Abstract
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.
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Acknowledgements
This work was supported by grants SS201613 (to Dr. Wang) and SS201756 (to Dr. An) from the Suzhou Science and Technology Development Plan; BK20141187 (to Dr. Wang) from the Jiangsu Natural Science Foundation; SYS201473 (to Dr. Qiao) from the Suzhou Science and Technology Development Plan; NSFC 81703501 (to Dr. Qiao) from the National Natural Science Foundation of China; and QNRC2016219 (to Dr. Qiao) from Jiangsu Key Talent Youth Awards in Medicine.
Author contributions
S-gQ, YS, and BS conceived and designed the experiments; H-lZ, J-zA, and CW conducted the experiments; S-gQ, YS, BS, AW, JQ, and LH were involved in the interpretation of the studies, analysis of the data and review of the manuscript; S-gQ, H-lZ, and CW wrote the paper.
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Qiao, Sg., Sun, Y., Sun, B. et al. Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism. Acta Pharmacol Sin 40, 35–45 (2019). https://doi.org/10.1038/s41401-018-0066-y
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DOI: https://doi.org/10.1038/s41401-018-0066-y
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