Cardiomyocyte apoptosis induced in ischemia-reperfusion Langendorff preparation and the development of new cardiac drug.

缺血再灌注Langendorff制剂诱导心肌细胞凋亡及新型心脏药物的开发

• 批准号: 14572168
• 负责人: HOTTA Yoshihiro
• 金额: $ 1.28万
• 依托单位: Aichi Medical University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572168/
• 关键词: guinea-pig Langendorff hearts; ischemia-reperfused injury; <31>^P-NMR; ESR; LVDP; apoptosis; Tuner; MPTP; guinea-pig; Langendorff hearts; free radical

1.Apoptosis in the ischemia-reperfusion Langendorff hearts was not induced by oxygen-deprivation alone, but the deprivation of glucose that induced myocardial cell death mainly by apoptosis in the presence or absence of oxygen. The deprivation of both oxygen and glucose exaggerated the apoptotic lesion morphologically. Glucose deprivation coincided with the decrease in ATPi content and intracellular acidosis in the presence or absence of oxygen (Tong et al., 2001).2.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+> by acidification and Ca changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to directly quench the active oxygen radical, though SM-198110 had no eff … More ect. The number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197278-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Hotta et al., 2003).3.5-HT_<1A> or cyclic dipeptides (in beer or the distilled residue of millet brandy) had a beneficial effect against ischemia/reperfusion injury with Alp contents, quenching the active oxygen radical and inhibition of mitochondrial Ca^<2+> by acidification or Ca^<2+> contents of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 (Huang and Akutagawa et al., 2004).4.Atractyroside (10^<->3 M), which opens mitochondrial permeability transition pores (MPTP) also caused similar increases in mitochondrial Ca^<2+> by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs 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 (Hotta et al., 2004). Less

1.缺血-再灌注Langendorff心脏中的细胞凋亡不是由单独的氧剥夺诱导的，而是在有氧或无氧的情况下主要通过细胞凋亡诱导心肌细胞死亡的葡萄糖剥夺。缺氧缺糖使凋亡性病变在形态学上加重。在存在或不存在氧的情况下，葡萄糖剥夺与ATPi含量的降低和细胞内酸中毒一致（Tong等人，2001).2. Na^+H^+交换（NHE）抑制剂SM-198110（结构中为Cl）和SM-197378（结构中为F）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抑制剂均抑制了酸化引起的线粒体Ca^<2+>和类似于全脑缺血后再灌注的Ca变化。SM-197378可直接淬灭活性氧自由基，而SM-198110则无此作用 ...更多信息 等方面在通过再灌注的长时间缺血后，SM-197278处理的心脏中凋亡细胞的数量显著小于SM-198110处理的心脏，这与半胱天冬酶-3的活性水平一致（Hotta等人，3.5-HT_2<1A>或环二肽（啤酒或小米白兰地蒸馏残渣）对缺血/再灌注损伤有保护作用，其作用机制与Alp含量、淬灭活性氧自由基、酸化抑制线粒体Ca^2+或灌流液Ca^2+含量有关。这些化合物还抑制凋亡细胞和半胱天冬酶-3的活性水平（Huang和Akutagawa等人，2004).4.能<->打开线粒体渗透性转换孔（MPTP）的红景天苷（10^ 3 M）也能通过酸化或Ca^2+含量的变化引起线粒体Ca^2+的类似增加。在<-4>Langendorff缺血/再灌注损伤模型中抑制MPTP的环孢菌素A（10 μ M）或促进LVDP良好恢复的许多药物也被抑制，但不抑制MPTP的FK 506（10 μ <-4>M）没有被抑制（Hotta等人，2004年）。少

项目成果

Tatsuya Muto et al.: "Protective effects of sarpogrelate, 5-HT_<2A> antagonists, against postischemic myocardial dysfunction in guinea pig hearts."Mol.Cell.Biochem.. (in press).

Tatsuya Muto 等人：“沙格雷酯、5-HT_2A 拮抗剂对豚鼠心脏缺血后心肌功能障碍的保护作用。”Mol.Cell.Biochem..（出版中）。

Michio Yajima et al.: "Protective effects of antioxidative radical scavenger edaravone against postischemic myocardial dysfunction in quinea-pig hearts:^<31>P-NMR and ESR measurements of cellular energy and free radical."J Pharmacol Sci. 91・Suppl. I. 152

Michio Yajima 等人：“抗氧化自由基清除剂依达拉奉对豚鼠心脏缺血后心肌功能障碍的保护作用：^ 31 P-NMR 和细胞能量和自由基的 ESR 测量。”J Pharmacol Sci 91・Suppl。一、152

Yoshihiro Hotta et al.: "Differences in the effects of Na^+-H^+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts."Mol.Cell.Biochem.. (In press).

Yoshihiro Hotta 等人：“Na ^ -H ^ 交换抑制剂对豚鼠缺血再灌注心脏的心脏功能和细胞凋亡的影响差异。”Mol.Cell.Biochem..（正在出版）。

Yoshihiro Hotta et al.: "The permeability transition pores (MPTP) against post-ischemic myocardial dysfunction."J.Pharmacol.Sci.. 94. 159 (2004)

Yoshihiro Hotta 等人：“针对缺血后心肌功能障碍的渗透性转变孔 (MPTP)。”J.Pharmacol.Sci.. 94. 159 (2004)

Lei Huang et al.: "Different effects on optical isomers of the 5-HT_<1A> antagonist pyrapyridolol against postischemic myocardial dysfunction in guinea-pig hearts."J.Pharmacol. Sci.. 94. 159 (2004)

Lei Huang等人：“5-HT_1A拮抗剂吡吡啶醇光学异构体对豚鼠心脏缺血后心肌功能障碍的不同作用。”J.Pharmacol。