Schiffrin E L, Deng L Y, Sventek P, Day R
MRC Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Quebec, Canada.
J Hypertens. 1997 Jan;15(1):57-63. doi: 10.1097/00004872-199715010-00005.
Endothelins are potent vasoconstrictors, and may also act as mitogens and hypertrophic agents. Expression of a member of this family of peptides, endothelin-1, is enhanced in the endothelium of blood vessels of rats with severe forms of hypertension, even in the absence of elevated plasma endothelin levels. In some of these hypertensive models enhanced endothelin-1 gene expression may contribute to vascular hypertrophy of small arteries and to elevation of blood pressure.
To establish whether endothelin-1 may play a role in essential hypertension in humans, in whom plasma levels are known to be usually within normal limits, by examining the expression of the endothelin-1 gene in resistance-size arteries of normotensive subjects, and in humans with mild and severe hypertension.
Using in-situ hybridization, the abundance of endothelin-1 messenger RNA transcripts was evaluated in small arteries of subcutaneous gluteal fat obtained by biopsy in normotensive and hypertensive patients.
Vessels from five normotensive subjects and four untreated mild essential hypertensive patients did not exhibit topographically localized specific labeling with the antisense human endothelin-1 probe. Biopsies from four untreated hypertensive patients with moderate-to-severe blood pressure elevation, in contrast, showed a heavy density of grains on endothelial cells of small arteries of gluteal subcutaneous fat, corresponding to hybridization of the antisense human endothelin-1 complementary RNA probe with endothelin-1 messenger RNA.
Some patients with moderate-to-severe essential hypertension, similar to some experimental rat models with severe blood pressure elevation, exhibit enhanced endothelial expression of the endothelin-1 gene. This is the first demonstration that overexpression of the endothelin-1 gene may occur in the vascular wall in a small sample of this subset of hypertensive patients. This pathophysiologic phenomenon could play a role in blood pressure elevation and perhaps in the pathogenesis of vascular hypertrophy. Treatment with endothelin receptor antagonists may offer a novel therapy for these moderate-to-severe hypertensive patients.
内皮素是强效血管收缩剂，也可能作为促细胞分裂剂和肥大因子发挥作用。在患有严重高血压的大鼠血管内皮中，该肽家族成员之一内皮素-1的表达增强，即使血浆内皮素水平未升高。在一些此类高血压模型中，内皮素-1基因表达增强可能导致小动脉血管肥大和血压升高。
通过检测正常血压受试者以及轻度和重度高血压患者的阻力动脉中内皮素-1基因的表达，确定内皮素-1是否在血浆水平通常在正常范围内的人类原发性高血压中起作用。
采用原位杂交技术，评估通过活检获取的正常血压和高血压患者臀下皮下脂肪小动脉中内皮素-1信使核糖核酸转录本的丰度。
来自5名正常血压受试者和4名未经治疗的轻度原发性高血压患者的血管，用反义人内皮素-1探针未显示出局部特异性标记。相比之下，4名未经治疗的中度至重度血压升高的高血压患者的活检显示，臀下皮下脂肪小动脉内皮细胞上有大量颗粒，对应于反义人内皮素-1互补核糖核酸探针与内皮素-1信使核糖核酸的杂交。
一些中度至重度原发性高血压患者，类似于一些严重血压升高的实验大鼠模型，表现出内皮素-1基因的内皮表达增强。这是首次证明在一小部分此类高血压患者的血管壁中可能发生内皮素-1基因的过表达。这种病理生理现象可能在血压升高中起作用，也许还在血管肥大的发病机制中起作用。内皮素受体拮抗剂治疗可能为这些中度至重度高血压患者提供一种新的治疗方法。
