Levy B I, Duriez M, Phillipe M, Poitevin P, Michel J B
Institut National de la Santé et de la Recherche Medical (INSERM), Unit 141, University Paris VII, France.
Circulation. 1994 Dec;90(6):3024-33. doi: 10.1161/01.cir.90.6.3024.
The effect of genetic hypertension and of chronic therapy by calcium entry blocker (CEB, isradipine) on the function and structure of large arteries has been studied in adult spontaneously hypertensive rats (SHR, n = 30) and in their normotensive control Wistar-Kyoto (WKY) rats (n = 30).
Fifteen-week-old rats were randomly allocated to treatment with isradipine (3 mg/kg subcutaneously once a day) or to placebo and followed for 12 weeks. Hemodynamic parameters, including instantaneous pressure and aortic velocity, were recorded under anesthesia at the end of the treatment period. Passive mechanical properties of carotid arteries were measured in situ in the presence or the absence of smooth muscle cell activity (potassium cyanide poisoning). Histomorphometric parameters of the carotid and aortic media, including cross-sectional area, medial thickness, nucleus density and size, and medial contents of proteins of interstitial matrix, were measured by an automated morphometric system. Untreated SHRs had greater peripheral resistance, stiffer and thicker arterial walls because of smooth muscle cell hyperplasia (thoracic aorta and carotid artery) and/or hypertrophy (thoracic aorta), and increased collagen content than did normotensive control rats. SHRs showed a significant left ventricular hypertrophy. For the whole duration of treatment, treatment with CEB normalized the arterial pressure in SHRs. We observed a significant decrease in peripheral resistance, increased cardiac output, and left ventricular contractility without significant reduction in left ventricular hypertrophy. Increases in diuresis and natriuresis were associated during the last week of treatment in both treated strains with marked increase in plasma renin activity; in contrast, urinary aldosterone was increased by treatment in WKY rats but not in SHRs. Arterial compliance was significantly increased by CEB under control and passive conditions. CEB induced a significant reduction in the medial hypertrophy of the aortic walls of SHRs and WKY rats associated with a reduction in medial hyperplasia. In the carotid artery, CEB reduced smooth muscle cell hypertrophy but did not affect the smooth muscle cell hyperplasia. Isradipine significantly reduced the arterial wall collagen contents in both strains, with marked increases in the elastin content in the carotid but not in the aortic wall.
These results suggest that (1) despite normalization of arterial pressure, chronic treatment with CEB in SHRs does not significantly reduce left ventricular hypertrophy, probably because of increase in myocardial contractility and/or increase in plasma renin activity; (2) mechanical properties of the arterial wall are normalized by treatment; and (3) remodeling of the arterial wall by CEB is not uniform according to the studied vessel.
在成年自发性高血压大鼠（SHR，n = 30）及其血压正常的对照Wistar - Kyoto（WKY）大鼠（n = 30）中，研究了遗传性高血压以及钙通道阻滞剂（CEB，伊拉地平）长期治疗对大动脉功能和结构的影响。
将15周龄的大鼠随机分为接受伊拉地平治疗组（3mg/kg皮下注射，每日1次）或安慰剂组，并随访12周。在治疗期结束时，于麻醉状态下记录血流动力学参数，包括瞬时压力和主动脉流速。在有无平滑肌细胞活性（氰化钾中毒）的情况下，原位测量颈动脉的被动力学特性。通过自动形态测量系统测量颈动脉和主动脉中膜的组织形态计量学参数，包括横截面积、中膜厚度、细胞核密度和大小以及间质基质蛋白质的中膜含量。未经治疗的SHR由于平滑肌细胞增生（胸主动脉和颈动脉）和/或肥大（胸主动脉）以及胶原含量增加，其外周阻力更高，动脉壁更硬更厚。SHR表现出明显的左心室肥大。在整个治疗期间，CEB治疗使SHR的动脉血压恢复正常。我们观察到外周阻力显著降低、心输出量增加以及左心室收缩力增强，而左心室肥大没有显著减轻。在两种治疗组大鼠治疗的最后一周，利尿和利钠增加与血浆肾素活性显著增加相关；相反，WKY大鼠经治疗后尿醛固酮增加，而SHR未增加。在对照和被动条件下，CEB均显著增加了动脉顺应性。CEB使SHR和WKY大鼠主动脉壁的中膜肥大显著减轻，同时中膜增生减少。在颈动脉中，CEB减轻了平滑肌细胞肥大，但未影响平滑肌细胞增生。伊拉地平显著降低了两种大鼠的动脉壁胶原含量，颈动脉弹性蛋白含量显著增加，而主动脉壁未增加。
这些结果表明：（1）尽管动脉血压恢复正常，但SHR长期接受CEB治疗并未显著减轻左心室肥大，可能是由于心肌收缩力增加和/或血浆肾素活性增加；（2）治疗使动脉壁的力学特性恢复正常；（3）根据所研究的血管不同，CEB对动脉壁的重塑并不一致。
