| Objective For good hemodynamic stability and high specificity to excite opioid receptors which brings about great abirritation, sufentanil is a kind of widely used opioid in cardiac sugeries.According to researches, Preconditioning as well as postconditioning of sufentanil confer cardioprotective effects indeed. Both type1and type2diabetic mellitus abolish cardioprotective effects of sufentanil postconditioning with the exact mechanisms remains unclear:some scholars hold that this cancellation might connect with weakening of glycogen synthase kinase3β(GSK-3β) phosphorylation expression,however,others predicted histone acetylation-GSK-3β related regulatory pathways of epigenetics should be an important pharmacotherapy target to restore the cardioprotection once abrogated by factors of diabetic mellitus.In the case that type2diabetic mellitus possesses great guiding significance, for it shares the majority of our clinicals,we tended to discuss the effects of suberoylanilide hydroxamic acid(S AHA, as a histone deacetylase inhibitor) on the facs that type2diabetes mellitus abrogating cardioprotective effects of sufentanil postconditioning and tried to explain it in the point of epigenetics.Methods Male SD rats were included, with initial weeks between5to6as well as original weight ranged from160to180gram. The NDM group received normal diet and intraperitoneal injection of sodium citrate while Type2diabetic rat models were established with combination of high-fat diet and low-dose streptozotocin treatment. The rats of both types succeeded in going through the schedule described above were divided into6groups respectively using random number table method:non-diabetic sham-operated group (group NDM-S); non-diabetic ischemia-reperfusion group (group NDM-I/R); non-diabetic sufentanil postconditioning group(group NDM-SP); non-diabetic suberoylanilide hydroxamic acid plus sufentanil postconditioning group (group NDM-SASP); non-diabetic DMSO plus sufentanil postconditioning group (group NDM-DSSP); non-diabetic suberoylanilide hydroxamic acid group(group NDM-SA); diabetic sham-operated group(group DM-S); diabetic ischemia-reperfusion group (group DM-I/R); diabetic sufentanil postconditioning group(group DM-SP); diabetic suberoylanilide hydroxamic acid plus sufentanil postconditioning group (group DM-SASP); diabetic DMSO plus sufentanil postconditioning group (group DM-DSSP); diabetic suberoylanilide hydroxamic acid group (group DM-SA). We adopted the way of threading below left anterior descending coronary artery to achieve the ischemia reperfusion heart model, including30mins of balance,30mins of ischemia and120mins of reperfusion.In group-S, rats received neither occlusion nor reperfusion. The sufentanil-intervened groups received sufentanil1μg/kg through the right jugular vein5mins before reperfusion while the SAHA-intervened and the DMSO-intervened were subjected to intraperitoneal injection of SAHA0.2mg/kg or same volume of DMSO for5days befor sugeries respectively,twice per day. Hemodynamic indexes such as ECG,HR,SBP,MAP were monitored during the sugery and records of indexes mentioned above were noted30mins of balance(To),30mins of ischemia(T1)and120mins of reperfusion(T2).After1ml blood samples collected for determination of plasma cTnI concentration at the end of reperfusion from right jugular artery, rats were then executed for measurement of IS, AAR and IS/AAR.4extra rats were randomly chosen from group-I/R, group-SA, group-SASP and group-SP from both types repectively.Myocardial apex tissue sample were collected five mins after reperfusion, expression of GSK-3β as well as p-GSK-3β were then assessed by Western blot.Results Characteristic of rats:After one week of injection of a single dose of streptozotocin, diabetic rats had dramatically higher levels of plasma glucose than that of non-diabetic rats (P<0.05). Body weight before surgery were lower in diabetic group than in the other (P<0.05). Hemodynamic parameters:Compared to MAP and RPP of monment To, both indexes significantly decreased after ischemia-reperfusion in all groups except for group NDM-S and group DM-S(P<0.05).Versus with the corresponding group-S,the MAP and RPP experienced falling down in the rest5groups (P<0.05).The HR levels were higher in NDM groups than that in DM groups (P<0.05).Myocardial infarct size and cTnl:In group NDM-SP, group NDM-SASP and group NDM-DSSP, the IS/ARR and plasma concentrations of cTnI significantly decreased compared with group NDM-I/R (P<0.05). In group DM-SASP, the IS, IS/ARR and plasma concentrations of cTnI significantly lower compared with group DM-I/R (P<0.05). Compared to their corresponding group of NDM, group DM-SP and DM-DSSP had higher levels of IS/AAR as well as plasma concentrations of cTnI (P<0.05). GSK-3β western blot analysis:The total GSK-3β levels did not vary among we studied above (P>05). Group NDM-SP and NDM-SASP had higher P-GSK-3β protein levels (p-GSK-3β/GSK-3β), compared with the group NDM-IR (P<0.05); p-GSK-3β protein levels was higher in DM-SASP group than in DM-IR group (P<0.05). Compared with group NDM-SP, p-GSK-3β protein levels significantly increased in group DM-SP (P<0.05).Conclusions SAHA could reverse the cardioprotective effects of sufentanil postconditioning which were cancelled due to type2diabetes mellitus factor, there might exist links between the mechanism of this cancellation and modification of histone deacetylases,which might be associated with GSK-3β. |
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