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雷米普利对自发性高血压大鼠脑动脉缝隙连接蛋白43表达的影响

田甜, 谭朝阳, 贾奇花, 丛雯雯, 田俊杰, 马克涛, 李丽, 司军强^*

石河子大学医学院生理学教研室/新疆地方与民族高发病教育部重点实验室，石河子 832002

摘要

本文旨在探讨血管紧张素转换酶抑制剂雷米普利(Ramipril)是否通过调节脑动脉血管细胞缝隙连接蛋白43 (connexin 43, Cx43)的表达发挥其降压及保护脑动脉的作用。Wistar-Kyoto (WKY)和自发性高血压大鼠(spontaneously hypertensive rat, SHR)随机分为4组：WKY组、WKY + Ramipril组、SHR组、SHR + Ramipril组(n = 8)。运用无创尾动脉测压仪测量收缩压；采用苏木素-伊红染色观察脑动脉病理学改变；应用压力肌动图技术检测各组脑动脉血管收缩率；应用免疫荧光和免疫组织化学技术分析脑动脉上Cx43的分布及表达；采用real-time PCR和Western blot技术分别检测脑动脉上Cx43 mRNA及蛋白表达。结果显示：(1) SHR组收缩压显著高于WKY组(P < 0.01, n = 8)；SHR + Ramipril组收缩压明显低于SHR组(P < 0.01, n = 8)。(2) 相比于WKY组，SHR组脑动脉管壁增厚明显(P < 0.01, n = 8)，而SHR + Ramipril组相比于SHR组，动脉管壁厚度明显减少。(3) SHR组脑动脉收缩率高于WKY组(P < 0.05, n = 8)；SHR + Ramipril组脑动脉收缩率低于SHR组(P < 0.05, n = 8)。应用2-APB (Cx43非特异性阻断剂)或Gap26 (Cx43特异性阻断剂)预孵育后，SHR + Ramipril组动脉收缩率显著下降(P < 0.05, n = 8)；给予Cx43非特异性激动剂AAP10预孵育后，SHR + Ramipril组动脉收缩率显著升高 (P < 0.05, n = 8)。(4) SHR组脑动脉上Cx43 mRNA及蛋白表达水平高于WKY组(P < 0.05, n = 8)；SHR + Ramipril组脑动脉上Cx43 mRNA及蛋白表达水平明显低于SHR组(P < 0.05, n = 8)。以上结果提示，雷米普利能够下调SHR脑动脉血管细胞间Cx43 mRNA和蛋白的表达，降低血压，改善高血压诱发的脑动脉重塑以及血管功能障碍。

关键词： 雷米普利; 自发性高血压; 肾素-血管紧张素-醛固酮系统; 脑动脉; 缝隙连接蛋白43

分类号：R331.3+3

Effects of Ramipril on the expression of connexin 43 in cerebral arteries of spontaneously hypertensive rats

TIAN Tian, TAN Chao-Yang, JIA Qi-Hua, CONG Wen-Wen, TIAN Jun-Jie, MA Ke-Tao, LI Li, SI Jun-Qiang^*

Department of Physiology, Shihezi University Medical College/Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education, Shihezi 832002, China

Abstract

The present study was designed to examine whether Ramipril (an inhibitor of angiotensin-converting enzyme) affected spontaneous hypertension-induced injury of cerebral artery by regulating connexin 43 (Cx43) expression. Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were randomly divided into WKY, WKY + Ramipril, SHR, and SHR + Ramipril groups (n = 8). The arterial pressure was monitored by the tail-cuff method, and vascular function in basilar arteries was examined by pressure myography. Hematoxylin-eosin (HE) staining was used to show vascular remodeling. The expression and distribution of Cx43 was determined by using immunofluorescence and immunohistochemistry analysis. The protein and mRNA levels of Cx43 were examined by Western blot and real-time PCR analysis, respectively. The results showed that chronic Ramipril treatment significantly attenuated blood pressure elevation (P < 0.01, n = 8) and blood vessel wall thickness in SHR (P < 0.01, n = 8). The cerebral artery contraction rate in the SHR group was higher than that in the WKY group (P < 0.05, n = 8). The cerebral artery contraction rate in the SHR + Ramipril group was lower than that in the SHR group (P < 0.05, n = 8). Pretreatment with 2-APB (Cx43 non-specific blocker) or Gap26 (Cx43 specific blocker) significantly decreased the vasoconstriction rate, while pretreatment with AAP10 (Cx43 non-specific agonist) significantly increased the vasoconstriction in the SHR + Ramipril group (P < 0.05, n = 8). In addition, the expression of Cx43 mRNA and protein in cerebral arteries of SHR group was higher than that of WKY group (P < 0.05, n = 8). The mRNA and protein expression of Cx43 in cerebral arteries of SHR + Ramipril group was significantly lower than that of SHR group (P < 0.05, n = 8). These results suggest that Ramipril can down-regulate the expression of Cx43 mRNA and protein in cerebral arterial cells of SHR, lower blood pressure, promote vasodilation, and improve arterial damage and vascular dysfunction caused by hypertension.

Key words: Ramipril; spontaneous hypertension; rennin-angiotensin-aldosterone system; cerebral artery; connexin 43

收稿日期：2018-07-03　　录用日期：2018-09-28

通讯作者：司军强　　E-mail: sijunqiang@shzu.edu.cn

DOI: 10.13294/j.aps.2019.0006

引用本文：

田甜, 谭朝阳, 贾奇花, 丛雯雯, 田俊杰, 马克涛, 李丽, 司军强. 雷米普利对自发性高血压大鼠脑动脉缝隙连接蛋白43表达的影响[J]. 生理学报 2019; 71 (3): 395-404.

TIAN Tian, TAN Chao-Yang, JIA Qi-Hua, CONG Wen-Wen, TIAN Jun-Jie, MA Ke-Tao, LI Li, SI Jun-Qiang. Effects of Ramipril on the expression of connexin 43 in cerebral arteries of spontaneously hypertensive rats. Acta Physiol Sin 2019; 71 (3): 395-404 (in Chinese with English abstract).