实验性高血压所致的基底动脉结构改变及血管紧张素转换酶抑制剂的影响

探讨高血压大鼠基底动脉结构的变化及血管紧张素转换酶抑制剂对其的影响。选用易卒中型肾血管性高血压大鼠模型 ,分为高血压组、卡托普利治疗组、假手术正常血压对照组。分别于肾动脉狭窄术后 4、8、12周处死动物 ,取基底动脉 ,制片后分别用光镜和透射电镜观察 ,并进行体视学定量分析。术后 4周时高血压组基底动脉光镜下无明显形态学变化 ,8周和 12周时中膜厚度、壁腔比值均比同时期正常血压对照组增加 ,有显著性差异 (P <0 .0 5 ) ;卡托普利治疗后中膜厚度、壁腔比值均小于高血压组 ,差异有显著性 (P <0 .0 5 )。术后 4周高血压组基底动脉平滑肌细胞间隙略增宽 ;术后 8周细胞器肿胀 ,部分溶解 ,间质轻度水肿 ;12周时平滑肌细胞肌丝变性、断裂、溶解 ,内质网扩张 ,线粒体部分空泡变性 ,细胞坏死。卡托普利组各时期超微结构改变不明显。表明高血压可致基底动脉肥厚和超微结构破坏 ,而卡托普利可以预防高血压所致的基底动脉结构破坏。     

实验性高血压大鼠大脑中动脉超微结构改变及其药物影响

目的探讨高血压大鼠大脑中动脉超微结构的变化及血管紧张素转换酶抑制剂的影响.方法选用易卒中型肾血管性高血压大鼠模型,分为高血压组、卡托普利治疗组,并与假手术正常血压大鼠作对照,分别于肾动脉狭窄术后4、8和12周处死动物,取大脑中动脉,制片后分别用光镜和透射电镜观察,并进行体视学定量分析.结果术后4周时高血压组大脑中动脉光镜下无明显形态学变化;8周和12周时中膜厚度、中膜与管腔比值与假手术对照组相比均有显著性差异(P<0.05);卡托普利治疗后中膜厚度、壁腔比值均小于高血压组,差异有显著性(P<0.05).术后4周高血压组大脑中动脉超微结构仅轻度异常;术后8周细胞间隙增宽,间质明显水肿;12周时平滑肌细胞坏死,内质网扩张,线粒体部分空泡变性,核自溶,间质增生;卡托普利组各时期超微结构改变不明显.结论高血压可致大脑中动脉肥厚和超微结构破坏,而卡托普利可以减轻高血压所致的大脑中动脉结构破坏.     

实验性高血压大鼠大脑中动脉超微结构改变及其药物影响

目的　探讨高血压大鼠大脑中动脉超微结构的变化及血管紧张素转换酶抑制剂的影响。方法　选用易卒中型肾血管性高血压大鼠模型 ,分为高血压组、卡托普利治疗组 ,并与假手术正常血压大鼠作对照 ,分别于肾动脉狭窄术后 4、8和 12周处死动物 ,取大脑中动脉 ,制片后分别用光镜和透射电镜观察 ,并进行体视学定量分析。结果　术后 4周时高血压组大脑中动脉光镜下无明显形态学变化 ;8周和 12周时中膜厚度、中膜与管腔比值与假手术对照组相比均有显著性差异 (P <0 .0 5 ) ;卡托普利治疗后中膜厚度、壁腔比值均小于高血压组 ,差异有显著性 (P <0 0 5 )。术后 4周高血压组大脑中动脉超微结构仅轻度异常 ;术后 8周细胞间隙增宽 ,间质明显水肿 ;12周时平滑肌细胞坏死 ,内质网扩张 ,线粒体部分空泡变性 ,核自溶 ,间质增生 ;卡托普利组各时期超微结构改变不明显。结论　高血压可致大脑中动脉肥厚和超微结构破坏 ,而卡托普利可以减轻高血压所致的大脑中动脉结构破坏。     

自发性高血压大鼠高血压前期及高血压期脑动脉的形态计量学研究

用半自动图像分析仪对7周和17周龄自发性高血压大鼠的脑动脉进行形态计量学研究,并与Wistar-Kyoto大鼠对照。结果表明,自发性高血压大鼠在高血压前期及高血压期脑动脉中膜与对照组比较均明显增厚;细动脉中膜增厚是因平滑肌细胞肥大所致。自发性高血压大鼠在高血压前期已有动脉中膜肥厚,提示这种血管壁结构变异对高血压的发生发展有重要意义。     

非降压剂量血管紧张素转换酶抑制剂对高血压冠状动脉肥厚的影响

目的　研究非降压剂量的血管紧张素转换酶抑制剂 (ACEI)对高血压冠状动脉肥厚的影响。方法 16周大鼠设4组 (各组n =6 ) :分别为自发性高血压大鼠 (SHR)组、SHR口服降压剂量卡托普利组 (40mg·kg- 1 ·d- 1 )、SHR口服非降压剂量卡托普利组 (2mg·kg- 1 ·d - 1 )和正常血压大鼠 (WKY)组 ,饲养 10周。结果　降压剂量卡托普利治疗显著降低SHR的收缩压 ,非降压剂量卡托普利治疗不降低SHR的收缩压 ;降压和非降压剂量卡托普利都显著减少了SHR冠状动脉壁横截面积、横截面积 内径比 ,减轻SHR冠状动脉前降支中层血管平滑肌细胞的肥大 ,都显著提高SHR的最大冠状动脉流量。结论　ACEI治疗对冠状动脉肥厚的逆转作用和对冠状动脉功能的改善作用可以不依赖于血压下降的效果 ,临床上应用ACEI降压不明显的病人继续使用ACEI可能有助于逆转血管壁肥厚 ,改善血管功能。     

高血压血管重构与药物干预

各类降压药物均能达到降压之目的,但对逆转血管重构的机制和效果不同。高血压治疗的现代策略认为:治疗不应仅局限在降低血压,还应该强调靶器官保护,阻止或逆转各种并发症,高血压血管重构及药物干预研究是该领域的热点问题,对高血压防治有重要意义。本文就高血压血管重构的特点、机制及药物逆转效应进行综述。1　血管重构概念血管重构(remodeling)又称血管重塑、重建。文献中常用来泛指各种类型结构和功能的改变。高血压时血管结构的改变主要表现为血管平滑肌细胞(VSMC)肥大、增生以及结缔组织增加,其结果是血管壁增厚尤其是中层肥厚,壁腔…     

卡托普地高血压冠状动脉壁肥和储备力下降的预防作用

目的 研究卡托普利对高血压冠状动脉壁肥厚和储备力下降的预防作用。方法 ４ｗ大鼠设３组：分别为自发性高血压大鼠（ＳＨＲ）组、ＳＨＲ口服卡托普利组（ＳＨＲ＋Ｃ）和正常血压大鼠（ＷＫＹ）组,饲养１２ｗ。结果 ＳＨＲ＋Ｃ组较ＳＨＲ组,收缩压、冠状动脉壁横截面积、横截面积与内径比及中层血管平滑肌细胞宽度显著下降,最大冠状动脉流量增加,与ＷＫＹ组无显著差异。结论 卡托普利能完全预防ＳＨＲ冠状动脉壁肥厚和储备力     

卡托普利抑制自发性高血压大鼠血管平滑肌细胞增殖的机制

卡托普利抑制自发性高血压大鼠血管平滑肌细胞增殖的机制王向宇吴可贵晋学庆许昌声王华军肾素－血管紧张素系统（ＲＡＳ）在高血压心血管肥厚中起重要作用。血管紧张素转换酶抑制剂（ＡＣＥＩ）降低血压、逆转心血管肥厚，主要是通过抑制心血管本身ＲＡＳ实现［１］。本实...     

内质网应激在压力性负荷高血压大鼠血管重构中的作用

目的研究内质网应激(ERS)在压力性负荷高血压大鼠血管重构中的作用。方法 90只Wistar大鼠分为对照组、模型组。模型组采用腹主动脉狭窄术建立高血压大鼠模型,各组按术后时间1 w、2 w、4 w、6 w时采用鼠尾动脉测压法测量动物血压,随后麻醉动物分离并截取主动脉标本行病理切片和免疫组化处理,再利用图像分析系统测量血管壁肌层厚度、Western印迹检测葡萄糖调节蛋白(GRP) 78和CHOP的表达、TUNEL法检测血管平滑肌细胞凋亡率。结果模型组术后血管平滑肌细胞形态改变,血压、动脉血管壁肌层厚度和平滑肌细胞凋亡率可时间依赖性增大,GRP78在术后1、2 w表达显著升高,4、6 w表达降低,而CHOP在术后2 w以后表达才升高,且随时间推迟,这种高表达越显著。结论 ERS的双向调节作用参与高血压血管重构,压力性负荷所致的高血压发生早期,ERS保护性因子GRP78占主导地位;应激中晚期,损伤因子CHOP表达升高发挥作用,使构成血管壁的肌层细胞凋亡增多,同时血管中膜肌层增厚。     

卡托普利对人离体动脉平滑肌细胞肾素－血管紧张素系统的影响

采用高血压患者（ＥＨ）的离体动脉血管，并分离、培养动脉平滑肌细胞（ＡＳＭＣ）．观察卡托普利对人ＡＳＭＣ合成和分泌肾素的影响。结果表明：体外培养的ＡＳＭＣ能合成和分泌肾素和血管紧张承Ⅱ（ＡｎｇⅡ）。ＥＨ组ＡＳＭＣ及培养液中的肾素活性（ＲＡ）和ＡｎｇⅡ显著高于正常血压组（ＮＴ）；ＲＡ和ＡｎｇⅡ与血压呈显著正相关（ｒ＝０．８４，０．９；Ｐ＜０．０１）。应用卡托普利后，ＥＨ组的ＡＳＭＣ内ＲＡ显著升高，而ＡｎｇⅡ则明显下降。结果提示血管存在着独立的肾素－血管紧张素系统（ＲＡＳ），高血压时血管ＲＡＳ异常活跃，卡托普利长期抗高血压的主要机理之一是抑制血管壁血管紧张素转换酶活性，减少局部ＡｎｇⅡ的产生。     

Evaluation of medial hypertrophy in resistance vessels of spontaneously hypertensive rats

The role of smooth muscle cell hypertrophy, hyperploidy, and hyperplasia in medial hypertrophy of mesenteric resistance vessels of 107- to 111-day-old spontaneously hypertensive rats (SHR) was examined using a combination of morphometric, biochemical, and immunological techniques. Mesenteric arteries were classified on the basis of branching order for comparative purposes. Branch level I vessels were those that directly enter the jejunal wall, while Branches II to IV represented more proximal vessels; Branch IV vessels were those that branch from the superior mesenteric artery. Medial hypertrophy was assessed in perfusion-fixed vessels by morphometric evaluation of medial cross-sectional area and smooth muscle content. Medial cross-sectional area and smooth muscle content were significantly increased in larger (Branches III and IV) but not smaller (Branches I and II) mesenteric resistance vessels of SHR compared with control normotensive Wistar-Kyoto rats (WKY). Smooth muscle cell hypertrophy and hyperploidy were evaluated in isolated cells obtained by enzymatic dissociation of mesenteric resistance vessels. Approximately 80% of the cells in these preparations were identified as smooth muscle cells using a smooth muscle-specific isoactin antibody. Feulgen-DNA microdensitometric evaluation of isolated cells showed that polyploid cells were present in mesenteric resistance vessels but at very low frequencies, and no differences were apparent between SHR and WKY. Likewise, no differences in cellular protein content or relative smooth muscle cell size (i.e., area profile) were observed between cells obtained from SHR and WKY vessels. These results demonstrate that the increase in medial smooth muscle content observed in larger mesenteric resistance vessels of SHR cannot be accounted for by smooth muscle hypertrophy and hyperploidy, inferring that hyperplasia must be present. Results indicate that studies of the initiating mechanisms for medial smooth muscle hypertrophy in SHR resistance vessels, at least relatively early in hypertension, should focus on examination of factors that induce true cellular proliferation rather than hypertrophy and hyperploidy.     

Differential effects of antihypertensive drug therapy on vascular smooth muscle cell hypertrophy, hyperploidy, and hyperplasia in the spontaneously hypertensive rat

The present report extends our previous studies of smooth muscle cell hypertrophy, hyperploidy, and hyperplasia in the 5-month-old spontaneously hypertensive and Wistar-Kyoto rats to include analyses of 3- and 7-month-old rats and explores the effects of antihypertensive drug treatment on the accelerated growth of vascular smooth muscle in aortas of spontaneously hypertensive vs. Wistar-Kyoto rats. Drug-treated rats were administered a combination of reserpine, hydralazine, and chlorathiazide in their drinking water, either between 3 and 5 months or between 5 and 7 months of age. Drug treatment decreased the blood pressure of spontaneously hypertensive rats to values at or below those of Wistar-Kyoto rats for both age-treatment groups. Smooth muscle growth was evaluated by morphometric analyses of aortic smooth muscle content, flow cytometric and microdensitometric measurements of the frequency of polyploid smooth muscle cells, biochemical estimates of aortic medial smooth muscle cell number, and microdensitometric measurements of individual smooth muscle cell protein content. The following results were obtained. Aortic medial smooth muscle content was not significantly increased in 3-month spontaneously hypertensive compared to Wistar-Kyoto rats, indicating that aortic smooth muscle hypertrophy occurred post-3 months, as well as after blood pressure was elevated. In 5-month-old spontaneously hypertensive and Wistar-Kyoto rats, medial smooth muscle hypertrophy could be accounted for by cellular hypertrophy without hyperplasia; in contrast, medial hypertrophy in 7-month-old spontaneously hypertensive rats involved both cellular hypertrophy and hyperplasia. Antihypertensive treatment prevented the accelerated growth of vascular smooth muscle that occurred in spontaneously hypertensive rats via cellular hypertrophy and hyperploidy, but it did not prevent an increase in smooth muscle cell number in spontaneously hypertensive rats between 5 and 7 months of age. Furthermore, it had no effect on the parallel increases in aortic medial smooth muscle cell number that occurred in both spontaneously hypertensive and Wistar-Kyoto rats between 3 and 5 months of age. Whereas drug treatment prevented accelerated development of smooth muscle cell polyploidism in spontaneously hypertensive rats, in no case (spontaneously hypertensive or Wistar-Kyoto rats) did it reverse changes in ploidy that existed at the time of initiation of drug treatment, although it did cause cellular atrophy in smooth muscle cells of each ploidy class.(ABSTRACT TRUNCATED AT 400 WORDS)     

Adrenergic mechanisms and remodeling of subcutaneous small resistance arteries in humans

BACKGROUND: Vascular structural alterations in small resistance arteries of patients with essential hypertension (EH) are mostly characterized by inward eutrophic remodeling. In fact, no difference in the smooth muscle cell volume (CV) between normotensive subjects (NT) and essential hypertensive patients was observed. However, experimental models of hypertension with chronic infusion of agonists of adrenergic receptors were characterized by the presence of smooth muscle cell hypertrophy or hyperplasia. Recently, we have observed the presence of vascular smooth muscle cell hypertrophy in patients with renovascular hypertension. OBJECTIVE: The aim of the study to investigate the structural characteristics of subcutaneous small resistance arteries of NT, of EH, and of patients with phaeochromocytoma (Phaeo). PATIENTS AND METHODS: Thirty Phaeo, 30 NT and 30 EH were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small resistance arteries (relaxed diameter 160-280 microm) were dissected and mounted on a micromyograph and the media : lumen ratio was calculated. In nine Phaeo, nine NT and 13 EH the cell volume was measured by an unbiased stereological principle, the 'disector' method.RESULTS No difference in smooth muscle cell volume was observed between groups. However, inward remodeling in Phaeo was less marked than in EH, although the increase in media : lumen ratio was similar compared with NT. However, the lack of changes in media cross-sectional area, compared with NT, suggest that there has been little hypertrophy, the changes observed thus being eutrophic. CONCLUSIONS: Our data show, based on a reasonably large sample, that a pronounced activation of the adrenergic system is not associated with vascular smooth muscle cell hypertrophy or hyperplasia in humans. It is therefore possible that adrenergic mechanisms may have a relevant role in the development of eutrophic remodeling in small vessels.     

Cellular hypertrophy in mesenteric resistance vessels from renal hypertensive rats

To determine whether the increased thickness seen in media of mesenteric resistance vessels of Wistar-Kyoto rats made hypertensive by a Goldblatt procedure (one-kidney, one clip model) was due to hypertrophy or hyperplasia of smooth muscle cells, the cellular dimensions of these vessels were estimated using a new, unbiased stereological method (the disector). Furthermore, to investigate whether the changes seen could be secondary to the increased blood pressure, morphometric measurements were also made in renal arcuate arteries, which, due to the constricting silver clip, probably had not been exposed to the increased pressure load. Vessels were mounted on a myograph, and their media thickness, lumen diameter, and maximum active wall tension response were measured. In the mesenteric vessels media thickness had increased by 58%, whereas no changes were seen in the renal vessels. Vessels were then fixed, and serial sections were made in the mesenteric vessels. The disector was used to calculate the numerical cell density in each vessel. By combining the myograph measurements and the estimated numerical cell density, the number of cells per segment unit length was calculated (renal hypertensive rats, 6.8 micron-1; sham-operated Wistar-Kyoto rats, 6.3 micron-1; p greater than 0.40) and mean cell volume was determined (renal hypertensive rats, 1541 micron 3; sham-operated Wistar-Kyoto rats, 1256 micron 3; p less than 0.02). No morphometrical changes were found in single sections of the renal arteries. We conclude that the increased media thickness observed in mesenteric resistance vessels of one-kidney, one clip Goldblatt hypertensive rats mainly was caused by smooth muscle cell hypertrophy.     

Airway remodeling in asthma and irreversible airflow limitation-ECM deposition in airway and possible therapy for remodeling-.

Airway remodeling in asthma is characterized by goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. The airway wall thickness increases because of subepithelial fibrosis, and hyperplasia and hypertrophy of the airway smooth muscle cells and submucosal glands. Airway remodeling, therefore, can often cause irreversible airflow limitation and an increase of airway hyperresponsiveness. Recent studies have described the molecular and cellular mechanisms of collagen deposition in the airway wall such as subepithelial fibrosis. Fibroblasts or myofibroblasts play a critical role in the exaggerated deposition of collagen in asthmatic airways. Bone marrow derived fibroblasts may play a role in fibrotic remodeling in asthmatic airways. Airway remodeling is induced by cytokines and mediators produced in chronic allergic airway inflammation. Since, once formed, remodeling is resistant to asthma therapy, early intervention with inhaled corticosteroid should be considered to prevent the progress of airway remodeling.     

Impairment of hypoxic pulmonary artery remodeling by heparin in mice

Chronic hypoxia produces pulmonary artery hypertension and remodeling of pulmonary arteries with hypertrophy of smooth muscle in the media and extension of smooth muscle into more distal small precapillary arteries. The present study investigated the influence of heparin, an inhibitor of platelet-derived growth factor, and of the clotting cascade on this remodeling. Mice maintained in room air or 10% O2 for 26 days were treated with low-dose heparin at 75 units/kg or high dose heparin at 300 units/kg. Pulmonary hypertension and right ventricular hypertrophy developed in the hypoxic mice compared with the room air mice as evidenced by the greater (p less than 0.05) right ventricular systolic pressure (36 +/- 4 SEM versus 21 +/- 1 mmHg) and the increase (p less than 0.05) in right heart weight/left ventricular plus septal weight (35 +/- 1.6 SEM versus 25.2 +/- 1.3). Hypoxia also induced smooth muscle hypertrophy in small pulmonary arteries, with an increase (p less than 0.05) in the percent media thickness/vascular diameter from 5.7 +/- 1 SEM to 13.3 +/- 3 and an apparent decrease (p less than 0.05) in distal small pulmonary arteries from 4.4 +/- 0.2 SEM to 2.05 +/- 0.1 per 100 alveoli. High-dose heparin partially but significantly (p less than 0.05) prevented the pulmonary artery hypertension (right ventricular systolic pressure of 28 +/- 2 mmHg), the right ventricular hypertrophy (right ventricular weight/left ventricular plus septal weight of 30.1 +/- 1) and remodeling of distal small pulmonary arteries (media thickness/vascular diameter of 8.4 +/- 1%, small pulmonary artery/100 alveoli of 3.63 +/- 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphometric study of mesenteric arteries from genetically hypertensive Dahl strain rats

Morphometric measurements on different arteries at the light-microscopic level and ultrastructural studies of the mesenteric arteries were carried out in salt-sensitive (DS) and salt-resistant (DR) Dahl rats given a high-salt (8%) or low-salt (0.4%) diet for 6-7 weeks. Hypertension was produced in DS rats given high-salt diet (DS-H), while only moderate hypertension was produced in DS rats given low-salt diet (DS-L). Blood pressure in DR rats given high salt (DR-H) and low salt (DR-L), however, was normal. Cross-sectional area of the media was increased significantly in the superior mesenteric artery (an elastic artery), large mesenteric arteries (muscular arteries) and small mesenteric arteries (small muscular arteries or arterioles) from DS-H rats. In all the vessel types, this increase was positively correlated with the increase in blood pressure. In the superior mesenteric artery, medial wall increase was probably due to an increase in intercellular space, and/or hypertrophy of the smooth muscle cells. Similarly, increase in the media of small mesenteric arteries was probably due to hypertrophy of the smooth muscle cells. In contrast, increase in the media of large mesenteric arteries was related to hyperplasia of the smooth muscle cells. Damage to endothelial cells was noted in the 3 vessel types from DS-H. Intimal lesions composed of myointimal cells were found in the superior mesenteric arteries of all the rat groups. Our results showed that the incidence of these lesion formations was higher in the following order: DS-H greater than DS-L greater than DR-H greater than DR-L, suggesting that the degree of hypertension (DS vs. DR rats) and the amount of salt in the diet (DR-H vs. DR-L) may be some of the factors contributing to the development of these lesions. We conclude that hyperreactivity of the arteries due to increase in medial smooth muscle mass (e.g. muscular arteries), and/or probably impaired relaxation capability of the arteries in the DS-H rats due to endothelial cell damage, may contribute to the elevation of BP in the Dahl model of genetic hypertension.     

Mechanisms underlying hypertrophic remodeling and increased stiffness of mesenteric resistance arteries from aged rats

The mechanisms associated with structural and mechanical alterations of mesenteric resistance arteries from aged rats were investigated by using pressure myography, confocal microscopy, immunofluorescence, and picrosirius red staining. Arteries from old rats showed: (i) increased wall and media thickness, greater number of smooth muscle cell (SMC) layers but decreased density of SMC; (ii) increased number of adventitial cells; (iii) hypertrophy of nuclei of SMC and endothelial cells; (iv) increased stiffness associated with increased total collagen content and collagen I/III deposition in the media; and (v) similar content but changes in elastin structure in the internal elastic lamina. Hypertrophic outward remodeling in aged rat resistance arteries involve adventitial cells hyperplasia, reorganization of the same number of hypertrophied SMC in more SMC layers leading to thickened media and endothelial cell hypertrophy. Fibrosis associated with collagen deposition and changes in elastin structure might be responsible for the increased stiffness of resistance arteries from aged rats.