Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Pharmacy Building, Ein Karem, Jerusalem 91120, Israel.
Bristol Medical School (THS), Faculty of Health Sciences, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK.
Cells. 2021 May 17;10(5):1223. doi: 10.3390/cells10051223.
The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 μM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca-induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca-induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism.
cAMP 类似物 8-Br-cAMP-AM（8-Br）可显著保护分离灌流心脏免受整体缺血/再灌注损伤。我们检验了以下假说：在临床相关条件（局部缺血）下，8-Br 无论是在缺血前应用还是在再灌注开始时应用，都具有保护作用，并且这种作用与线粒体通透性转换孔（MPTP）有关。在 30 分钟局部缺血结束前或结束时，用 Langendorff 灌注的大鼠心脏给予 8-Br（10 μM）5 分钟。在药物处理后，评估 Ca 诱导的线粒体肿胀（MPTP 开放的一种衡量标准）和己糖激酶 II（HKII）与线粒体的结合情况。在缺血和 2 小时再灌注期间监测血流动力学功能和室性心律失常。再灌注结束时评估梗塞面积。缺血前给予 8-Br 可减轻室性心律失常，改善血流动力学功能，并减少缺血/再灌注期间的梗塞面积。缺血结束时应用 8-Br 可在再灌注期间保护心脏。8-Br 促进 HKII 与线粒体的结合，并减少 Ca 诱导的线粒体肿胀。因此，8-Br 在局部缺血前或再灌注开始时给予可保护心脏。这种作用与通过 HKII 与线粒体结合抑制 MPTP 有关，这可能是保护机制的基础。
