Gender-Related Difference Of Sevoflurane Postconditioning In Rats: Focus On Phosphatidylinositol-3-kinase/Akt Signalling

Objective:It was revealed that female gender confers cardioprotection against ischemia/reperfusion injury, which may be associated with phosphatidylinositol-3-kinase/AKT (PI3K/AKT) pathway activated by estrogen. Cardioprotection of ischemic postconditioning had been proved to be correlation with gender. In our previous studies, we have proved that myocardial protection by sevoflurane postconditioning was mediated by PI3K/AKT pathway in male rats, but whether females are similarly protected by sevoflurane postconditioning need further research. Thus, we hypothese that sevoflurane postconditioning mediated-induction of PI3K/AKT would also demonstrate sex specificity.Methods:Isolated hearts from 2 month old male and female rats were subjected to ischemia for 40 min and reperfusion for 2 h in the Langendorff preparation. Isolated male or female rat hearts were randomly assigned to the following groups: ischemia/reperfusion (Con), sevoflurane postconditioning (SPC), Con plus 100 nmol/L wortmannin(Con+Wort), SPC+Wort and Con+0.04% dimethylsulphoxide (DMSO). Postconditioning was performed with administration of 3% sevoflurane at the first 10 mins of reperfusion. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), heart rate(HR), and lactate dehydrogenase (LDH) were measured. Infarct size were detected by riphenyltetrazolium chloride staining (TTC). Western blot analysis was used to determine total AKT (t-AKT), phosphorylated AKT (p-AKT) and P-actin.Results:The female CON group showed higher LVDP and lower LVEDP than the male CON group after reperfusion 30,60,90 and 120 min, the LDH release and infarct size were smaller in the female CON group (P<0.05). Sevoflurane postconditioning selectively improved LV function and decreased LDH, infarct size in the male SPC group(P<0.05) but not in the female SPC group, as compared with corresponding CON group in the same gender. HR was at the same level in all groups. Wortmannin abolished the cardioprotection of sevoflurane postconditioning in the male SPC+Wort group compared with the male SPC group(P<0.05). But in the female rats, wortmannin damage the LV function and increased LDH, infarct size in Con+Wort(or SPC+Wort) group as related to CON(or SPC) group. The t-AKT andβ-actin protein expression was at the same level in all groups, the trend of p-Akt expression was higher in male SPC group than male CON group (P<0.05). The level of p-Akt in female CON and SPC group was similar, but they both showed higher level than the male CON group (P<0.05). Wortmannin decreased the activated p-AKT in male SPC+Wort group, female Con+Wort and SPC+Wort group. DMSO had no extra effect on cardiac function as compared with corresponding CON group. Conclusion:We found that female rat hearts showed greater resistance to ischemia, sevoflurane postconditioning developed cardioprotection in male rats but not in female rats. The PI3K/AKT pathway was involved in mechanism of the twogenders.