【作者】 秦旭平；

【导师】 李元建； 廖端芳；

【作者基本信息】 中南大学 ， 心血管药理， 2003， 博士

【摘要】 第一章 降钙素基因相关肽介导氯沙坦和培哚普利的降压作用 研究背景 肾素-血管紧张素系统(RAS)在高血压发生发展过程中起重要特性。近年研究发现，血管紧张素Ⅱ(angiotensin Ⅱ，AngⅡ)除缩血管效应外，还具有生长因子样作用，可通过激活原癌基因表达增加，引起心肌和血管壁重构。 降钙素基因相关肽(calcitonin gene-related peptide，CGRP)为一个37个氨基酸组成的神经肽，是辣椒素敏感的感觉神经递质，广泛分布于中枢和外周的心血管系统。CGRP具有强效舒血管作用，在调节血管外周阻力中起重要作用。文献报道，原发性高血压病人和自发性高血压大鼠血浆中的CGRP浓度均降低。然而，在其它高血压动物模型，辣椒素敏感的感觉神经活性表现有代偿性增加，如去氧皮质醇加盐高血压模型、肾次全切除术加盐大鼠高血压模型，背根神经节中CGRP mRNA表达及血浆中CGRP水平均升高。两肾一夹(2K1C，Golgblatt)大鼠模型是研究肾血管性高血压经典实验模型，其高血压的形成主要与激活PAS及神经系统有关。文献报道，肾性高血压的发生发展也涉及神经机制。然而，两肾一夹(2K1C，Golgblatt)高血压大鼠模型是否涉及辣椒素敏感的感觉神经活性的变化，尚未见报道。 本研究以肾血管性 ZKIC（G＊dbl圳高血压大鼠模型为研究对象，探讨辣椒素敏感的感觉神经在此高血压模型中的功能变化，以及培跺普利或氯沙坦的降压作用是否与促进感觉神经递质CGRP合成与释放有关。 方 法 在SD大鼠，通过用银夹缩窄左肾动脉，建立两肾一夹型 （G＊dblatt）大鼠高血压模型。在肾动脉结扎后第 4周末，以血压维持在 160 mmHg以上为本达到高血压标准。氯沙坦惶0mg／kg．d）或血培跺普利 omg／kg巾 口服连续 6周。采用鼠尾动脉测压法记录每周血压的变化。放射免疫分析法测定血浆中CGRP、Augl工含量及肾素活性的值，RTPCR技术观察脊髓背根神经节 a－CGRP m RNA的表达量。切取心脏，并计算心脏与体重比值。主动脉血管和肠系膜动脉血管经在体固定后，石蜡切片，HE染色，采用高清晰度显微图像分析系统软件测定血管壁和管腔的面积比，血管壁厚度和管腔内径 b匕。 结 果 高血压大鼠血浆CGRP浓度和脊髓背根神经节u－CGny mRNA 的表达轻微升高u＜0．05＊胸主动脉和肠系膜动脉表现向心性重构或肥厚，心脏和体重比值增加。给予氯沙坦＊0mg／kg．山和培跺普利 Omgjkg血治疗能显著降低收缩压和平均动脉压，防止血管重构，降 豆且低心脏体重比值，同时伴有血浆CGny及其背根神经节Q－CGny＜ NNA的表达显著升高k叼＊人 氯沙坦和培跺普利治疗组血浆肾素活性、血管紧张素＊浓度也显著升高。 结 论 1．在 ZKIC高血压大鼠模型，血浆中 CGRP增高表现为一种代偿性增高。 2．氯沙坦和培跺普利降压和防止血管壁重构作用可能与促进CGRP合成和释放有关。更多还原

【Abstract】 Renin-angiotensin system (RAS) have been shown to play pivotal roles in the development of blood pressure, angiotensin II (Ang II) , besides regulating vascular smooth muscle tone, has properties of growth factors which induces cell hyperplasia or hypertrophy, via over expression of original cancer genes, resulting in cardiac or vascular remodeling.Calcitonin gene-related peptide (CGRP), a 37-amino acid peptide, is distributed widely in vascular tissues of both the central nervous system and the periphery. CGRP is a potent vasculator and plays an important role in modulation of the total peripheral resistance of the systemic circulation through reflex mechanisms. Recently, it has been shown that CGRP concentration in the plasma is decreased in patients with essential hypertension and in spontaneously hypertensive rats, suggesting that the alteration in the level of CGRP may be related to the development ofhypertension. However, the expression of CGRP varies considerably in different animal models of hypertension. To our knowledge, the hypothesis of capsaicin-sensitive sensory nerves has not yet been tested in the 2-kidneys, 1-clip (2K1C, Goldblatt) hypertensive model.In the present studies, therefore, we examined whether the depressor effects of perindopril and losartan are involved in endogenous CGRP in 2K1C Goldblatt rats.METHODSThe Sprague-Dawley rats (220-250g) were anesthetized with sodium Phenobarbital (60mg/kg, i.p.). The left renal artery was separated and clipped with a 0.3 mm silver clip. The control group underwent the same procedure, but without clipping the renal artery. At the end of the fourth, week, the rats were treatment with losartan (20mg/kg) or perindopril (3mg/kg) for 6 weeks. Systolic blood pressure was recorded, once a week, using the tail-cuff method. Concentration of Ang II and CGRP and the activity of renin in the plasma were measured by radioimmunoassay methods. The expression of CGRP mRNA in DRG was determined by RT-PCR. The ratio of heart and body was calculated. Aortic and mesenteric arteries were prepared with methylaldehyde, and the color slides of these tissues stained with hematoxylin and eosin were analyzed using the software of higher clear graphic assay system.RESULTSIn the 2K1C rats, systolic blood pressure and mean artery pressure were significantly raised compared with control group (p<0.01), and the level of CGRP was raised in plasma (p<0.05). A state of thickening in aortas or remodeling mesnenteric arteries was shown in hypertensive rats. Treatment with losartan or perindopril significantly decreased the blood pressure, concomitantly with an increased the plasma concentration of CGRP and the expression of α -CGRP mRNA in dorsal root ganglia. Losartan or peridopril treatment significantly decreased the thickening or remodeling in vascular tissues and diminished radio of heart to body. In the losartan or peridopril-treatment group, the plasma level of Ang II and the plasma activity of rennin were increased.CONCLUSIONS1. The 2K1C Goldblatt model exhibits a compensatory increase of sensory nerve actions.2. The depressor effects and the regressive effect of vascular remodeling of losartan or prindopril may be related stimulation of the synthesis and release of CGRP in the 2K1C Goldblatt hypertensive rats.更多还原