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（结构中为Cl）和SM-197378（结构中为F）的保护作用对Langendorff心脏的缺血/再灌注损伤具有LVDP的有益作用（约100% vs.无药物心脏39%）。在灌流的fura-2负载的线粒体制备物中，两种NHE抑制剂均抑制了线粒体通过酸化的Ca^2+摄取和与全脑缺血后再灌注相似的Ca^2+含量变化。发现SM-197378直接淬灭活性氧自由基，尽管SM-198110没有效果。SM-197378处理的心肌细胞凋亡数明显少于SM-198110处理的心肌细胞，这与caspase-3的活性水平一致Eur.J.Pharmacol.2004。2.5HT_<2A>（Mol.Cell.Biochem.2005）、5 HT_<1A>（Eur.J.Pharmacol.2006）拮抗剂或SSRI（Life Sciense，in preparation）对缺血/再灌注损伤具有保护作用，其作用机制与ATP含量、活性氧自由基的猝灭和细胞凋亡有关。 ...更多信息 d.酸化或灌流液中Ca^&lt;2 +&gt;含量对线粒体Ca^&lt;2+&gt;升高的抑制作用。这些化合物还抑制凋亡细胞和与5-HT相关的caspase-3活性水平。3.酪氨酸苷（10 μ <-3>M）可打开线粒体通透性转换孔（MPTP），也可通过酸化或Ca^2+含量变化引起线粒体Na^+、Ca^2+摄取的类似增加。抑制MPTP的环孢菌素A（10 μ <-4>M）或许多促进兰根多夫缺血/再灌注损伤模型中LVDP良好恢复的药物（Na-Ca交换或Na-H抑制剂）也受到抑制，但不抑制MPTP的FK 506（10 μ <-4>M）（Eur.J.Pharmacol.in制备）。这一结果可能与线粒体Na^+、Ca^&lt;2+&gt;及MPTP抗缺血再灌注损伤有关<ATP>（Ther.Res.2005），一种绿色茶儿茶素（Eur.J.Pharmacol.In press，Life Science，in preparation），或环二肽（在啤酒或小米白兰地的蒸馏残留物中）像NO供体一样，离体ESR波谱法可直接测定豚鼠脑缺血再灌注损伤模型中活性氧（ROS）的产生，猪Langendorff心脏制备（J.Pharmacol.Sci.2005）这些结果表明，ROS和NO在缺血后心肌功能障碍中通过MPTP诱导心肌细胞凋亡的作用密切相关。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