芬太尼对2型糖尿病大鼠心脏的保护作用及对蛋白激酶D和内质网应激激活的调节作用

Fentanyl protects heart of type 2 diabetic rats and regulates protein kinase D and endoplasmic reticulum stress activation

目的:探讨芬太尼对2型糖尿病(T2D)大鼠心脏的作用及其及对蛋白激酶D和内质网应激激活的调节作用。方法:采用腹腔注射链脲佐菌素及高糖高脂饮食构建T2D大鼠模型;给药组每天注射0.5、1.0、2.0μg/kg的芬太尼,阳性药物对照组大鼠每天灌胃给予75 mg/kg二甲双胍,对照组和模型组分别注射等量生理盐水,连续2周。全自动化学分析仪检测血样中血糖(FBG)、总胆固醇(TG)、三酰甘油(TC)含量,MRBP鼠无创血压计测量心率(HR)、收缩压(SBP)和舒张压(DBP),HE染色观察心脏损伤,流式细胞术检测心肌细胞凋亡情况,Western blot检测心肌细胞中Bax、Bcl-2、Cleaved caspase-3、PKD和GRP78蛋白表达情况,ELISA检测血样中胰岛素(FINS)、IL-6、TNF-α、IL-10、IL-1β含量和心肌细胞中cTnⅠ和CK-MB含量。结果:高剂量芬太尼能够明显降低T2D模型大鼠血液中FBG、TG、TC和FINS含量(P<0.01),明显降低HR(P<0.05),减轻心肌损伤,降低心肌细胞凋亡率、心肌细胞中CK-MB和cTnⅠ含量、Bax/Bcl-2、Cleaved caspase-3蛋白表达、磷酸化PKD和GRP78蛋白表达及血液中炎症因子IL-6、TNF-α、IL-10、IL-1β含量(P<0.01)。结论:芬太尼对T2D大鼠心脏具有保护作用,同时抑制蛋白激酶D和内质网应激激活。

Objective:To investigate the effects of fentanyl on the heart of type 2 diabetic(T2D)rats and its regulation of protein kinase D and endoplasmic reticulum stress activation.Methods:A rat model of T2D was established by intraperitoneal injection of streptozotocin and a high-sugar,high-fat diet.Drug-administered group was injected with 0.5,1.0,2.0μg/kg of fentanyl daily,and positive drug control group was intragastrically administered with 75 mg/kg metformin per day.Control group and model group were injected with the same amount of normal saline,for 2 consecutive weeks.Content of fasting plasma glucose(FBG),total cholesterol(TG)and triglycerides(TC)in blood were detected by a fully automatic chemical analyzer.Measurement of heart rate(HR),systolic blood pressure(SBP),diastolicblood pressure(DBP)in rats by MRBP mouse non-invasive sphygmomanometer.Heart damage was observed by HE staining,Cardiomyocyte apoptosis was detected by flow,expression of Bax,Bcl-2,Cleaved caspase-3,PKD and GRP78 protein in cardiomyocytes was detected by Western blot.Contents of FINS,IL-6,TNF-α,IL-10,IL-1β,cTnⅠand CK-MB were detected by ELISA.Results:High-dose fentanyl has significantly reduced levels of FBG,TG,TC and FINS in blood of T2D rats(P<0.01),significantly reduced HR(P<0.05),decreased myocardial damage,apoptosis rate of cardiomyocytes,reduced levels of CK-MD and cTnⅠ,expression of Bax/Bcl-2 and Cleaved caspase-3,expression of phosphorylated PKD and GRP78 protein in cardiomyocytes and levels of inflammatory factors IL-6,TNF-α,IL-10 and IL-1βin blood(P<0.01).Conclusion:Fentanyl has a protective effect on the heart of T2D rats,while inhibiting protein kinase D and endoplasmic reticulum stress activation.