Cardiomyocyte apoptosis related with mitochondrial PTP in ischemia-reperfusion injury and the development of new cardiac drug.

1.Na^+-H^+交换（NHE）抑制剂SM-198110 （Cl -结构）和SM-197378 （F -结构）对Langendorff心脏缺血/再灌注损伤的LVDP（约100% vs.无药心脏39%）有保护作用。在灌注的fura-2负载线粒体制备中，两种NHE抑制剂均抑制了酸化后线粒体Ca^<2+>摄取和Ca^<2+>含量变化，类似于全脑缺血后的再灌注。SM-197378可以直接淬灭活性氧自由基，而SM-198110则没有作用。sm -197378处理的心脏缺血再灌注后凋亡细胞数量明显少于sm -198110处理的心脏，与caspase-3活性水平一致（eu . j . pharmacol .2004）.2.5 ht_ <2A>(Mol.Cell.Biochem. 2004)。2005), 5HT_<1A> (Eur.J.Pharmacol.2006)拮抗剂或SSRI （Life science，制剂）对缺血/再灌注损伤具有ATP含量，猝猝活性氧自由基和抑制线粒体Ca^<2+>升高的作用。这些化合物还能抑制凋亡细胞和与5HT.3相关的caspase-3活性水平。白术皂苷（10^<-3> M）打开线粒体通透性过渡孔（MPTP），也引起线粒体Na^+、Ca^<2+>的酸化吸收增加或Ca^<2+>含量变化。抑制MPTP的环孢素A （10^<-4> M）和许多促进Langendorff缺血/再灌注损伤模型LVDP良好恢复的药物（Na-Ca交换或Na-H抑制剂）也被抑制，但不抑制MPTP的FK506 （10^<-4> M）被抑制（eurj . pharmacol）。在准备)。这可能与线粒体Na^+或Ca^<2+>和MPTP对缺血再灌注损伤的作用有关。一种K_<ATP>通道开启剂（thera . res .）。2005)，一种绿茶儿茶素(Eur.J.Pharmacol。在Life Science， In preparation)，或环二肽（在啤酒或小米白兰地的蒸馏渣中）像NO供体一样，具有抑制MPTP5的有益作用。体外ESR光谱法可以直接测定豚鼠Langendorff心脏制剂缺血再灌注损伤模型中活性氧（ROS）的产生[j]。这些结果表明，ROS和NO与MPTP诱导心肌细胞凋亡在缺血后心肌功能障碍中的作用密切相关。少

1.The protective effects of Na^+-H^+ exchange (NHE) inhibitors SM-198110 (Cl in structure) and SM-197378 (F in structure) had beneficial effects of LVDP (about 100% vs. drug free heart 39%) from ischemia/ reperfusion injury in Langendorff hearts. In perfused fura-2 loaded mitochondria preparation, mitochondrial Ca^<2+> uptake by acidification and Ca^<2+> content changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to quench directly the active oxygen radical, though SM-198110 had no effect. Number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197378-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Eur.J.Pharmacol.2004).2.5HT_<2A>(Mol.Cell.Biochem.2005), 5HT_<1A> (Eur.J.Pharmacol.2006) antagonist or SSRI (Life Sciense, in preparation) was beneficial effect against ischemia/reperfusion injury with ATP contents, quenching the active oxygen radical an … More d inhibition of mitochondrial Ca^<2+> upteke by acidification or Ca^<2+> content of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 in related with 5HT.3.Atractyroside (10^<-3> M), which opens mitochondrial permeability transition pore (MPTP) also caused similar increases in mitochondrial Na^+, Ca^<2+> uptake by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs (Na-Ca exchange or Na-H inhibitor) that promote good recovery of the LVDP in the Langendorff ischemia/reperfusion injury model were also suppressed, but not FK506 (10^<-4> M), which does not inhibit MPTP (Eur.J.Pharmacol.in preparation). This result may be relate with mitochondrial Na^+ or Ca^<2+> and MPTP against ischemia-reperfusion injury.4.Nicorandil, a K_<ATP>-channel opener (Ther.Res.2005), a green tea cathechin (Eur.J.Pharmacol.In press, Life Science, in preparation), or cyclic dipeptides (in beer or the distilled residue of millet brandy) like the NO donor, was beneficial effect with inhibit MPTP5.Ex-vivo ESR spectrometry could measure directly the generation of reactive oxygen species (ROS) in ischemia-reperfusion injury model of guinea-pig Langendorff heart preparation (J.Pharmacol.Sci.2005)These results suggested that ROS and NO are closely involved to the role of the induction of myocardial cell apoptosis through MPTP in post-ischemic myocardial dysfunction. Less