硫化氢在大鼠阿霉素心肌病发病中的意义  

The role of hydrogen sulfide in adriamycin-induced dilated cardiomyopathy in rats

作　　者：梁银芳[1] 韩薇[1] 唐朝枢[2] 杜军保[1] 

机构地区：[1]北京大学第一医院儿科,北京100034 [2]北京大学第一医院心血管病研究所,北京100034

出　　处：《中国药理学通报》2007年第9期1160-1166,共7页Chinese Pharmacological Bulletin

基　　金：国家重点基础研究发展规划(973规划)资助项目(No2006CB503807);国家自然科学基金重点资助项目(No30630031);国家杰出青年科学基金资助项目(No30425010)

摘　　要：目的探讨新型气体信号分子硫化氢(hydrogen sul-fide,H2S)对阿霉素(adriamycin,ADR)心肌病大鼠心肌细胞凋亡的影响。方法♂性Wistar大鼠66只,随机分为6组①阿霉素组(ADR组,n=12):腹腔注射ADR,每次2.5mg.kg-1,1次/周,共用药10wk;②ADR+小剂量NaHS组(n=12):ADR用药方法同ADR组,同时经腹腔注射H2S供体NaHS,2.8μmol.kg-1.d-1,连续用药10wk;③ADR+大剂量NaHS组(n=12):ADR用药方法同ADR组,同时经腹腔注射NaHS,14μmol.kg-1.d-1,连续用药10wk;④ADR+PPG组(12只):ADR用药方法同ADR组,同时经腹腔注射PPG30mg.kg-1.d-1,连续用药10wk;⑤对照组(n=9):用相同容量的生理盐水代替ADR,给药方法同ADR组;⑥NaHS组(n=9):经腹腔注射NaHS,14μmol.kg-1.d-1,连续用药10wk。于第10周检测大鼠心功能和血流动力学指标,处死大鼠,取心肌组织制作病理切片,分别于光镜及透射电镜下观察其显微以及超微结构,用TdT介导dUTP缺口末端标记法(TUNEL)方法检测心肌细胞凋亡及用免疫组化测定心肌细胞中Fas和Bcl-2蛋白的表达,同时用敏感硫电极法测定血浆及心肌组织里的H2S含量。结果阿霉素组大鼠左室内压最大上升速率(+dp/dtmax)及左室内压最大下降速率(-dp/dtmax)明显降低(P均<0.01),心肌病理结果显示阿霉素组心肌细胞变性、线粒体和肌浆网水肿、细胞内空泡增多,呈心肌病样改变;心肌细胞凋亡数明显增加,心肌细胞中的Fas蛋白表达明显增加,Bcl-2蛋白的表达明显降低(P均<0.01);同时大鼠血浆及心肌组织H2S含量均明显低于对照组(P<0.01)。经外源性补充H2S供体NaHS后,大鼠心功能较前明显改善,光镜及电镜显示ADR+小剂量NaHS组及ADR+大剂量NaHS组心肌组织病理损害程度明显较阿霉素组减轻;心肌细胞凋亡率明显降低,Fas蛋白表达明显降低,Bcl-2蛋白表达明显增加(P均<0.01)。ADR+PPG组与ADR组相比较,差异无显著性,NaHS组和对照组相比较,差异无显著性(P>0.05)。结论H2S参与大鼠阿霉素心Aim To investigate the effect of hydrogen sulfide（H2S） on apoptosis of myocardial tissues of adriamycin-induced dilated cardiomyopathy in rats and to explore the underlying mechanisms.Methods Weight-matched male Wistar rats were randomly divided into 5 groups as follows：（1） ADR group（n=12）,2.5 mg·kg^-1 of adriamycin was injected intraperitoneally once a week for 10 weeks（total dose of 25 mg·kg^-1）;（2） ADR＋small-dose-NaHS group（n=12）,the dosage and use of adriamycin were as mentioned above,while NaHS solution was injected to rats at a dosage of 2.8 μmol·kg-1·d-1 at the same time;（3） ADR＋large-dose-NaHS group（n=12）,the dosage and use of adriamycin were as mentioned above,while NaHS solution was injected to rats at a dosage of 14 μmol·kg-1·d-1 at the same time;（4） ADR＋PPG group（n=12）,in which the dosage and use of adriamycin were as mentioned above,while PPG solution was injected to rats at a dosage of 30 mg·kg^-1d-1;（5） control group（n=9）,an equivalent volume of physiological saline was administered weekly for 10 weeks.（6） NaHS group（n= 9）,14 μmol·kg-1 of NaHS solution was injected to rats intraperitoneally for 10 weeks.Hemodynamic and echocardiographic measurements were obtained 10 weeks after treatment.Histological examination was implemented at the 10th week after sacrificed.And apoptotic index,Fas and Bcl-2 expressions in myocardiocytes were analyzed semiquantitatively by TUNEL or immunohistochemical analysis.Meanwhile,H2S concentrations in serum and myocardial tissues were evaluated by a modified sulfide electrode-based method.Results Left ventricular systolic pressure（LVSP）,difference of left ventricular pressure（△LVP=left ventricular systolic pressure minus left ventricular diastolic pressure） and ventricular peak rate of contraction（＋LV dp/dtmax）,peak rate of relaxation（-LV dp/dtmax） were significantly reduced in the group of ADR rats（P〈0.01）.Left ventricular diastolic pressure（LVDP）,the ratio of LVW/BW

关 键 词：硫化氢 硫氢化钠 阿霉素心肌病 FAS BCL-2 TUNEL 

分 类 号：R-332[医药卫生] R329.24