Pharmacological Research 56 (2007) 42–48 Therapeutic modulation of the nitric oxide: all ace inhibitors are not equivalent L. Comini a,∗ , T. Bachetti a , A. Cargnoni a , D. Bastianon a , G.L. Gitti a , C. Ceconi b , R. Ferrari b a Cardiovascular Pathophysiology Research Center, “Salvatore Maugeri” Foundation, IRCCS, Gussago, Brescia, Italy b Chair of Cardiology, University of Ferrara, Italy Accepted 19 March 2007 Abstract 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 g -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 g -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 ≈ quinapril ≈ ramipril ≈ 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. © 2007 Elsevier Ltd. All rights reserved. Keywords: ACE inhibitor; NO synthase; Endothelium; Cardiac myocyte; Bradykinin 1. Introduction Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of cardiovascular and renal diseases [1–4]. Although they differ in chemical structure [5], potency, bioavail- ability, plasma half-life, distribution, and affinity for tissue ACE [6], as well as whether their activity is exerted at the prodrug Abbreviations: ACE, angiotensin-converting enzyme; Ang I, Ang II, angiotensin I, angiotensin II; BK, bradykinin; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; NOx, nitrites/nitrates ∗ Corresponding author at: Cardiovascular Pathophysiology Research Cen- ter, “Salvatore Maugeri” Foundation, IRCCS, Via Pinidolo, 23, 25064 Gussago (Brescia), Italy. Tel.: +39 030 2528391; fax: +39 030 2522362. E-mail address: lcomini@fsm.it (L. Comini). or drug stage, all ACE inhibitors are known to alter the balance between the actions of angiotensin II (Ang II) [7], i.e., vasocon- striction, salt retention, and hypertrophy, and those of bradykinin (BK) [8], i.e., vasodilation and natriuresis. From a clinical point of view, the effects of ACE inhibitors are often considered the result of a class action. How- ever, this opinion has been challenged by the findings from recent clinical trials such as EUROPA [9] (European trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), HOPE [10] (Heart Outcomes Pre- vention Evaluation), PEACE [11] (Prevention of Events with Angiotensin-Converting Enzyme inhibition), and QUIET [12] (QUinapril Ischemic Event Trial). Interestingly, these trials showed that different ACE inhibitors produced different effects, particularly with respect to secondary cardiovascular preven- 1043-6618/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2007.03.004