奥美沙坦对肥胖大鼠肝脏甘油三酯代谢的影响

Effects of angiotensin H type 1 receptor blocker on triglyceride metabolism in the liver： experiment with Zucker fatty rats

目的观察血管紧张素Ⅱ受体拮抗剂奥美沙坦对胰岛素抵抗的Zucker肥胖大鼠（ZF鼠）肝脏甘油三酯（TG）代谢的影响。方法8周龄ZF鼠（22只）及其对照（ZL鼠，12只）分别给予含0．01％奥美沙坦饮用水治疗4周。结果奥美沙坦在两组大鼠均明显降低了血压。ZF鼠的胰岛素敏感性指数[SI，（0．31±0．22）μU·ml^-1·min^-1·10^-4vs（3．54±0．30）μU·ml^-1·min^-1·10^-4，P〈0．01）]和葡萄糖效应[（SG，（1．35±0．51）min^-1·10^-2vs（3．40±0．14）min^-1·10^-2，P〈0．01）较ZL鼠明显减低，而血糖水平明显升高[（11．4±2．6）mmol／Lvs（9．2±0．6）mmol／L，P〈0．01]，奥美沙坦治疗后SI和SG明显改善。ZF鼠血TG浓度为ZL鼠的6倍，奥美沙坦治疗明显降低了ZF鼠的血游离脂肪酸水平[治疗前2．70±0．69mmol／Lvs治疗后（1．98±0．43）mmol／L，P〈0．01]，但对血TG水平无明显影响（P〉0．05）。奥美沙坦使zF鼠肝甘油三酯分泌率（TGSR）下降了50％[（0．56±0．08）mg·min^-1·100g^-1vs（0．30±0．07）mg·min^-1·100g^-1P〈0．01]。奥美沙坦治疗后（12．8±1．7）mg／s，肝脏甘油三酯含量比治疗前[（22．7±4．2）mg／g明显降低，P〈0．01）]，而肝胆固醇含量不受影响。奥美沙坦治疗后ZF鼠肝细胞脂滴沉积明显得到改善。结论奥美沙坦对肥胖大鼠肝脏甘油三酯的产生和积累有明显的抑制作用；这一作用不依赖于药物的降压效应。

Objective To investigate the effects of angiotensin receptor blocker （ARB） on triglyceride （TG） metabolism and mechanism thereof. Methods Zucker fatty （ZF） rats and Zucker lean （ZL） rats were fed with water containing 0.01% olmesartan medoxiomil, a highly specific ARB for 4 weeks. Frequently sampled intravenous glucose tolerance test was conducted to calculate the area under the glucose （AUCG）, insulin sensitivity index （SI）, glucose effectiveness （SG）, Blood glucose, TC, TG, nonesterified fatty acid （NEFA）, and HDL-C were measured with standard assay kit. Triton WR-1339 technique was used to detect the TG secretion rate （TGSR）. After TGSR and FS-IVGTT the levers were collected. The total cholesterol （TC） of the liver was detected, and Sudan Ⅳ staining was used to detect the triglyceride in the liver. Enzymatic method was used to measure the TG and TC in the liver extract. Results The blood pressure of both groups was lowered in both strains to the same extent after olmesartan taking. The SI value of the ZF rats was （0.31 ± 0.22 ）μU·ml^-1·min^-1·10^-4 significantly lower than that of the ZL rats （3.54 ± 0.30 ）μU·ml^-1·min^-1·10^-4 p 〈 0.01 ）. Bergman＇s minimal model showed that the SG value of the ZF rats was （1.35±0.51 ） min^-1· 10^-2, significantly lower than that of the ZL rats （3.40 ± 0.14 min^-1· 10^-2, P 〈0.01）. The plasma glucose levels of the ZF rats was（ 11.4 ±2.6） mmol/L, significantly higher than hat of the L rats [ （9.2 ±0. 6） retool/L, P 〈 0. 01 ]. Olmesartan treatment substantially elevated both the baseline SI and SG levels of the ZF rats. The TG of the ZF rats was 6 times as high as that of the ZL rats. The plasma NEFA level after olmesartan treatment of the ZF rats was Olmesartan treatment, significantly lower than that before treatment [ （2.70±0.69） mEq/L, P 〈0.01 ], however, the plasma TG level of the ZF rats after the treatment was not significantly different from that before treatment （P 〉 0.05）. The TGSR rate of the ZF rats was almost 6 times that of the ZL rats. Olmesartan treatment lowered the TG overproduction by half （0. 56 ± 0.08） mg·min^-1· 100 g^-1 BW vs（ 0. 30 ± 0.07 ）mg·min^-1· 100 g^-1 BW, （P〈0.01）. The liver TG content of the ZF rats was 10 times that of the ZL rats. Olmesartan treatment lowered the liver TG content from （22.7 ±4.2） mg/g to （ 12.8 ± 1.7） mg/g （P 〈0.01 ） without affecting the cholesterol content. Pathology showed that the fatty liver developed in the ZF rats was significantly ameliorated by olmesartan treatment. Olmesartan treatment had no significant effect on TG metabolism or insulin sensitivity in the ZL rats. Conclusion ARB improves the overproduction and accumulation of TG in the liver associated with insulin resistance, and does so through mechanisms independent of its hypotensive action.