Comini L, Bachetti T, Cargnoni A, Bastianon D, Gitti G L, Ceconi C, Ferrari R
Cardiovascular Pathophysiology Research Center, Salvatore Maugeri Foundation, IRCCS, Gussago, Brescia, Italy.
Pharmacol Res. 2007 Jul;56(1):42-8. doi: 10.1016/j.phrs.2007.03.004. Epub 2007 Mar 27.
The properties of the angiotensin-converting enzyme (ACE) inhibitors have largely been attributed to a class effect. However, this opinion is now increasingly challenged in view of the findings from recent clinical trials, which have demonstrated differential effects of ACE inhibitors, in particular with respect to secondary cardiovascular prevention outcomes. In this experimental study, Sprague-Dawley rats were treated with five different ACE inhibitors (enalapril, perindopril, quinapril, ramipril, and trandolapril) at equihypotensive doses. All ACE inhibitors increased endothelial nitric oxide synthase (eNOS) protein expression and activity in the aorta (both P<0.0001 versus vehicle) and in cardiac myocytes (both P<0.05 versus vehicle). A highly significant effect was observed with perindopril when compared with vehicle in the modulation of eNOS protein expression and activity in aorta (22.52+/-1.09 versus 9.12+/-0.57 AU microg(-1) protein and 1.59+/-0.03 versus 0.77+/-0.02 pmol l(-1) citrulline min(-1)mg protein(-1), respectively) and in cardiac myocytes (17.64+/-0.94 versus 11.30+/-0.59 AU microg(-1) protein and 0.93+/-0.02 versus 0.62+/-0.03 pmol l(-1) citrulline min(-1)mg protein(-1), respectively). On the basis of the eNOS protein expression in the rat aorta, the other ACE inhibitors had similar, but lower effects. Indeed, the rank of potency - based both on eNOS protein expression and activity - was perindopril>trandolapril approximately quinapril approximately ramipril approximately enalapril (P<0.05 perindopril versus trandolapril and ramipril and P<0.01 perindopril versus enalapril, respectively). Levels of circulating nitrite/nitrate, the end-metabolites of nitric oxide, were also significantly affected by ACE inhibition, with the same order of potency. Our findings provide further evidence in favor of differential effects associated with ACE inhibitor therapy and suggest that the clinical benefits associated with these drugs may not solely reflect a class effect extending their benefit beyond blood pressure-lowering effect.
血管紧张素转换酶（ACE）抑制剂的特性很大程度上归因于类效应。然而，鉴于近期临床试验的结果，这一观点现在受到越来越多的挑战，这些试验表明ACE抑制剂具有不同的效应，特别是在二级心血管预防结果方面。在这项实验研究中，用五种不同的ACE抑制剂（依那普利、培哚普利、喹那普利、雷米普利和群多普利）以等降压剂量治疗Sprague-Dawley大鼠。所有ACE抑制剂均增加了主动脉（与溶剂相比，两者P<0.0001）和心肌细胞（与溶剂相比，两者P<0.05）中内皮型一氧化氮合酶（eNOS）蛋白表达和活性。与溶剂相比，培哚普利在调节主动脉（分别为22.52±1.09对9.12±0.57 AU μg（-1）蛋白和1.59±0.03对0.77±0.02 pmol l（-1）瓜氨酸min（-1）mg蛋白（-1））和心肌细胞（分别为17.64±0.94对11.30±0.59 AU μg（-1）蛋白和0.93±0.02对0.62±0.03 pmol l（-1）瓜氨酸min（-1）mg蛋白（-1））中eNOS蛋白表达和活性方面观察到高度显著的效应。根据大鼠主动脉中的eNOS蛋白表达，其他ACE抑制剂具有相似但较低的效应。实际上，基于eNOS蛋白表达和活性的效价顺序为培哚普利>群多普利≈喹那普利≈雷米普利≈依那普利（培哚普利与群多普利和雷米普利相比，P<0.05；培哚普利与依那普利相比，P<0.01）。循环亚硝酸盐/硝酸盐（一氧化氮的终代谢产物）水平也受到ACE抑制的显著影响，效价顺序相同。我们的研究结果提供了进一步的证据支持与ACE抑制剂治疗相关的不同效应，并表明与这些药物相关的临床益处可能不仅仅反映类效应，其益处超出了降压作用。
