Li J S, Schiffrin E L
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Quebec, Canada.
J Cardiovasc Pharmacol. 1996 Jul;28(1):68-74. doi: 10.1097/00005344-199607000-00011.
Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto control rats (WKY) were treated for 14 weeks with a novel calcium channel blocker, mibefradil (Ro40-5967), or an angiotensin-converting enzyme inhibitor, cilazapril. Blood pressure was significantly reduced by treatment in SHRs from > 200 mm Hg to 155 +/- 2 mm Hg by mibefradil and to 138 +/- 1 mm Hg by cilazapril (p < 0.01). Cardiac hypertrophy was significantly reduced by treatment but to a greater degree with cilazapril than with mibefradil. Conduit and large arteries also had significant regression of hypertrophy. Small arteries (luminal diameter, 200-300 microns) of the coronary, renal, mesenteric, and femoral circulations exhibited significant hypertrophy and remodeling in SHRs in comparison to WKYs. Cilazapril treatment resulted in increased lumen, reduced media thickness, and media-to-lumen ratio in all four vascular beds. Mibefradil treatment induced regression of luminal diameter to a significant degree only in the mesenteric and femoral small arteries but decreased media thickness and media to lumen diameter in all four vascular beds. The greater extent of regression of cardiac and vascular hypertrophy and remodeling with cilazapril than with mibefradil may relate to the degree of blood pressure reduction, which, with the doses used, was larger with the angiotensin-converting enzyme inhibitor than with the calcium channel blocker. In WKY rats, treatment had no effect except with cilazapril on lumen diameter of small arteries and with mibefradil on heart weight, both of which increased. These results demonstrate the blood-pressure dependence of regression of cardiovascular hypertrophy and remodeling and the possibility of achieving "reverse remodeling" of large and small arteries with converting enzyme inhibition or calcium channel blockade in SHRs, as well as the near absence of effects of these agents on cardiovascular characteristics in WKYs.
将自发性高血压大鼠（SHRs）和Wistar-Kyoto对照大鼠（WKY）用新型钙通道阻滞剂米贝拉地尔（Ro40-5967）或血管紧张素转换酶抑制剂西拉普利治疗14周。米贝拉地尔治疗使SHRs的血压从>200 mmHg显著降低至155±2 mmHg，西拉普利使其降至138±1 mmHg（p<0.01）。治疗可显著减轻心脏肥大，但西拉普利的效果比米贝拉地尔更显著。传导血管和大动脉的肥大也有显著消退。与WKYs相比，SHRs的冠状动脉、肾动脉、肠系膜动脉和股动脉的小动脉（管腔直径200-300微米）表现出显著的肥大和重塑。西拉普利治疗导致所有四个血管床的管腔增大、中膜厚度减小以及中膜与管腔比值降低。米贝拉地尔治疗仅在肠系膜和股部小动脉中使管腔直径有显著程度的缩小，但在所有四个血管床中均降低了中膜厚度和中膜与管腔直径比值。与米贝拉地尔相比，西拉普利在减轻心脏和血管肥大及重塑方面程度更大，这可能与血压降低程度有关，在所使用的剂量下，血管紧张素转换酶抑制剂降低血压的幅度大于钙通道阻滞剂。在WKY大鼠中，除西拉普利对小动脉管腔直径有影响以及米贝拉地尔对心脏重量有影响（二者均增加）外，治疗无其他作用。这些结果证明了心血管肥大和重塑消退对血压的依赖性，以及在SHRs中通过转换酶抑制或钙通道阻滞实现大小动脉“逆向重塑”的可能性，同时也表明这些药物对WKYs的心血管特征几乎没有影响。
