Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism.
Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism.
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DOI：
10.1097/aln.0b013e3181c4a607
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发表时间：
2010-01
期刊：
影响因子：
8.8
通讯作者：
Warltier DC
中科院分区：
文献类型：
--
作者：
Ge ZD;Pravdic D;Bienengraeber M;Pratt PF Jr;Auchampach JA;Gross GJ;Kersten JR;Warltier DC
内皮型一氧化氮合酶（eNOS）在异氟醚后处理（IsoPC）引起的心脏保护中的作用尚不清楚。我们使用eNOS-/-小鼠解决了这个问题。在体内或Langendorff灌注的小鼠心脏进行了30分钟的缺血，然后2小时的再灌注的存在和不存在的后处理产生的异氟烷缺血前5分钟和再灌注后3分钟。在分离的线粒体中评估Ca 2+诱导的线粒体渗透性转换孔开放。超声心动图评价心室功能。用0.5、1.0和1.5最小肺泡浓度的异氟烷进行后处理，可使梗死面积从对照组的56 ± 10%（n = 10）分别降低至48 ± 10%、41 ± 8%（n = 8，P <0.05）和38 ± 10%（n = 8，P < 0.05），并改善野生型小鼠的心功能。在缺血前或再灌注开始时给予NG-硝基-L-精氨酸甲酯（一种非选择性NOS抑制剂）阻断IsoPC对心功能的改善。与对照组相比，从后处理心脏分离的线粒体需要显著更高的体外Ca 2+负荷（78 ± 29 vs. 40 ± 25 μM CaCl 2 mg protein-1，n = 10，P < 0.05）来打开线粒体通透性转换孔。与野生型心脏相比，eNOS-/-小鼠的心脏在梗死面积、心功能和线粒体通透性转换孔对Ca 2+的敏感性方面没有显着差异。然而，与对照心脏相比，IsoPC未能改变梗死面积、心脏功能或打开从eNOS-/-心脏分离的线粒体中的线粒体渗透性转换孔所需的Ca 2+的量。IsoPC通过eNOS依赖的方式阻止MPT孔开放来保护小鼠心脏免受再灌注损伤。一氧化氮作为IsoPC产生的心脏保护的触发器和介体发挥作用。
The role of endothelial nitric oxide synthase (eNOS) in isoflurane postconditioning (IsoPC)-elicited cardioprotection is poorly understood. We addressed this issue using eNOS-/- mice. In vivo or Langendorff-perfused mouse hearts underwent 30 min of ischemia followed by 2 h of reperfusion in the presence and absence of postconditioning produced with isoflurane 5 min before ischemia and 3 min after reperfusion. Ca2+-induced mitochondrial permeability transition pore opening was assessed in isolated mitochondria. Echocardiography was used to evaluate ventricular function. Postconditioning with 0.5, 1.0, and 1.5 minimum alveolar concentrations of isoflurane decreased infarct size from 56 ± 10% (n = 10) in control to 48 ± 10%, 41 ± 8% (n = 8, P < 0.05), and 38 ± 10% (n = 8, P < 0.05), respectively and improved cardiac function in wild-type mice. Improvement in cardiac function by IsoPC was blocked by NG-nitro-L-arginine methyl ester (a nonselective NOS inhibitor) administered either prior to ischemia or at the onset of reperfusion. Mitochondria isolated from postconditioned hearts required significantly higher in vitro Ca2+ loading than control (78 ± 29 vs. 40 ± 25 μM CaCl2 mg protein-1, n = 10, P < 0.05) to open the mitochondrial permeability transition pore. Hearts from eNOS-/- mice displayed no marked differences in infarct size, cardiac function, and sensitivity of mitochondrial permeability transition pore to Ca2+, compared to the wild-type hearts. However, IsoPC failed to alter infarct size, cardiac function or the amount of Ca2+ necessary to open the mitochondrial permeability transition pore in mitochondria isolated from the eNOS-/- hearts compared to control hearts. IsoPC protects mouse hearts from reperfusion injury by preventing MPT pore opening in an eNOS-dependent manner. Nitric oxide functions as both a trigger and a mediator of cardioprotection produced by IsoPC.