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激活KATP通道是心肌保护的重要机制,有该效应的最著名内源性分子是硫化氢,但过去从没有人想到氢气也竟然具有这样的作用。
关于硫化氢激活KATP通道的机制目前也不完全清楚,尽管基本上确定硫化氢通过氧化还原调节该通道上的半胱氨酸残基。现在又出现氢气影响该通道的报道,氢气是如何影响其活性的分子机制更不清楚。
本人推测有三种可能:一是氢气直接发挥调节作用,通过氧化还原调节,这个似乎不可能。或者至少需要其他的酶或者金属离子或两者的共同参与协助下才可以完成,因为氢气的化学性质决定难以发挥这样强的作用;二是间接影响其他调节分子活性,例如促进硫化氢或其他能激活KATP通道的作用,或者通过阻断其他能抑制KATP通道活性的物质;三是阻断阻断剂,发挥竞争性阻断效应,直接阻断其他抑制KATP通道活性的物质发挥阻断作用,最终的效应是激活。
该研究的具体内容,呼吸氢气治疗疾病的机制目前不十分清楚,尽管大部分人用抗氧化作为许多疾病治疗的解释,但也有不同看法。而且没有使用大动物来验证氢气对心脏缺血的保护作用。因此,本研究采用狗作为研究对象,探讨氢气对狗心脏缺血再灌注损伤的作用及其机制。在机制研究上主要是通过使用KATP通道阻断剂和线粒体通透性转运孔开放剂(激活物?)来探讨氢气治疗是否存在上述两种和心肌损伤关系密切的机制(5-hydroxydecanoate (5-HD), or atractyloside。
心肌梗死模型是将动物冠状动脉临时阻断90分钟,然后再灌注6小时。在缺血后80分钟开始呼吸1.3%氢气,并持续70分钟(到再灌注1小时),再灌注6小时后处死动物进行治疗效果观察、氧化指标、细胞凋亡和NAD含量检测。研究结果发现,呼吸氢气可以显著减少缺血梗死体积(20.6 对 44.0),而KATP通道阻断剂和线粒体通透性转运孔开放剂在可以完全逆转氢气的治疗作用。结果提示,氢气治疗心肌缺血再灌注损伤是通过打开KATP通道并阻断线粒体通透性转运孔实现的。作者因此推论,氢气可以作为人类心肌梗死的潜在治疗药物。
文章发表在Cardiovascular Drugs and Therapy,特别强调的是,该研究同时发现氢气在治疗心肌缺血的同时并不影响NAD含量、细胞凋亡数量和8-OhdG阳性细胞数量。这和过去认为氢气具有抗氧化和抗凋亡的作用向左。
关于Katp有一个问题,一种治疗糖尿病的药物是KATP的阻断剂,因为阻断Beta细胞上该通道可以促进胰岛素的释放,机制是当血糖增加时候,细胞内ATP增加,可以使该通道关闭,而关闭可以引起细胞膜更容易去极化(?),从而引起胰岛素释放。药物正是模拟血糖的这个效应通过阻断该通道促进胰岛素释放。另一方面,心脏上该通道的开放是心脏保护的重要方式。那么就存在一个矛盾,使用这类糖尿病药物是否会引起心脏更容易损伤?
Purpose
Inhalation of hydrogen (H2) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H2 gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mKATP) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H2 gas in canine hearts.
Methods
The left anterior descending coronary artery of beagle dogs was occluded for 90 min followed by reperfusion for 6 h. Either 1.3% H2 or control gas was inhaled from 10 min prior to start of reperfusion until 1 h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mKATP blocker), or atractyloside (Atr; a mPTP opener).
Results
Systemic hemodynamic parameters did not differ among the groups. Nevertheless, H2 gas inhalation reduced infarct size normalized by risk area (20.6 ± 2.8% vs. control gas 44.0 ± 2.0%; p < 0.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H2 gas (42.0 ± 2.2% with 5-HD and 45.1 ± 2.7% with Atr; both p < 0.001 vs. H2 group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H2 was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway.
Conclusions
Inhalation of H2 gas reduces infarct size in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mPTP. H2 gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.
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