Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Anesthesiology. 2010 Dec;113(6):1289-98. doi: 10.1097/ALN.0b013e3181f97fec.
Sevoflurane induces preconditioning (SevoPC). The effect of aprotinin and the involvement of endothelial nitric-oxide synthase (NOS) on SevoPC are unknown. We investigated (1) whether SevoPC is strengthened by multiple preconditioning cycles, (2) whether SevoPC is blocked by aprotinin, and (3) whether endothelial NOS plays a crucial role in SevoPC.
Anesthetized male Wistar rats were randomized to 15 groups (each n = 6) and underwent 25-min regional myocardial ischemia and 2-h reperfusion. Controls were not treated further. Preconditioning groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min (SEVO-I), twice for 5 min each (SEVO-II), three times for 5 min each (SEVO-III), or six times for 5 min each (SEVO-VI). Aprotinin was administered with and without sevoflurane. Involvement of endothelial NOS was determined with the nonspecific NOS blocker N-nitro-l-arginine-methyl-ester, the specific neuronal NOS blocker 7-nitroindazole, and the specific inducible NOS blocker aminoguanidine.
SevoPC reduced infarct size in all protocols (SEVO-I, 42 ± 6%; SEVO-II, 33 ± 4%; SEVO-III, 11 ± 5%; SEVO-VI, 16 ± 4%; all P < 0.001 vs. control, 67 ± 3%) and was least after three and six cycles of sevoflurane (P < 0.001 vs. SEVO-II and -I, respectively). Aprotinin alone had no effect on infarct size but blocked SevoPC. N-nitro-l-arginine-methyl-ester abolished SevoPC (67 ± 4%; P < 0.05 vs. SEVO-III). Aminoguanidine and 7-nitroindazole blocked SevoPC only partially (25 ± 6 and 31 ± 6%, respectively; P < 0.05 vs. SEVO-III and control). SevoPC induced endothelial NOS phosphorylation, which was abrogated by aprotinin.
SevoPC is strengthened by multiple preconditioning cycles, and phosphorylation of endothelial NOS is a crucial step in mediating SevoPC. These effects are abolished by aprotinin.
七氟醚可诱导预处理（SevoPC）。关于抑肽酶对 SevoPC 的影响以及内皮型一氧化氮合酶（NOS）的参与情况尚不清楚。我们研究了（1）多次预处理循环是否会增强 SevoPC，（2）SevoPC 是否会被抑肽酶阻断，以及（3）内皮型 NOS 是否在内皮型 NOS 发挥关键作用 SevoPC 中。
麻醉雄性 Wistar 大鼠随机分为 15 组（每组 n = 6），并接受 25 分钟区域心肌缺血和 2 小时再灌注。对照组未进一步治疗。预处理组吸入 1 个最低肺泡浓度的七氟醚 5 分钟（SEVO-I），2 次各 5 分钟（SEVO-II），3 次各 5 分钟（SEVO-III）或 6 次各 5 分钟（SEVO-VI）。七氟醚与抑肽酶联合使用和不联合使用。非特异性 NOS 阻断剂 N-硝基-L-精氨酸甲酯、特异性神经元 NOS 阻断剂 7-硝基吲唑和特异性诱导型 NOS 阻断剂氨基胍确定内皮 NOS 的参与。
所有方案的 SevoPC 均降低了梗死面积（SEVO-I，42 ± 6%；SEVO-II，33 ± 4%；SEVO-III，11 ± 5%；SEVO-VI，16 ± 4%；均 P < 0.001 与对照相比，67 ± 3%），并且在三个和六个七氟醚循环后最少（分别与 SEVO-II 和 -I 相比，P < 0.001）。抑肽酶单独使用对梗死面积没有影响，但可阻断 SevoPC。N-硝基-L-精氨酸甲酯完全阻断 SevoPC（67 ± 4%；P < 0.05 与 SEVO-III 相比）。氨基胍和 7-硝基吲唑仅部分阻断 SevoPC（分别为 25 ± 6%和 31 ± 6%；P < 0.05 与 SEVO-III 和对照相比）。SevoPC 诱导内皮型 NOS 磷酸化，该磷酸化被抑肽酶阻断。
多次预处理循环可增强 SevoPC，内皮型 NOS 的磷酸化是介导 SevoPC 的关键步骤。这些作用被抑肽酶阻断。
