Hausenloy Derek J, Wynne Abigail M, Yellon Derek M
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK.
Basic Res Cardiol. 2007 Sep;102(5):445-52. doi: 10.1007/s00395-007-0656-1. Epub 2007 May 29.
Emerging studies suggest that signaling during the myocardial reperfusion phase contributes to ischemic preconditioning (IPC). Whether the activation of PKC, the opening of the mKATP channel, redox signaling and transient acidosis specifically at the time of myocardial reperfusion are required to mediate IPC-induced protection is not known. Langendorff-perfused rat hearts were subjected to 35 min ischemia followed by 120 min reperfusion at the end of which infarct size was determined by tetrazolium staining. Control and IPC-treated hearts were randomized to receive for the first 15 min of reperfusion: (1) DMSO (0.02%) vehicle control; (2) chelerythrine (10 micromol/l), a PKC antagonist; (3) 5 hydroxydecanoate (5- HD,100 micromol/l), a mKATP channel blocker; (4) N-mercaptopropionylglycine (MPG,1 mmol/l), a reactive oxygen species scavenger; (5) NaHCO3 (pH 7.6), to counteract any acidosis. Interestingly, all four agents given at the time of myocardial reperfusion abolished the infarct reduction elicited by IPC (N>6/group): (1) DMSO at reperfusion: 49.3+/-3.6% in control versus 21.0+/-3.6% with IPC:P<0.05; (2) chelerythrine at reperfusion: 57.1+/-2.5% in control versus 60.1+/-3.3% with IPC:P=NS; (3) 5-HD at reperfusion: 53.4+/-6.5 % in control versus 42.6+/-4.4% with IPC:P=NS; (4) MPG at reperfusion: 55.3+/-4.6% in control versus 43.9+/-5.2% with IPC:P=NS; (5) NaHCO3 at reperfusion 53.4+/-2.5% in control versus 59.0+/-3.3% with IPC:P=NS. In conclusion, we report for the first time that PKC activation, mKATP channel opening, redox signaling and a low pH at the time of myocardial reperfusion are required to mediate the cardioprotection elicited by ischemic preconditioning.
新出现的研究表明，心肌再灌注阶段的信号传导有助于缺血预处理（IPC）。目前尚不清楚心肌再灌注时PKC的激活、mKATP通道的开放、氧化还原信号传导和短暂性酸中毒是否是介导IPC诱导的保护作用所必需的。采用Langendorff灌注的大鼠心脏，先进行35分钟的缺血，然后进行120分钟的再灌注，再灌注结束时通过四氮唑染色确定梗死面积。将对照和IPC处理的心脏随机分组，在再灌注的前15分钟给予：（1）二甲基亚砜（DMSO，0.02%）作为溶剂对照；（2）白屈菜红碱（10微摩尔/升），一种PKC拮抗剂；（3）5-羟基癸酸（5-HD，100微摩尔/升），一种mKATP通道阻滞剂；（4）N-巯基丙酰甘氨酸（MPG，1毫摩尔/升），一种活性氧清除剂；（5）碳酸氢钠（pH 7.6），以抵消任何酸中毒。有趣的是，在心肌再灌注时给予的所有四种药物都消除了IPC引起的梗死面积减小（每组N>6）：（1）再灌注时给予DMSO：对照组为49.3±3.6%，IPC组为21.0±3.6%：P<0.05；（2）再灌注时给予白屈菜红碱：对照组为57.1±2.5%，IPC组为60.1±3.3%：P=无显著性差异；（3）再灌注时给予5-HD：对照组为53.4±6.5%，IPC组为42.6±4.4%：P=无显著性差异；（4）再灌注时给予MPG：对照组为55.3±4.6%，IPC组为43.9±5.2%：P=无显著性差异；（5）再灌注时给予碳酸氢钠：对照组为53.4±2.5%，IPC组为59.0±3.3%：P=无显著性差异。总之，我们首次报道心肌再灌注时PKC激活、mKATP通道开放、氧化还原信号传导和低pH值是介导缺血预处理引起的心脏保护作用所必需的。
