Department of Pharmacology and Laboratory of Cerebrovascular and Cardiovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
Institute of Clinical Medicine Research, the Affiliated Suzhou Hospital of Nanjing Medical University; Suzhou Science and Technology Town Hospital, Suzhou, 215153, China.
Acta Pharmacol Sin. 2019 Jan;40(1):35-45. doi: 10.1038/s41401-018-0066-y. Epub 2018 Jul 12.
Volatile anesthetics improve postischemic cardiac function and reduce infarction even when administered for only a brief time at the onset of reperfusion. A recent study showed that sevoflurane postconditioning (SPC) attenuated myocardial reperfusion injury, but the underlying mechanisms remain unclear. In this study, we examined the effects of sevoflurane on nitric oxide (NO) release and autophagic flux during the myocardial ischemia/reperfusion (I/R) injury in rats in vivo and ex vivo. Male rats were subjected to 30 min ischemia and 2 h reperfusion in the presence or absence of sevoflurane (1.0 minimum alveolar concentration) during the first 15 min of reperfusion. We found that SPC significantly improved hemodynamic performance after reperfusion, alleviated postischemic myocardial infarction, reduced nicotinamide adenine dinucleotide content loss, and cytochrome c release in heart tissues. Furthermore, SPC significantly increased the phosphorylation of endothelial nitric oxide synthase (NOS) and neuronal nitric oxide synthase, and elevated myocardial NOS activity and NO production. All these effects were abolished by treatment with an NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.). We also observed myocardial I/R-induced accumulation of autophagosomes in heart tissues, as evidenced by increased ratios of microtubule-associated protein 1 light chain 3 II/I, up-regulation of Beclin 1 and P62, and reduced lysosome-associated membrane protein-2 expression. SPC significantly attenuated I/R-impaired autophagic flux, which were blocked by L-NAME. Moreover, pretreatment with the autophagic flux blocker chloroquine (10 mg/kg, i.p.) increased autophagosome accumulation in SPC-treated heart following I/R and blocked SPC-induced cardioprotection. The same results were also observed in a rat model of myocardial I/R injury ex vivo, suggesting that SPC protects rat hearts against myocardial reperfusion injury by restoring I/R-impaired autophagic flux via an NO-dependent mechanism.
挥发性麻醉剂可改善缺血后心脏功能并减少梗死，即使在再灌注开始时仅短暂给予。最近的一项研究表明，七氟醚后处理（SPC）可减轻心肌再灌注损伤，但潜在机制尚不清楚。在这项研究中，我们在体内和离体研究了七氟醚对大鼠缺血/再灌注（I/R）损伤期间一氧化氮（NO）释放和自噬流的影响。雄性大鼠在缺血 30 分钟和再灌注 2 小时期间，在再灌注的前 15 分钟内存在或不存在七氟醚（1.0 最低肺泡浓度）。我们发现 SPC 可显著改善再灌注后的血流动力学性能，减轻缺血后心肌梗死，减少烟酰胺腺嘌呤二核苷酸含量损失和细胞色素 c 在心脏组织中的释放。此外，SPC 可显著增加内皮型一氧化氮合酶（NOS）和神经元型 NOS 的磷酸化，并升高心肌 NOS 活性和 NO 生成。所有这些作用均被一氧化氮合酶抑制剂 NG-硝基-L-精氨酸甲酯（L-NAME，10mg/kg，iv）的治疗所消除。我们还观察到心肌 I/R 导致心脏组织中自噬体的积累，这表现为微管相关蛋白 1 轻链 3 II/I 的比值增加，Beclin 1 和 P62 的上调以及溶酶体相关膜蛋白-2 表达减少。SPC 可显著减轻 I/R 受损的自噬流，而 L-NAME 可阻断该作用。此外，自噬流阻断剂氯喹（10mg/kg，ip）的预处理会增加 SPC 处理后的心脏在 I/R 后的自噬体积累，并阻断 SPC 诱导的心脏保护作用。在离体大鼠心肌 I/R 损伤模型中也观察到了相同的结果，表明 SPC 通过恢复 I/R 受损的自噬流来保护大鼠心脏免受心肌再灌注损伤，这是通过 NO 依赖性机制实现的。
