Hausenloy Derek J, Maddock Helen L, Baxter Gary F, Yellon Derek M
The Hatter Institute for Cardiovascular Studies, Center for Cardiology, University College London Hospitals and Medical School, Grafton Way, UK.
Cardiovasc Res. 2002 Aug 15;55(3):534-43. doi: 10.1016/s0008-6363(02)00455-8.
We propose that ischemic preconditioning (IPC) and mitochondrial K(ATP) channel activation protect the myocardium by inhibiting mitochondrial permeability transition pore (MPTP) opening at reperfusion.
Isolated rat hearts were subjected to 35 min ischemia/120 min reperfusion and assigned to the following groups: (1) control; (2) IPC of 2x5 min each of preceding global ischemia; (3,4,5) 0.2 micromol/l cyclosporin A (CsA, which inhibits MPTP opening), 5 micromol/l FK506 (which inhibits the phosphatase calcineurin without inhibiting MPTP opening), or 20 micromol/l atractyloside (Atr, a MPTP opener) given at reperfusion; (6,7) pre-treatment with 30 micromol/l diazoxide (Diaz, a mitochondrial K(ATP) channel opener) or 200 nmol/l 2 chloro-N(6)-cyclopentyl-adenosine (CCPA, an adenosine A1 receptor agonist); (8) IPC+Atr; (9) Diaz+Atr; (10) CCPA+Atr. The effect of mitochondrial K(ATP) channel activation on calcium-induced MPTP opening in isolated calcein-loaded mitochondria was also assessed.
IPC, CsA when given at reperfusion, and pre-treatment with diazoxide or CCPA all limited infarct size (19.9+/-2.6% in IPC; 24.6+/-1.9% in CsA, 18.0+/-1.7% in Diaz, 20.4+/-3.3% in CCPA vs. 44.7+/-2.0% in control, P<0.0001). Opening the MPTP with atractyloside at reperfusion abolished this cardio-protective effect (47.7+/-1.8% in IPC+Atr, 42.3+/-3.2% in Diaz+Atr, 51.2+/-1.6% in CCPA+Atr). Atractyloside and FK506, given at reperfusion, did not influence infarct size (45.7+/-2.1% in Atr and 43.1+/-3.6% in FK506 vs. 44.7+/-2.0% in control, P=NS). Diazoxide (30 micromol/l) was shown to reduce calcium-induced MPTP opening by 52.5+/-8.0% in calcein-loaded mitochondria. 5-Hydroxydecanoic acid (100 micromol/l) was able to abolish the cardio-protective effects of both diazoxide and IPC.
One interpretation of these data is that IPC and mitochondrial K(ATP) channel activation may protect the myocardium by inhibiting MPTP opening at reperfusion.
我们提出缺血预处理（IPC）和线粒体K（ATP）通道激活通过抑制再灌注时线粒体通透性转换孔（MPTP）开放来保护心肌。
将离体大鼠心脏进行35分钟缺血/120分钟再灌注，并分为以下几组：（1）对照组；（2）先前进行两次每次5分钟全心缺血的IPC组；（3、4、5）再灌注时给予0.2微摩尔/升环孢素A（CsA，抑制MPTP开放）、5微摩尔/升FK506（抑制钙调磷酸酶而不抑制MPTP开放）或20微摩尔/升苍术苷（Atr，一种MPTP开放剂）组；（6、7）用30微摩尔/升二氮嗪（Diaz，一种线粒体K（ATP）通道开放剂）或200纳摩尔/升2-氯-N（6）-环戊基腺苷（CCPA，一种腺苷A1受体激动剂）预处理组；（8）IPC+Atr组；（9）Diaz+Atr组；（10）CCPA+Atr组。还评估了线粒体K（ATP）通道激活对钙诱导的离体钙黄绿素负载线粒体中MPTP开放的影响。
IPC、再灌注时给予CsA以及用二氮嗪或CCPA预处理均限制了梗死面积（IPC组为19.9±2.6%；CsA组为24.6±1.9%，Diaz组为18.0±1.7%，CCPA组为20.4±3.3%，而对照组为44.7±2.0%，P<0.0001）。再灌注时用苍术苷开放MPTP消除了这种心脏保护作用（IPC+Atr组为47.7±1.8%，Diaz+Atr组为42.3±3.2%，CCPA+Atr组为51.2±1.6%）。再灌注时给予苍术苷和FK506不影响梗死面积（Atr组为45.7±2.1%，FK506组为43.1±3.6%，而对照组为44.7±2.0%，P=无显著差异）。二氮嗪（30微摩尔/升）显示可使钙黄绿素负载线粒体中钙诱导的MPTP开放减少52.5±8.0%。5-羟基癸酸（100微摩尔/升）能够消除二氮嗪和IPC的心脏保护作用。
这些数据的一种解释是，IPC和线粒体K（ATP）通道激活可能通过抑制再灌注时MPTP开放来保护心肌。
