普罗布考和阿托伐他汀联合用药对高脂饮食自发性高血压大鼠肝脏的影响

The Hepatic Effects of Combination Therapy of Probucol and Atorvastatin in Spontaneously Hypertensive Rats with High Lipids Diet

目的对普罗布考和阿托伐他汀联合用药对肝脏的安全性进行评价。方法将92只雄性自发性高血压大鼠随机分为5组,对照组:普通饲料+生理盐水;高脂组:高脂饲料+生理盐水;普罗布考组:高脂饲料+普罗布考150mg/(kg·d);阿托伐他汀组:高脂饲料+阿托伐他汀10mg/(kg·d);联合用药组:高脂饲料+阿托伐他汀10mg/(kg·d)+普罗布考150mg/(kg·d),实验8周后处死。实验结束时抽血测血脂、高敏C-反应蛋白和肝功能,留肝脏标本行病理切片观察其脂肪变性及炎症程度。结果①高脂饮食各组总胆固醇和低密度脂蛋白胆固醇均高于对照组(P<0.01),而二药合用组较普罗布考组、阿托伐他汀组明显降低(P<0.05);②高脂组血清高敏C-反应蛋白、丙氨酸氨基转移酶和天门冬氨酸氨基转移酶水平较对照组明显升高(P<0.01),二药合用组明显低于高脂组和阿托伐他汀组(P<0.01);③高脂饮食各组均发生肝脏脂肪变性,高脂组最重,二药合用组较普罗布考组和阿托伐他汀组明显减轻(P<0.05);④肝脏炎性活动度评分二药合用组明显低于高脂组、阿托伐他汀组(P<0.01)。结论①高脂饮食可引起血脂、炎症因子的紊乱,并可导致肝功能的损害和肝细胞脂肪变性及坏死;②普罗布考联合阿托伐他汀可减轻血脂和炎症因子的紊乱以及肝脏的脂肪变性和坏死程度,较二者单独用药效果更好;③二者联合用药可明显减轻高脂饮食引起的肝功能损害,且可减轻阿托伐他汀的肝毒性。

Aim To evaluate the hepatic security of combination therapy of probucol and atorvastatin. Methods 92 spontaneously hypertensive rats were randomized into 5 groups： control group fed with normal diet, High lipids group, atorvastatin group, probucol group and combination therapy group all fed with high lipids diet. At the same time, probucol group [ probucol 150 mg/（kg· d） ], atorvastatin group [ atorvastatin 10 mg/（ kg ·d） ], and combination therapy group [ probucol plus atorvastatin ] were administrated drugs. After 8 weeks, all rats were killed. Serum TC, TG, LDLC, hs-CRP and ALT, AST levels were measured after experiment. At last liver pathological sections were observed on fatty degeneration and inflammation degree. Above indexes were compared inter-groups. Results①Serum TC and LDL-C levels in every groups with high lipids diet were higher than control group （ P 〈 0.01 ）. Combination therapy group were obviously lower than probucol group （ P 〈 0.01 ） and atorvastatin group（ P 〈 0.01）. ② Serum hs-CRP, ALT and AST levels in high lipids group were obviously higher than control group （ P 〈 0.01 ） , and combination therapy group were obviously lower than high lipids group and atorvastatin group（ P 〈 0.01 ）. ③ Every group with high lipids diet had fatty degeneration, and the degrees of fatty degeneration in high lipids group were severe, yet in combination therapy group were better than atorvastatin group and probucol group （ P 〈 0.05 ）.④The scores of inflammation degree in combination therapy group were lower than high lipids group and atorvastatin group （ P 〈 0. 01 ）. Conclusion ① High lipids diet may lead to the disorder of serum lipids and inflammatory factors, the damage of hepatic function, even hepatocyte fatty degeneration and necrosis. ② Combination therapy of probueol and atorvastatin may lighten the disorder of serum lipids and inflammatory factors, and decrease obvious hepatoeyte fatty degeneration and necrosis degree caused by high lipids diet, and the effects were better than that of monotherapy. ③ Combination therapy may decrease obviously the damage of hepatic function caused by high lipids diet, even reduce the hepatic negative effects of atorvastatin.