不同剂量培哚普利对缺血性心功能障碍家兔心功能及ACE2/Ang-(1-9)/Ang-(1-7)轴的影响

 目的: 探讨不同剂量培哚普利对缺血性心功能障碍家兔心功能的影响。方法: 采用结扎冠状动脉前降支的方法制作缺血性心功能障碍家兔模型。利用随机数字表法将30只家兔随机分为培哚普利大、小剂量组和心功能障碍组。大、小剂量组分别给予培哚普利生理盐水溶液(浓度分别为1 g/L、0.33 g/L)2 mL·kg^-1·d^-1灌胃;心功能障碍组给予等量生理盐水灌胃。4周后心脏超声测定心功能;real-time PCR检测血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)和血管紧张素2型受体(angiotensin type 2 receptor,AT2R) mRNA表达;ELISA检测家兔血清血管紧张素(angiotensin,Ang)-(1-9)和Ang-(1-7)水平。结果: 与心功能障碍组相比,不同剂量培哚普利均可改善心功能(P<0.01),大剂量培哚普利比小剂量培哚普利改善心功能的效果显著(P<0.05);心功能障碍家兔应用培哚普利后,血清Ang-(1-9)和Ang-(1-7)水平均增高(P<0.01),ACE2和AT2R mRNA表达均增加(P<0.01);与小剂量组相比,大剂量组心肌ACE2和AT2R mRNA表达均增高(P<0.01),血清Ang-(1-9)水平增高(P<0.05),血清Ang-(1-7)水平无明显增加。相关性分析发现,左室射血分数与血清Ang-(1-9)、ACE2及AT2R水平呈正相关关系(P<0.01),与血清Ang-(1-7)水平无相关关系。结论: 大剂量培哚普利较小剂量培哚普利可以更有效改善缺血性心功能障碍家兔心功能,其心功能的改善可能与Ang-(1-9)水平增多,引起AT2R活化相关。

Effects of perindopril at different doses on cardiac function and ACE2/Ang-(1-9)/Ang-(1-7) axis of ischemic cardiac dysfunction rabbits

AIM: To investigate the different dose of perindopril on cardiac function in the rabbits with ischemic cardiac dysfunction. METHODS: Male rabbits weighing 2.5~3.0 kg(n=30) were randomly divided into 3 groups(n=10):high dose perindopril group(HD group), low dose perindopril group(LD group) and cardiac dysfunction group(CD group). The Left anterior descending coronary artery of the rabbits was ligatured for model preparation. In HD group, the rabbits were treated with perindopril split normal saline solution(1 g/L)2 mL·kg^-1·d^-1. In LD group, the rabbits were treated with perindopril split normal saline solution(0.33 g/L)2 mL·kg^-1·d^-1. In CD group, the rabbits were treated with normal saline solution 2 mL·kg^-1·d^-1. Four weeks after treatment, the cardiac function was measured via echocardiography, the mRNA expression of angiotensin-converting enzyme 2(ACE2) and angiotensin type 2 receptor(AT2R) was analyzed by real-time PCR, serum angiotensin(Ang)-(1-9) and Ang-(1-7) levels were detected by ELISA. RESULTS: Compared with CD group, the cardiac function of the 2 groups treated with perindopril was significantly improved(P<0.01), and more improvement in HD group was observed than LD group(P<0.05). The serum angiotensin(Ang)-(1-9) and Ang-(1-7) level and the mRNA expression of ACE2 and AT2R in the 2 groups treated with perindopril were significantly improved(P<0.01). Compared with LD group, the mRNA expression of ACE2 and AT2R and the serum levels of Ang-(1-9) in HD group were significant improved(P<0.05), while no difference of serum Ang-(1-7) level was observed. Correlation analysis revealed that the improvement of the cardiac function was associated with serum Ang-(1-9) level, mRNA expression of ACE2 and AT2R(P<0.01), but has no significant correlation with serum Ang-(1-7) level. CONCLUSION: High dose of perindopril may improve more cardiac function in ischemic cardiac dysfunction model in rabbits. The mechanism may relate to increasing serum Ang-(1-7) level to activate AT2R.