Different effects of optical isomers of the 5-HT1A receptor antagonist pyrapyndolol against postischemic guinea-pig myocardial dysfunction and apoptosis through the mitochondrial permeability transition pore
Different effects of optical isomers of the 5-HT1A receptor antagonist pyrapyndolol against postischemic guinea-pig myocardial dysfunction and apoptosis through the mitochondrial permeability transition pore
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DOI：
10.1016/j.ejphar.2006.01.040
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发表时间：
2006-03-18
影响因子：
5
通讯作者：
Shimada, Y
中科院分区：
文献类型：
--
作者：
Huang, L;Hotta, Y;Shimada, Y
新的5-HT 1A受体拮抗剂的光学异构体（S）-（-）-吡唑醇（5 × 10（-8）M）对Langendorff豚鼠心脏缺血-再灌注损伤的左心室发展压力的恢复率（%）（90.7%）大于（R）-（+）-吡唑醇（66.2%，对照：34.4%）。在灌注的线粒体制备物中，（S）-（-）-pyrapyridolol抑制由灌注液的Ca 2+含量或pH的变化引起的线粒体Ca 2+（Cam）升高，与众所周知是线粒体渗透性转换孔（MPTP）的所有抑制剂的环孢菌素A的发现相似。线粒体KNIT通道开放剂二氮嗪也能抑制CaM的升高，但线粒体K-ATP通道拮抗剂5-羟基癸酸则能减弱CaM的升高。与对照组或（R）-（+）-吡唑醇组相比，（S）-（-）-吡唑醇组心肌中TUNEL阳性细胞数量明显减少，caspase-3活性降低。因此，这些结果表明，（S）-（-）-吡唑醇可能通过防止缺血-再灌注心脏中与内源性5-HT积累相关的Cam过载诱导的细胞凋亡来抑制MPTP的开放。(c)2006 Elsevier B. V.保留所有权利。
The recovery (%) of the left ventricular developed pressure by (S)-(-)-pyrapyridolol (5 x 10(-8) M) (90.7%), ail optical isomer of a new 5-HT1A receptor antagonist, was greater than that by (R)-(+)-pyrapyridolol (66.2%, control: 34.4%) against ischemia-reperfusion injury in perfused Langendorff guinea-pig hearts. In the perfused mitochondrial preparation, (S)-(-)-pyrapyridolol inhibited the mitochondrial Ca2+ (Cam) elevation that was brought about by the change of Ca2+ content or pH of perfusate, similar to findings with cyclosporin A, well known to be all inhibitor of the mitochondrial permeability transition pore (MPTP). The mitochondrial KNIT channel opener, diazoxide, also inhibited the Cam elevation, but the mitochondrial K-ATP, channel antagonist, 5-hydroxydecanoic acid, attenuated it. There were significantly fewer numbers of TUNEL-positive cells in these (S)-(-)-pyrapyridolol -treated hearts than the control or (R)-(+)-pyrapyridolol, with decreases of the caspase-3 activity. Therefore, these results suggest that (S)-(-)-pyrapyridolol likely inhibits the opening of the MPTP by preventing the Cam overload induced apoptosis related to endogenous 5-HT accumulation in ischemia-reperfusion hearts. (c) 2006 Elsevier B.V. All rights reserved.