CARDIOVASCULAR DISEASE MANAGEMENT | REVIEW Safety and Efficacy of the bi-Sulfydryl ACE-Inhibitor Zofenopril in the Management of Cardiovascular Disease Claudio Napoli, Department of General Pathology, Division of Clinical Pathology & Excellence Research Centre on Cardiovascular Disease Recieved 15/08/2009, Reviewed 21/08/2009, Accepted 27/08/2009 Keywords: ACE, zofenopril, atherosclerosis, acute myocardial infarction DOI:10.5083/ apjcm.20424906.05 ABSTRACT CORRESPONDENCE In the 1970s, pharmacological therapy interrupting the renin-angiotensin system was considered Claudio Napoli beneficial for patients with high-renin hypertension. Angiotensin-converting enzyme (ACE) Department of inhibitors proved to be effective not only in patients with high renin and elevated blood pressure, General Pathology, but also in many hypertensive patients with normal levels of plasma renin activity. ACE inhibitors are Division of Clinical Pathology used in a wide range of chronic illnesses such as atherosclerosis, hypertension, myocardial infarction, and Excellence Research Centre on Cardiovascular heart failure, diabetic complications, and stroke. To date, more than ninety controlled clinical trials Disease, evaluating the beneficial effects of 14 different ACE inhibitors were conducted. Moreover, data from 1st School of Medicine, experimental studies showed that ACE inhibitors can attenuate the development of atherosclerosis, II University of Naples, oxidative stress, and vascular inflammation in a wide range of species indicating that ACE inhibition Complesso S. Andrea also favourably affects the vasculature. More than fifteen years ago, the bi-sulfydryl ACE-inhibitor delle Dame, zofenopril has shown an excellent clinical safety and efficacy in patients with hypertension and in 80138 Naples, those with myocardial infarction. More recently, this compound exhibited a potent antioxidant and Italy. antiatherosclerotic effect indicating a clinical useful vasoprotective action. Email: [email protected] or claudio. [email protected] Rationale of the use of ACE Inhibitors NO induces vasodilation, inhibits expression of Acknowledgments as Vasculoprotective Agents adhesion molecules, and decreases platelet ag- gregation and VSMC proliferation.4 ANG II coun- This work was made possible through a grant from Angiotensin-converting enzyme (ACE), which teracts NO by its vasoconstricting properties “Regione Campania 2008” is responsible for conversion of angiotensin I to and, more important, by altering NO bioactiv- 1,4 and an unrestricted educational angiotensin II (ANG II) and degradation of ity. Although ANG II infusion increases plasma grant from Menarini Foundation, bradykinin, is a component of the renin-angio- NO, it can interfere with tissue NO bioactivity, Milan, Italy. tensinaldosterone axis. ANG II is a potent probably via increased production of superox- vasoconstrictor and the principal active peptide ide radicals (and other ROS) by VSMCs.1,4 In turn, of the reninangiotensin system. ANG II also reduced NO synthesis increases levels of super- Disclosure regulates cellular proliferation, inflammation, oxide and nuclear factor-kB, thereby increasing The authors report no conflicts oxidation-sensitive mechanisms, and endothe- ACE expression and ANG II–receptor type 1. ac- of interest. lial function.1 tivation.1,4 The ACE inhibitor captopril has a sulfydryl group Accordingly, chronic antagonism of nitric oxide to coordinate to the active site zinc ion, enala- synthase (NOS) can lead to increased ANG II- prilat has a carboxylate group, and fosinopril has receptor type 1 gene transcription, which also a phosphate group; zofenopril has 2 sulfydryl suggests that endothelial dysfunction can di- groups.2,3 Enalapril, ramipril and cilazapril are rectly increase the ANG IIinduced adverse vascu- ethyl-ester derivatized prodrugs that are well lar effects.1–6 By contrast, bradykinin stimulates absorbed from the gut and, although inactive in NO synthesis by the endothelium. ANG II and vitro, are hydrolysed to the active diacid forms bradykinin have opposite effects on fibrinolysis: (enalaprilat, ramiprilat and cilazaprilat) in vivo angiotensin metabolites increase plasminogen by esterases in the liver, blood and other tissues. activator inhibitor-1 activity, whereas bradyki- In plaques from human coronary arteries, ACE nin increases levels of tissue plasminogen acti- and ANG II were found to be overexpressed in vator.1–6 Because ANG II and bradykinin affect unstable atherosclerotic lesions,1–3 primarily at endothelial function, oxidation-sensitive mech- the site of plaque rupture where macrophages anisms, and arterial inflammation, and because and interleukin-6 colocalize. Interleukin-6 ex- ACE activity is mainly (.90%) localized in the pression in VSMCs and macrophages is stimu- endothelium, using ACE inhibitors to treat ath- lated by ANG II.1 erosclerosis and its clinical sequalae is consistent with the hypothesis.1–5 ISSN 20424906 20 THE ASIA-PACIFIC JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE I SAFETY AND EFFICACY OF THE BI-SULFYDRYL ACE-INHIBITOR ZOFENOPRIL IN THE MANAGEMENT OF CARDIOVASCULAR DISEASE Since then, an expanded view of RAS has gradually emerged.6 Specifically, some trials of patients with heart failure (HF) following Local tissue RAS systems have been identified in most organs. acute myocardial infarction (AMI) support the benefit of ACE inhi- Recently, evidence for an intracellular RAS has been reported. bition in this large patient population. In the SOLVD study, at 40 The new expanded view of RAS therefore covers both endocrine, months, enalapril lowered significantly the risk of AMI by 23% and paracrine and intracrine functions. Other peptides of RAS have unstable angina by 20%,20 and continued to lower the rates of cor- been shown to have biological actions; angiotensin 2–8 hepta- onary events throughout follow-up. In the SAVE trial, AMI survivors peptide (Ang III) has actions similar to those of Ang II.6 Further, the with reduced left ventricular function were randomly assigned to angiotensin 3–8 hexapeptide (Ang IV) exerts its actions via insulin- receive captopril or placebo.21 After 42 months of followup, capto- regulated amino peptidase receptors while angiotensin 1–7 (Ang pril not only reduced all-cause mortality by 19%, but also lowered 1–7) acts via mas receptors.6 The discovery of another ACE2 and of significantly the risk of recurrent infarction by 25%.21 In the Acute renin receptors has made our view of RAS unexpectedly complex.6 Infarction Ramipril Efficacy (AIRE)22 and Trandolapril Cardiac Evalu- Great expectations are now generated by the introduction of renin ation (TRACE)23 clinical trials, patients with HF were randomly as- inhibitors. signed to receive an ACE inhibitor or placebo within days after AMI. Experimental Studies in which the The rate of recurrent infarction did not differ between groups; how- Sulfydryl ACE-Inhibitor Zofenopril Exerted ever, a systematic overview of these trials reported a significant 24 Potent Vasoprotective Effects reduction in recurrent infarction with ACE inhibition. Another detailed meta-analysis of trials of ACE inhibitors after AMI found Different ACE inhibitors have quite different chemical functional that ACE inhibitor therapy lowered the risk of sudden cardiac death 25 groups and these structural variations may account for different significantly (odds RATIO = 0.80; [CI]: 0.70 to 0.92). Taken togeth- in vivo and in vitro effects. The ACE inhibitor captopril has a sulfy- er, these clinical data can be interpreted that ACE inhibitors lower dryl group to coordinate the zinc ion of the active site, enalaprilat the risk of coronary events attributed to plaque instability and/or 2,17–19 has a carboxylate group, and zofenopril has 2 sulfydryl groups.1–3,7 rupture. In the Prevention of Atherosclerosis with Ramipril-2 26 Sulfhydryl ACE-inhibition, in particular zofenopril, stimulates the (PART-2) study, patients with carotid atherosclerosis were as- NO activity and decreases oxidative stress in human endothelial signed to receive ramipril or placebo. Throughout the 4-year follow- cells.4,8,9 Zofenopril decreases atherosclerotic development also up, carotid artery wall thickness and plaques differed between the reducing reactive oxygen species in rabbits and mice.10,11 This two groups favoring placebo. effect was more potent than that achieved by the sulfhydryl ACE inhibitor captopril. Nevertheless, ramipril reduced significantly cardiovascular mortali- ty or nonfatal AMI by 34%.26 Similar findings were reported in a trial Consistently, zofenopril induced cardioprotective effect in per- of simvastatin and enalapril administered randomly to normocho- 27 fused rat heart subjected to ischemia and reperfusion12 as well as lesterolemic patients. Angiographic measures of coronary ath- attenuated hypertrophic response in rats with myocardial infarc- erosclerosis did not differ between enalapril- and placebo-treated tion.13 Moreover, the impact of zofenopril in comparison to the patients, although fewer patients receiving enalapril experienced 27 non-sulfhydryl ACE-inhibitor enalapril was studied in in non non- clinical events at 4-year follow-up. In the Study to Evaluate Ca- obese diabetic mice (NOD).14 Insulin-dependent diabetes mellitus rotid Ultrasound Changes in Patients Treated with Ramipril and Vi- 28 (IDDM) development was monitored weekly through glycosuria tamin E (SECURE), a substudy of the Heart Outcomes Prevention 29 measurement. Evaluation (HOPE) trial, patients at high risk of coronary