Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism

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.

Deferoxamine Treatment Combined With Sevoflurane Postconditioning Attenuates Myocardial Ischemia-Reperfusion Injury by Restoring HIF-1/BNIP3-Mediated Mitochondrial Autophagy in GK Rats

“…From clinical practice, SPostC is easier to control than ischemic postconditioning and can exert similar myocardial protective effects as ischemic postconditioning Li et al, 2008). Studies have shown that in non-diabetic conditions, SPostC promotes autophagic flux against myocardial ischemia-reperfusion injury through a NO-dependent mechanism, but the effect of SPostC on mitochondrial autophagy and related receptors was not mentioned (Qiao et al, 2019). Zhang et al found that SPostC promoted autophagic flow against myocardial I/RI by reducing the accumulation of autophagosomes, but the role of signaling pathways that mediate autophagy was not discussed further (Zhang et al, 2014b).…”

“…Sevoflurane is an inhaled volatile anaesthetic that is widely used in clinical and basic research due to its pharmacological characteristics such as induction of stability and rapid recovery. Many studies have confirmed that sevoflurane postconditioning (SPostC) can alleviate ischemia-reperfusion injury effectively in healthy myocardium (Yu et al, 2015;Wu et al, 2017b;Qiao et al, 2019). However, in the diabetic state, myocardial protection of SPostC is weakened (Drenger et al, 2011;Tai et al, 2012;Gao et al, 2016), and the specific mechanism remains unclear.…”

Intralipid postconditioning in patients of cardiac surgery undergoing cardiopulmonary bypass (iCPB): study protocol for a randomized controlled trial

“…So even they will provide the trial intervention, but they will not be involved in either the postoperative treatment or the analysis. Secondly, since the inhaled anesthetic sevoflurane is considered to be significantly cardioprotective and the high-dose propofol has also been reported to have a certain myocardial protective effect [ 27 – 29 ], both of which are currently widely used in clinical anesthetics, how to reduce their interference on the results of intralipid postconditioning is of great importance. In our previous pilot study [ 18 , 19 ], all included patients were given total intravenous anesthesia to eliminate the interference of sevoflurane.…”

Intralipid postconditioning in patients of Cardiac surgery undergoing cardioPulmonary Bypass (iCPB): study protocol for a randomized controlled trial

“…Secondly, since the inhaled anesthetic sevoflurane is considered to be significantly cardioprotective and the high-dose propofol has also been reported to have a certain myocardial protective effect [26][27][28], both of which are currently widely used in clinical anesthetics, how to reduce their interference on the results of intralipid postconditioning is of great importance. In our previous pilot study [18,19], all included patients were given total intravenous anesthesia to eliminate the interference of sevoflurane.…”