Objective: To investigate the inhibitory effect of Zhenwu Decoction on ventricular hypertrophy in rats with uremic cardiomyopathy and explore the mechanism.
Methods: Cardiocytes isolated from suckling rats were divided into control group and indoxyl sulfate (IS) group, and the protein synthesis was assayed with [3H]- leucine incorporation and cellular protein expressions were detected using Western blotting. Fifty SD rats were randomly divided into sham operation group, model group, and low- and high-dose Zhenwu Decoction treatment groups, and except for those in the sham operation group, all the rats underwent 5/6 nephrectomy. Four weeks after the operation, the rats in low- and high-dose treatment groups were given Zhenwu Decoction via gavage at the dose of 4.5 g/kg and 13.5 g/kg, respectively; the rats in the sham-operated and model groups were given an equal volume of distilled water. After 4 weeks of treatment, serum levels of IS were determined, and cardiac and ventricular mass indexes were measured in the rats; cardiac ultrasound was performed and Western blotting was used to measure the expressions of BNP, p-ERK1/2, p-p38 and p-JNK in the myocardium.
Results: Rat cardiomyocytes treated with IS showed significantly enhanced protein synthesis and increased expression levels of BNP, p-erk1/2, and p-p38 as compared with the control cells (P < 0.01), but the expression of p-jnk was comparable between the two groups. In the animal experiment, the rats in the model group showed significantly increased serum creatinine (SCr) and urea nitrogen (BUN) levels, 24-h urine protein (24 hUpro), plasma IS level, left ventricular mass index (LVMI) and whole heart mass index (HMI) compared with those in the sham group (P < 0.01); Both LVESD and LVEDD were significantly reduced and LVAWS, LVAWD, LVPWS and LVPWD were significantly increased in the model rat, which also presented with obvious cardiomyocyte hypertrophy and increased myocardial expressions of BNP, p-ERK1/2, p-p38 and p-jnk (P < 0.01). Compared with the rats in the model group, the rats treated with low-dose and high-dose Zhenwu Decoction had significantly lowered levels of SCr, BUN, 24 hUpro and IS (P < 0.05) and decreased LVMI and HMI; LVESD, LVEDD, LVPWS, LVAWS, and LVAWD were improved more obviously in the high-dose group, and the myocardial expressions of BNP, p-ERK1/2, p-p38 and p-JNK was significantly downregulated after the treatment.
Conclusions: Zhenwu Decoctin can reduce plasma IS levels and inhibit ventricular hypertrophy to delay ventricular remodeling in rats with uremic cardiomyopathy.
目的: 探讨真武汤对尿毒症心肌病大鼠心室肥厚的作用及可能机制。
方法: （1）提取SD乳鼠心肌细胞，将其分为对照组及硫酸吲哚酚（indoxyl sulfate, IS）组（10 μm刺激），通过[3H]亮氨酸掺入法、Western blot（WB）检测两组细胞蛋白表达情况；（2）将50只SD大鼠随机分成假手术组、模型组、真武汤低（4.5 g/kg）、高剂量干预组（13.5 g/kg），除假手术组外，其他各组均予5/6肾切除术。术后4周，低剂量组及高剂量组分别每天给与真武汤灌胃，假手术组和模型组给予等量蒸馏水灌胃。给药4周后，检测各组大鼠血生化、血浆硫酸吲哚酚水平（IS），心脏及心室重量指数、心脏彩超、心肌组织BNP、p-ERK1/2、p-p38及p-JNK蛋白表达等情况。
结果: （1）细胞实验中，IS组心肌细胞蛋白质合成速率明显增加, 而BNP、p-ERK1/2、p-p38表达均较对照组升高（均P < 0.01），而P-JNK蛋白则与对照组相比未见明显差异；（2）与假手术组相比，模型组的血肌酐（SCr）、尿素氮（BUN）、24小时尿蛋白（24 hUpro）、IS及左室质量指数（LVMI）、全心质量指数（HMI）均升高（P < 0.01）；左心室收缩末期内径（LVESD）、左心室舒张末期内径（LVEDD）均有显著降低，左心室前壁收缩末期厚度（LVAWS）、左心室前壁舒张末期厚度（LVAWD）、左心室后壁收缩期厚度（LVPWS）、左心室后壁舒张期厚度（LVPWD）则明显增厚；HE染色示心肌细胞肥大。心肌组织蛋白BNP、p-ERK1/2、p-p38、p-jnk的表达均升高（P < 0.01）；（3）低剂量和高剂量组SCr、BUN、24 hUpro及IS较模型组降低（P < 0.05），LVMI及HMI在低剂量、高剂量组中下降；LVESD、LVEDD、LVPWS、LVAWS、LVAWD等在高剂量组中改善较为显著，心肌组织蛋白BNP、p-ERK1/2、pp38及p-JNK的表达下调。
结论: 真武汤可降低尿毒症心肌病大鼠血浆IS水平，进而延缓IS对心肌肥厚作用，延缓心室重构。
Keywords: Zhenwu Decoction; cardiac hypertrophy; uremic cardiomyopathy; ventricular remodeling.