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Study on the Role of Mitochondrial Permeability Transition Pore in Type2Diabetes Mellitus Abrogating Cardioprotective Effects of Sufentanil Postconditioning

Author: WangLiZhen
Tutor: GuErWei
School: Anhui Medical University,
Course: Anesthesiology
Keywords: Diabetes mellitus,type2 sufentanil postconditioning myocardialreperfusion injury mitochondrial permeability transiation pore
CLC: R614
Type: Master's thesis
Year: 2013
Downloads: 14
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Objective Diabetes mellitus has been known as one of factors that to mitigate ischemic or pharmacologic postconditioning in ischemia-reperfusion injuries. Overwhelmingly, type2diabetes mellitus is the most type in the global diabetes population. Sulfentanil is an opioid analgesics that superactivated the μ-receptor specifically, has good hemodynamic stability and also call ensuring adequate myocardial oxygen supplement. Sufentanil is a widely used opioid in cardiac anesthesia that confers a cardioprotective effect against ischemia-reperfusion injury. Studies have showed that pharmacological postconditioning possed cardioprotective effects because of inhibiting the opening of mitochondrial permeability transition pore (mPTP) eventually. The purpose of this study was to evaluate whether type2diabetes mellitus abrogates cardioprotective effects of sufentanil postconditioning in ischemia-reperfused rat heart and to investigate the effect of mPTP.Methods Healthy adult male SD rats were weighing160-180g, which diabetes mellitus model was successfully established by combination of4weeks high-fat diet-fed and low-dose (35mg/kg) streptozotocin-treated. The ischemia reperfuion injury model was induced by30min occlusion of left anterior descending branch of coronary artery (LAD) followed by120min reperfusion. Rats were randomly respectively divided into10groups:non-diabetic sham operation group (NDM-S);non-diabetic ischemia-reperfusion group (NDM-I/R); non-diabetic cyclosporin A group (NDM-CP); and non-diabetic sufentanil postconditioning group (NDM-SP); non-diabetic cyclosporin A plus sufentanil postconditioning group(NDM-SCP); diabetic sham operation group (DM-S); diabetic ischemia-reperfusion group (DM-I/R); diabetic cyclosporin A group (DM-CP); diabetic sufentanil postconditioning group (DM-SP); diabetic cyclosporin A plus sufentanil postconditioning group(DM-SCP). In group-CP,-SP and-SCP, cyclosporin A5mg/kg, sufentanil1μg/kg or cyclosporin A5mg/kg plus sufentanil1μg/kg was injected intravenously at5min before reperfusion respectively while equal volume of normal saline was injected in group I/R. In group-S, rats were received no occlusion or reperfusion. At10min of reperfusion, the hearts of6rats in each group were excised, the myocardial mitochondrial were immediately isolated and the activity of mPTP was assayed by spectrophotometry. MAP and HR were recorded before ischemia (To),30min of ischemia (T1) and120min of reperfusion (T2) and RPP (MAP×HR) was calculated. Arterial blood samples were obtained at120min of reperfusion for determination of the plasma cardiac troponin I (cTnI) concentration. Then the animals were sacrificed for determination of infarct area (IS), area at risk (AAR), and IS/AAR was calculated. Mitochondrial ultrastructure was examined by electron microscopic.Results Characteristic of rats:After one week of administration of a single dose of streptozotocin, diabetic rats had significantly higher levels of plasma glucose than the non-diabetic rats (P<0.05). Body weight and heart weight were lower in the diabetic group than in the non-diabetic group (P<0.05). Hemodynamic parameters:Compared to baseline, the MAP and RPP significantly decreased after ischemia-reperfusion in all groups except NDM-S group and DM-S group (P<0.05). HR levels had no statistic changes between different time points and groups. Myocardial infarct size and cTnI: Compared to their corresponding S group, all groups had higher plasma concentrations of cTnI. In NDM-CP group, NDM-SP group and NDM-SCP group, the IS/ARR and plasma concentrations of cTnI significantly decreased compared with NDM-I/R group (P<0.05).In DM-CP group and DM-SCP group, the IS, IS/ARR and plasma concentrations of cTnI significantly lower compared with DM-I/R group (P<0.05), while there were no significant differences in these variables between the DM-SP group and DM-I/R group(P>0.05). Mitochondrial structure:Mitochondria in the NDM-S and DM-S group were round and hadnumerous transverse cristae with parallel alignment. The outer and inner mitochondrial membranes were clearly distinguishable. Mitochondria from the NDM-I/R and DM-I/R group showed swelling, disruption and loss of cristae. In the NDM-SP, NDM-CP, NDM-SCP, DM-CP, DM-SCP groups, the mitochondrial cristae were slightly disrupted. Mitochondrial swelling, loss of cristae and mitochondrial vesicles were observed in the DM-SP group. The opening of mPTP: Compared to their corresponding S group, all groups had a higher degree of opening of mPTP. Compared with NDM-I/R group, the opening degree was decreased in NDM-CP group, NDM-SP group and NDM-SCP group (P<0.05). Compared with DM-I/R group, mPTP opening was lower in both DM-CP group and DM-SCP group (P<0.05). However, there were no significant differences in the degree of mPTP opening between the DM-SP group and DM-I/R group (P>0.05).Conclusions Sufentanil postconditioning can protect myocardium against I/R injury in nondiabetic rat heart. However, this effect can be abolished by type2diabetes mellitus, which is associated with the opening of mPTP. Our results also suggest that mPTP inhibitor cyclosporine A can protect both diabetic and nondiabetic hearts against I/R injury.

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