧。 H/R 后使用 500 µg/L T3 可以最大程度地保留活力（所有细胞的 27 ± 4%，而时间匹配的对照中为 5 ± 3%）。 RISK-BL 再次取消了保护（11 ± 3%）。再灌注早期，从缓冲液灌注的大鼠心脏中分离线粒体，分别在再灌注时不含或含 iPoCo 或 300 µg/L T3。 T3 改善线粒体功能（即：增加呼吸、三磷酸腺苷生成、钙保留能力和减少活性氧形成），其程度与 iPoCo 相似。再灌注时的 T3 通过激活 RISK 通路来减少梗塞面积。 T3 的保护是一种心肌细胞现象，并针对线粒体。