厄贝沙坦和咪哒普利抑制自发性高血压大鼠阻力血管重塑的实验研究

目的 :探讨厄贝沙坦、咪哒普利对自发性高血压大鼠 (SHR)阻力血管重塑的抑制作用并比较二者的作用效果。方法 :选用 1 3周龄的SHR30只、WKY大鼠 1 0只随机分为四组 :SHR组 ,厄贝沙坦组 ,咪哒普利组 ,WKY组。实验期 1 5周。观察指标 :血压 ,肠系膜动脉中膜厚度 /管腔半径、中膜面积 /腔面积、管腔半径 /血管半径 ,肠系膜动脉的形态学 (光镜、电镜 ) ,血浆、肠系膜动脉AngⅡ浓度。 结果 :咪哒普利组、厄贝沙坦组血压控制良好 ,肠系膜动脉重塑的各项指标改善 ,在这些指标上二者无显著性差异 ;肠系膜动脉结构改变尤其是纤维化均减轻 ,咪哒普利组减轻更明显。结论 :咪哒普利、厄贝沙坦不仅能良好地控制血压而且可以抑制自发性高血压大鼠阻力血管重塑 ;在防止肠系膜动脉结构改变尤其是纤维化方面 ,咪哒普利作用优越于厄贝沙坦。     

螺内酯和缬沙坦对高血压大鼠肠系膜微动脉重塑的影响

目的:观察盐皮质激素受体拮抗剂螺内酯和血管紧张素Ⅱ(AngⅡ)AT1受体拮抗剂缬沙坦对自发性高血压大鼠(SHR)肠系膜微动脉形态、超微结构和Ⅰ型胶原mRNA表达的影响。方法:将18只雄性SHR随机分为三组,每组6只,其中两组分别用螺内酯20mg/kg/天、缬沙坦30mg/kg/天溶于饮水中灌胃,连续治疗13周,对照组不用药,正常饮水,并与WKY大鼠(6只)比较。鼠尾法测量大鼠动脉收缩压;应用计算机图像分析系统,计算大鼠肠系膜微动脉管壁与管腔横截面积比;用透射电镜观察大鼠肠系膜微动脉结构的变化;用RT-PCR方法检测肠系膜微动脉Ⅰ型胶原mRNA水平。结果:实验第13周末,SHR对照组血压明显高于WKY组(P<0.01);缬沙坦组和螺内酯组血压明显低于SHR对照组(P<0.01);缬沙坦组的血压与WKY组接近(P>0.05)。螺内酯组和缬沙坦组大鼠肠系膜微动脉的中膜厚度/管腔半径值及中膜面积/管腔面积值仍显著大于WKY组(P<0.05),但较SHR组明显降低(P<0.01)。透射电镜见SHR肠系膜动脉壁有大片纤维组织增生,螺内酯组和缬沙坦组肠系膜动脉壁内仅见少许纤维组织增生。螺内酯组和缬沙坦组Ⅰ型胶原mRNA水平明显低于SHR对照组(P<0.01)。结论:螺内酯和缬沙坦均能抑制SHR的Ⅰ型胶原合成,表明盐皮质激素受体和AngⅡ受体在高血压阻力血管的重塑中起着重要作用。     

高血压大鼠大小动脉血管重构的差异比较

目的:探讨自发性高血压大鼠(SHR)大、小动脉血管重构的差异。方法:以20周龄雄性SHR为实验组,同龄Wistar-Kyoto(WKY)大鼠为对照组。每周测量体重和血压,43周龄大鼠麻醉取血,留取胸主动脉和肠系膜小动脉组织。HE染色观察比较大、小动脉形态学变化,天狼星红-维多利亚蓝染色检测胶原纤维和弹力纤维变化,激光扫描共聚焦显微镜和Western blot分析Ⅰ、Ⅲ型胶原蛋白的表达,透射电子显微镜观察动脉超微结构变化,原位末端标记法(TUNEL)和增殖细胞核抗原(PCNA)检测评估血管壁细胞凋亡与增殖情况。结果:小动脉血管内径(ID)和血管腔横截面积(LCSA)减小,壁厚内径比(WT/ID)和壁腔横截面积比(WCSA/LCSA)增大,外膜成纤维细胞增殖并部分迁移,胶原增多,以III型胶原增多为主,血管壁细胞的增殖指数和凋亡指数增加;主动脉ID、LCSA、WT/ID和WCSA/LCSA均增大,中层血管平滑肌细胞(VSMCs)肥大增生明显,胶原增多,血管壁细胞的增殖指数和凋亡指数增加。结论:高血压大鼠大、小动脉血管重构差异明显,小动脉以基质增多,特别是外膜III型胶原蛋白增多为主,血管壁细胞凋亡增加;大动脉以血管壁细胞增生,特别是VSMCs增生、肥大为主。     

氯沙坦逆转高血压大鼠阻力血管重塑的实验研究

目的:探讨氯沙坦对自发性高血压大鼠(SHR)阻力血管重塑的影响。方法:将雄性SHR20只随机分为氯沙坦治疗组和SHR对照组。另选同系雄性WKY大鼠10只作为正常对照组。治疗组给予氯沙坦30mg/kg/天,溶于饮水灌胃治疗17周。颈动脉插管,心电血流动力学监护仪测定动脉收缩压,应用计算机图像分析,计算血管壁腔面积比,用光镜和透射电镜观察SHR肠系膜动脉三级分支结构的变化;血浆放免法测肾素活性和血管紧张素Ⅱ(AngⅡ)含量。结果:氯沙坦治疗组的血管壁腔面积比与SHR对照组相比有所降低(P<0.05),但与WKY相比有所升高(P<0.05);血浆肾素活性在WKY组和SHR对照组之间无明显差异(P>0.05),治疗组肾素活性高于SHR对照组(P<0.05);治疗组的AngⅡ水平高于SHR对照组(P<0.01)。结论:氯沙坦具有逆转SHR血管重塑的作用。     

抗高血压因子对大鼠血管平滑肌钙内流的影响

实验观察了从原发性高血压病患者红细胞中提取的抗高血压因子(AHF)对自发性高血压大鼠(SHR)、肾性高血压大鼠(RHR)和正常血压的WKY大鼠和Wistar大鼠主动脉和肠系膜动咏平滑肌Ca~(2+)内流的影响。结果表明,SHR和RHR的肠系膜动脉Ca~(2+)内流显著高于主动脉;AHF可显著抑制SHR和RHR主动脉和肠系膜动脉Ca~(2+)内流,抑制作用呈剂量依赖性,且对肠系腆动脉Ca~(2+)内流抑制作用更明显;AHF也可抑制正常动物血管平滑肌Ca~(2+)内流。本工作提示,AHF的降压机制可能与其抑制血管平滑肌特别是小动脉血管平滑肌Ca~(2+)内流有关。     

血管紧张素Ⅱ受体拮抗剂对高血压肾小动脉重建的影响

目的:研究血管紧张素II(AngII)受体拮抗剂对高血压肾小动脉重建的影响。方法:18只4周龄雄性大鼠分为:正常血压大鼠(WKY)组、自发性高血压大鼠(SHR)组、SHR口服losartan组,均饲养至16周。在肾组织切片上分别用光镜和电镜配合计算机图像分析法观测肾组织内小动脉的几何形态学指标和小动脉平滑肌及其间隙,离体肾脏灌流法测定最小肾血管阻力。结果:Losartan组的尾动脉收缩压、肾小动脉壁厚、壁面积、壁厚内径比和中层血管平滑肌细胞宽度以及最小肾血管阻力,均显著低于高血压对照组。结论:AngII受体拮抗剂losartan能预防SHR肾小动脉的重建。     

自发性高血压大鼠勃起功能及海绵体形态结构的改变

目的：探讨自发性高血压大鼠(SHR)勃起功能的改变及其发病机理。方法：雄性 SHR 及同系 WKY 大鼠,夹尾法测量大鼠收缩压(SBP),皮下注射阿朴吗啡(APO)检测阴茎勃起功能,光镜及透射电镜观察海绵体形态结构的变化。结果：SHR 组及 WKY 组阴茎勃起次数分别为0．6±0．5和2．4±0．6,差异非常显著。光镜下 SHR 大鼠阴茎海绵体血窦、内皮细胞、平滑肌细胞分布杂乱,血管内皮细胞连续性破坏；其内皮细胞及平滑肌细胞超微结构线粒体退变、内质网扩张,糖原颗粒、吞饮小泡及微丝减少。还可见大量间质组织增生及微血管腔闭塞。结论：高血压严重影响阴茎勃起功能,海绵体组织超微结构的病理改变可能是自发性高血压大鼠勃起功能下降的机理之一。     

不同年龄高血压大鼠血管平滑肌中ERK和MKP-1的表达

目的：研究不同年龄的自发性高血压大鼠（SHR）和Wistar Kyoto大鼠（WKY）主动脉平滑肌中丝裂原活化蛋白激酶（MAPK）及其磷酸酶（MKP-1）的表达及其与高血压的关系。 方法： 用tail-cuff测量大鼠尾动脉血压；分别用Western blotting法和RT-PCR法半定量测定血管平滑肌中磷酸化细胞外信号调节激酶（p-ERK）和MKP-1的蛋白表达以及MKP-1 mRNA的含量。 结果： （1）SHR的血压自8周龄起明显高于WKY（P<0.01），且随年龄增长而升高（P<0.05）至14周以后趋于稳定；（2）SHR主动脉平滑肌中的p-ERK表达明显高于同年龄的WKY（P<0.01），随年龄增长而递增（P<0.05），与血压呈正相关；（3）SHR主动脉平滑肌中MKP-1蛋白明显高于同龄WKY，而mRNA的表达在5周龄时明显高于WKY，之后均随年龄的增长而递减（P<0.05），与血压和ERK呈负相关，而WKY下降不明显。 结论： MKP-1在高血压的发生和发展过程中起重要作用，其表达逐渐下降可能是导致ERK激活增加，从而导致血管平滑肌细胞增殖、血压升高的重要原因。     

氯沙坦（Losartan）逆转高血压大鼠血管壁超微结构的研究

目的 观察氯沙坦（Losartan）对自发性高血压大鼠（SHR）及正常对照组（WKY）的淋巴细胞胞浆游离钙[Ca^2 ]i、血管紧张素Ⅱ（AngⅡ）水平和血管壁超微结构的影响及其降压效应。方法 SHR28只分为3组，分别为3月龄对照组（SHRi）、6月龄对照组（SHR2）和Losartan治疗组（SHR3）。治疗组从3月龄开始予Losartan 20mg/kg/d治疗至6月龄。治疗前后检测鼠尾收缩压、淋巴细胞胞浆游离钙[Ca^2 ]i、血浆AngⅡ和肠系膜动脉超微结构。结果 Losartan对SHR有显著降压作用。治疗前SHR的淋巴细胞钙[Ca^2 ]i水平均显著性增加，随鼠龄增大而加大。肠系膜动脉出现明显血管壁损害，内皮细胞和平滑肌线粒体比表面均显著减少，而平滑肌细胞线粒体密度则显著增加。经Losartan治疗后，在降压的同时淋巴细胞[Ca^2 ]i显著性下降，血管壁超微结构的损害得到明显逆转。结论 高血压与血管平滑肌细胞存在的钙超负荷状态有关，并存在小动脉血管壁平滑肌和内皮细胞的超微结构损害。Losartan能有效逆转血管平滑肌的钙超负荷状态，降低SHR的动脉血压的同时逆转血管壁超微结构的损害。     

U 50 488H 对高血压大鼠的利尿作用及机制

目的： 观察κ阿片受体激动剂U50 488H对自发性高血压大鼠（SHR）的利尿作用并探讨其作用机制。 方法： 用整体实验观察U50 488H对WKY大鼠和SHR血压和尿量的影响；应用放射免疫分析方法观察WKY大鼠和SHR血浆中体液因子的变化。 结果： U50 488H显著降低WKY大鼠和SHR的血压，对SHR产生的降压效应大于WKY大鼠；U50 488H剂量依赖性地引起WKY大鼠和SHR尿量的增加，而且对SHR的利尿作用强于WKY大鼠；测定血浆因子水平发现，U50 488H不仅能引起WKY大鼠和SHR血浆ADH水平的显著下降，并且对SHR血浆ADH水平的降低效应大于WKY大鼠；另外，U50 488H对WKY大鼠血浆AngⅡ水平无明显影响，但可以引起SHR血浆AngⅡ水平显著下降。U50 488H的以上效应均可被选择性κ阿片受体阻断剂nor-BNI所阻断。 结论： κ阿片受体激动剂U50 488H显著下调血浆中抗利尿激素和血管紧张素Ⅱ的水平可能与其引起SHR强利尿效应有关。     

Cholecalciferol treatment restores the relaxant responses of spontaneously hypertensive rat arteries to bradykinin

The vasodilation and hyperpolarization induced by bradykinin (BK) in the mesenteric vascular bed and mesenteric arteries from spontaneously hypertensive rats (SHR) and from normotensive Wistar rats (NWR), as well as Wistar Kyoto rats (WKY), was investigated before and after prolonged oral treatment with cholecalciferol (125 mg kg⁻¹ body weight per day) for 3 weeks. The cholecalciferol treatment caused a decrease in the SHR blood pressure, as well as a normalization in the resting potential of the smooth muscle cell membrane of mesenteric arteries and restored their hyperpolarizing response to BK. The concentration–response curves for the vasodilator effect of BK on the mesenteric vascular bed were significantly decreased in SHR and in WKY when compared with NWR. Cholecalciferol treatment improved the maximum responses of the SHR preparation, bringing them to levels similar to those of the NWR preparations, which themselves were unaffected by the treatment. In the presence of apamin, a Ca²⁺-dependent K⁺ channel inhibitor, the maximum responses to BK in preparations from NWR or cholecalciferol-treated SHR decreased to values similar to those observed in untreated SHR. Our results indicate that the low responsivity of the SHR resistance vessels to the relaxant effect of BK is due to impaired Ca²⁺-dependent K⁺ channels and that reversion of this impairment contributes to the blood pressure reduction caused by the cholecalciferol treatment. However, the mechanism of the low responsivity in WKY remains to be investigated.     

Morphological and mechanical properties of small mesenteric arteries and veins in spontaneously hypertensive rats

Segments of small mesenteric arteries (—150 μm lumen diameter) and of corresponding veins were taken from 5-month-old spontaneously hypertensive rats (SHR) and from age matched Wistar Kyoto (WKY) controls. The segments were mounted on a myograph which enabled their mechanical and morphological parameters to be investigated simultaneously. Compared with the WKY arteries the lumen diameter of the SHR arteries was smaller while the media thickness and active wall tension response were greater. On the other hand there were no differences between the corresponding veins from SHR and WKY animals although, compared with the arteries, the veins had a greater lumen diameter, a smaller media thickness and a smaller tension response. The findings suggest that the morphological and mechanical differences seen in arteries from SHR are not found on the venous side.     

自发性高血压大鼠主动脉弓重建的形态学研究

目的　研究高血压动脉重建规律,为揭示高血压主动脉弓的血流动力学特点提供形态学基础。　方法　应用组织学和计算机图像分析技术,对３６ 例ＳＨＲ和ＷＫＹ大鼠（各分４周、１６ 周和２６ 周）主动脉弓进行定量形态学研究。　结果　随着年龄增长,大鼠主动脉弓形态和显微结构发生重建。高血压主动脉弓重建以壁厚、中膜厚、管壁面积、中膜面积和中膜厚内径比以及血管平滑肌、弹性纤维和胶原纤维等结构成分的相对含量显著增大为特征。　结论　ＳＨＲ成年以前主动脉重建是年龄不断增长和血压逐步升高综合作用的结果,其中高血压是主要因素。大鼠主动脉弓形态结构在血管周向呈显著非均匀性,并在高血压重建中变得更为显著。     

丝裂原活化蛋白激酶参与胰岛素对自发性高血压大鼠血管平滑肌细胞的增殖研究

目的:探讨高血压血管平滑肌细胞(VSMC)在胰岛素作用下胞内信号转导途径之一丝裂原活化蛋白激酶(MAPK)的影响,及其与VSMC增殖的关系。方法:选用6周龄自发性高血压大鼠(SHR)和WKY大鼠,无菌分离主动脉,体外纯化培养VSMC至6~8代,加胰岛素干预和蛋白激酶C(PKC)抑制剂,采用胶内髓磷脂碱性蛋白原位磷酸化法测定VSMC中MAPK活性,并用Western Blot检测VSMC中MAPK的含量, [³H]-TdR测定VSMC的DNA合成量。结果:胰岛素作用后,SHR组的DNA合成量显著增加,MAPK活性及蛋白含量也显著增加,PKC抑制剂可明显降低MAPK活性。结论:SHR体外培养的VSMC增殖与MAPK活性增加有关,胰岛素可影响其活性,并且可能存在胰岛素-PKC-MAPK轴。     

Morphology of the carotid sinus wall in normotensive and spontaneously hypertensive rats

The morphology of the carotid sinus region of the internal carotid artery was studied in spontaneously hypertensive rats (SHR) at 5, 8, 16, and 24 weeks of age. The carotid sinus region occupied the proximal millimeter of the internal carotid artery, and was easily recognizable by the presence of an extensive adventitial capillary plexus, which was absent on adjacent arteries (e.g., common and external carotid arteries). Methylene blue-stained whole-mount preparations showed the extent of baroreceptor nerves over the sinus. Baroreceptor fibers terminated in distinctive bulbous-like endings, which, at the ultrastructural level, were filled with mitochondria. No differences were noted in the sinus adventitial capillary network or baroreceptor distribution between SHR and age-matched Wistar-Kyoto (WKY) normotensive control animals. With the onset of a significant rise in SHR blood pressure, the carotid sinus wall increased in thickness and total vessel size. The wall/lumen ratios were significantly larger in the SHR than in age-matched WKY ratios in all age groups. SHR carotid sinus vessel enlargement was uniform throughout the vessel tunics, with no significant change in the proportion of the tunica media occupied by smooth muscle cells. The increase in the carotid sinus wall thickness associated with increasing hypertension could affect the ability of the sinus to distend and may play a secondary role in the maintenance of hypertension by compromising baroreceptor nerve ending sensitivity.     

Role of smooth muscle cell membrane potential in neointima formation in arteries of spontaneously hypertensive rats

Based on observations that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) have altered resting potentials as well as abnormal cell proliferation rates, neointima formation after controlled balloon injury was compared in arteries from SHR and Wistar Kyoto rats (WKY). SHR aortic VSMC showed hyperpolarized resting membrane potentials (−93±8 mV) when compared to those from WKY (−61±6 mV). Histomorphometric analysis of cross sections from aortic segments submitted to balloon injury showed reduced neointima formation in SHR (neointima/media ratio: 0.04±0.03) as compared to WKY (0.2±0.1). On the other hand, in injured carotid arteries, neointima formation was more extensive in SHR (neointima/media ratio 5.0±0.9) than in WKY (0.8±0.7), leading in most cases to luminal occlusion. Measurements of VSMC resting potential showed that carotid artery cells from SHR were depolarized with respect to those from WKY (−46±4 vs. −69±5 mV, respectively). The results demonstrate an inverse relationship between VSMC membrane polarization and neointima formation in SHR arteries, suggesting that genetic modifications in SHR determine a dysfunctional cellular physiology that may influence cell proliferation subsequent to injury.