Department of Anesthesiology, Fuwai Cardiovascular Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Acta Anaesthesiol Scand. 2013 Sep;57(8):1024-31. doi: 10.1111/aas.12156. Epub 2013 Jul 12.
Sevoflurane post-conditioning (SpostC) protects young hearts against ischemia-reperfusion injury. It is unknown whether the infarct-limiting effect is also maintained in aged cohorts and whether there are age-associated differences in the underlying mechanisms.
Young or old rats were randomly subjected to 30-min myocardial ischemia, followed by 120-min reperfusion in vivo, with or without SpostC in the presence or absence of phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor. Western blotting was used to determine the phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). Myocardial nicotinamide adenine dinucleotide (NAD(+) ) level was measured to indicate mitochondrial permeability transition pore (mPTP) opening.
SpostC significantly decreased infarct size in young (35 ± 4% vs. 56 ± 3%, P < 0.05) but not old rats (45 ± 3% vs. 47 ± 4%, P > 0.05) compared with each control group. SpostC substantially augmented phosphorylation of Akt (0.74 ± 0.03 arbitrary units vs. 0.27 ± 0.03 arbitrary units, P < 0.05) or ERK1/2 (0.85 ± 0.04 arbitrary units vs. 0.29 ± 0.04 arbitrary units, P < 0.05) compared with control group, which was abolished by PI3K or MEK1/2 inhibitor in young rats, respectively, but failed to activate Akt and ERK1/2 in old rats. NAD(+) level (nmol/g tissue) was higher in SpostC group in young (118.57 ± 9.27 vs. 46.78 ± 4.54, P < 0.05) but not old rats (58.50 ± 7.16 vs. 61.15 ± 5.50, P > 0.05) compared with each control group. PI3K or MEK1/2 inhibitor abrogated the infarct-sparing effect and inhibition of loss of NAD(+) induced by SpostC in young rats, respectively.
SpostC-mediated cardioprotection in young rats is not effective in senescent rats, which may at least be the consequence of failure to activate Akt and ERK1/2, and resultant failure to inhibit mPTP opening.
七氟醚后处理（SpostC）可保护年轻的心脏免受缺血再灌注损伤。但尚不清楚这种梗死限制作用是否也能维持在老年群体中，以及在潜在机制中是否存在与年龄相关的差异。
年轻或老年大鼠随机接受 30 分钟心肌缺血，然后在体内进行 120 分钟再灌注，在存在或不存在磷脂酰肌醇 3-激酶（PI3K）或丝裂原活化蛋白激酶激酶 1/2（MEK1/2）抑制剂的情况下，给予或不给予 SpostC。采用 Western blot 法测定蛋白激酶 B（Akt）和细胞外信号调节激酶 1/2（ERK1/2）的磷酸化。测定心肌烟酰胺腺嘌呤二核苷酸（NAD(+)）水平以指示线粒体通透性转换孔（mPTP）开放。
与各自的对照组相比，SpostC 可显著降低年轻大鼠（35±4%比 56±3%，P<0.05）而非老年大鼠（45±3%比 47±4%，P>0.05）的梗死面积。与对照组相比，SpostC 可显著增加 Akt 的磷酸化（0.74±0.03 任意单位比 0.27±0.03 任意单位，P<0.05）或 ERK1/2 的磷酸化（0.85±0.04 任意单位比 0.29±0.04 任意单位，P<0.05），这分别被年轻大鼠中的 PI3K 或 MEK1/2 抑制剂所消除，但未能在老年大鼠中激活 Akt 和 ERK1/2。与各自的对照组相比，SpostC 组的 NAD(+)水平（nmol/g 组织）在年轻大鼠中更高（118.57±9.27 比 46.78±4.54，P<0.05）而非老年大鼠中更低（58.50±7.16 比 61.15±5.50，P>0.05）。PI3K 或 MEK1/2 抑制剂分别消除了 SpostC 诱导的年轻大鼠的梗死保护作用和 NAD(+)丢失抑制作用。
SpostC 介导的年轻大鼠的心脏保护作用在衰老大鼠中无效，这至少是由于未能激活 Akt 和 ERK1/2，以及由此未能抑制 mPTP 开放所致。
