CAJ | 학술논문

目的:探讨二甲双胍(MET)对高血压大鼠心肌肥厚的影响及其机制.方法:制作腹主动脉缩窄(TAC)大鼠高血压心肌肥厚模型,术后1周随机分为5组(每组8只),灌胃给药8周:sham组:假手术,予蒸馏水2 mL;TAC组:TAC大鼠,予蒸馏水2 mL;MET组:TAC大鼠,予MET 300 mg·kg~(-1)·d~(-1);MN组:TAC大鼠,同时给予MET 300 mg·kg~(-1)·d~(-1)和NG-硝基-L-精氨酸甲酯(L-NAME,NOS抑制剂)50 mg·kg~(-1)·d~(-1);NAME组:TAC大鼠,予L-NAME50 mg·kg~(-1)·d~(-1).处理8周后测定超声心动图、血流动力学、心肌组织学、心肌AMP 激活的蛋白激酶(AMPK)及内皮型一氧化氮合酶(eNOS)的水平及活性.结果:处理8周后,TAC组大鼠左心室室壁厚度、心脏重量/体重(HW/BW)以及左心室心肌血管周围纤维化及心肌间质纤维化程度较sham组显著升高,给予MET 300 mg·kg~(-1)·d~(-1) 8周后,左心室肥厚及心肌纤维化显著减轻,心肌收缩及舒张功能改善(P＜0.05).同时给予NOS抑制剂L-NAME则显著抑制MET上述效应.MET组大鼠左心室心肌p-AMPKα~(Thr172)和 p-eNOS~(Ser1177)水平以及心肌及血清一氧化氮水平较TAC组显著升高.结论:长期给予MET治疗,显著抑制压力负荷高血压大鼠心肌肥厚及心肌纤维化程度,同时心功能改善.其机制可能与MET激活AMPK-eNOS信号通路有关.
목적:탐토이갑쌍고(MET)대고혈압대서심기비후적영향급기궤제.방법:제작복주동맥축착(TAC)대서고혈압심기비후모형,술후1주수궤분위5조(매조8지),관위급약8주:sham조:가수술,여증류수2 mL;TAC조:TAC대서,여증류수2 mL;MET조:TAC대서,여MET 300 mg·kg~(-1)·d~(-1);MN조:TAC대서,동시급여MET 300 mg·kg~(-1)·d~(-1)화NG-초기-L-정안산갑지(L-NAME,NOS억제제)50 mg·kg~(-1)·d~(-1);NAME조:TAC대서,여L-NAME50 mg·kg~(-1)·d~(-1).처리8주후측정초성심동도、혈류동역학、심기조직학、심기AMP 격활적단백격매(AMPK)급내피형일양화담합매(eNOS)적수평급활성.결과:처리8주후,TAC조대서좌심실실벽후도、심장중량/체중(HW/BW)이급좌심실심기혈관주위섬유화급심기간질섬유화정도교sham조현저승고,급여MET 300 mg·kg~(-1)·d~(-1) 8주후,좌심실비후급심기섬유화현저감경,심기수축급서장공능개선(P＜0.05).동시급여NOS억제제L-NAME칙현저억제MET상술효응.MET조대서좌심실심기p-AMPKα~(Thr172)화 p-eNOS~(Ser1177)수평이급심기급혈청일양화담수평교TAC조현저승고.결론:장기급여MET치료,현저억제압력부하고혈압대서심기비후급심기섬유화정도,동시심공능개선.기궤제가능여MET격활AMPK-eNOS신호통로유관.
AIM: To study the effects of metformin on the pressure overload-induced cardiac hypertrophy in rats. METHODS: Transverse aortic constriction (TAC) model of rat was made through laparotomy. One week after TAC surgery, the rats were randomly divided into 5 groups (n=8 in each group) and were administered with the corresponding drugs orally every day for 8 weeks: sham group (sham surgery, administered with 2 mL distilled water);TAC group (TAC rats, administered with 2 mL distilled water);metformin(MET) group (TAC rats, administered with MET at dose of 300 mg·kg~(-1)·d~(-1));MN group [TAC rats, administered with MET at dose of 300 mg·kg~(-1)·d~(-1) plus NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) 50 mg·kg~(-1)·d~(-1)] and L-NAME group (TAC rats, administered with L-NAME at dose of 50 mg·kg~(-1)·d~(-1)). After treated for 8 weeks, the echocardiography, hemodynamics, the ratio of heart weight to body weight (HW/BW) and histological examination of the heart were performed. The levels of myocardial AMP-activated protein kinase subunit α (AMPKα), p-AMPKα~(Thr172), endothelial nitric oxide synthase (eNOS) and p-eNOS~(Ser1177) were detected by Western blotting. Plasma and myocardial nitric oxide (NO) were detected biochemically. RESULTS: After 8 weeks treatment, the wall thickness of left ventricle, the heart weight/body weight ratio (HW/BW), and the left ventricular myocardial perivascular fibrosis and myocardial interstitial fibrosis of the animals in TAC group were significantly increased as compared to those in sham rats. Treatment with MET for 8 weeks significantly attenuated left ventricular hypertrophy and improved cardiac function in TAC rats. These effects of MET were mostly abolished by L-NAME. Molecular biology and biochemical testing revealed that the levels of left ventricular myocardial p-AMPKα~(Thr172) and p-eNOS~(Ser1177), as well as the levels of myocardial and serum NO were significantly increased in MET group. CONCLUSION: Long-term MET treatment significantly inhibits the cardiac hypertrophy and the myocardial fibrosis and improves the cardiac functions in pressure-overload rats. The anti-hypertrophic effects of MET may be mediated via activation of AMPK-eNOS signaling pathway.