缬沙坦与螺内酯对肾血管性高血压大鼠心肌中TGF-β_1表达的影响

Effects of valsartan and spironolactone on the expression of TGF-β1 in the myocardium of renovascular hypertension rats

目的探讨在高血压左室肥厚形成过程中缬沙坦和螺内酯对肾血管性高血压大鼠心肌纤维化以及TGF-β1表达的影响。方法采用两肾一夹的方法建立肾血管性高血压大鼠模型,随机分为高血压组(H组)、组观螺(内察螺酯各内组组酯(大螺5鼠0内m心酯g·脏5k结0g-m1·构dg·和-1+k功g缬-1·能沙d的-坦1灌变3胃0化m,;Sg·放组k射)g-、1·免缬d疫-沙1灌法坦胃检组,(S测+缬各V沙组组坦)大,3并鼠0以m心g假·肌k手组g-术1·织d组中-1灌大血胃鼠管(,紧VC张组组))素及为Ⅱ螺对(内照An酯。gⅡ和采)缬用、醛沙心固坦脏酮联超用的声浓度;Woessner法测定心肌组织中胶原含量。用免疫组化法检测各组大鼠心肌组织中TGF-β1的表达情况。结果用药8周后V组、S+V组血压、左室收缩期径线室壁应力、舒张末期左室后壁厚度及室间隔厚度均明显低于H组及S组(P<0.05),V组、S组、S+V组血浆AngⅡ均高于H组,其中V组与H组比较差异有统计学意义(P<0.05)。S组、V组、S+V组心肌组织中AngⅡ低于H组(P<0.05)。V组、S组、S+V组心肌胶原总量、心肌内血管周围胶原面积、胶原容积分数均明显低于H组(P<0.05)。H组与S组心肌细胞及间质细胞中TGF-β1表达量较C组、V组及S+V组明显上升(P<0.01)。结论 TGF-β1在肾血管性高血压大鼠的心肌细胞及间质细胞中表达明显增强,在血管紧张素Ⅱ1型(AT1)及ALD受体水平上阻断肾素–血管紧张素–醛固酮系统可以使TGF-β1的表达明显下调、心肌纤维化改善,这一作用是独立于机械负荷及室壁应力增加存在的重要因素。

Objective To assess the roles of valsartan and spironolactone on the myocardial fibrosis and the expression of TGF-β1 during the development of left ventricular hypertrophy （LVH） in renovascular hypertension rats.Methods Two-kidney, one-clip （2K1C） renovascular hypertension was induced in Sprague-Dawley rats. The rats were randomized into untreated hypertension group （H group）, spironolactone group （spironolactone 50 mg·kg-1·d-1,S group）, valsartan group （valsartan 30 mg·kg-1·d-1, V group）, and spironolactone plus valsartan group （spironolactone 50 mg·kg-1·d-1 and valsartan 30 mg·kg-1·d-1 at the same time, S＋V group）. Sham-operated rats served as controls （C group）. The changes of heart structure and function in all groups were observed with echocardiogram. Left ventricle concentration of angiotensin Ⅱ （AngⅡ） and ALD was assessed by radioimmunoassay. The Woessner’s method was used to estimate the collagen content in left ventricle. Immunohistochemistry was adopted to examine the protein expression of TGF-β1. Results After 8 weeks treatment, carotid systolic pressure, MESS （meridian end systolic stress ）, LVPWd （left ventricular posterior wall thickness at end diastolic） , IVSd （interventricular septal thickness at end diastolic） in V group and S＋V group were decreased significantly compared with those in H group and S group （P〈0.05）. The left ventricle concentration of AngⅡ and ALD was much lower in S group, V group and S＋V group than those in H group （P〈0.05）.The collagen content, PVCA and CVF in H group were much higher than those in other groupS（P〈0.05）.The expression of TGF-β1 was much higher in H group and S group than that in C group, V group and S＋V group （P〈0.01）. Conclusion The positive immunoreactivity of TGF-β1 is much higher in left ventricle cardiomyocytes and interstitial cells of renovascular hypertension rats. Both AT1 receptor antagonist and ALD receptor antagonist can reduce myocardial fibrosis and the expression of TGF-β1.This effect is more important and independent factor than mechanical stresses.