[en] The functional integrity of the endothelium is essential for vascular health. In addition to maintaining a delicate balance between vasodilation and vasoconstriction, the endothelium has numerous other complex roles involved in the maintenance of vascular homeostasis. Chronic exposure to cardiovascular risk factors and oxidative stress results in an imbalance in these functions, creating an environment that favors reduced vasodilation and a proinflammatory and prothrombic state. The involvement of endothelial dysfunction in all stages of the cardiovascular continuum makes it an important target for treatment. One of the major endothelial-derived factors involved in the maintenance of endothelial function is nitric oxide (NO). Angiotensin-converting enzyme (ACE) inhibitors increase NO production both directly and indirectly by preventing production of angiotensin II (which diminishes NO production) and inhibiting the degradation of bradykinin (which stimulates local release of NO). Among the ACE inhibitors, perindopril appears to have the greatest effects on bradykinin and has demonstrated efficacy in a number of markers of endothelial dysfunction including arterial stiffness and progression of atherosclerosis. There is also strong evidence supporting the use of perindopril-based therapy for the treatment of hypertension and for reducing the risk of cardiovascular morbidity and mortality in a wide range of patients across the cardiovascular continuum.Funding: The journal's Rapid Service Fee was funded by Servier.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
ANCION, Arnaud ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Insuffisance cardiaque - Transplantation
TRIDETTI, Julien ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de cardiologie
NGUYEN TRUNG, Mai-Linh ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de cardiologie
Roth GA, Johnson C, Abaiobir A, et al. Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. J Am Coll Cardiol. 2017;70(1):1–25.
Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114:2850–70.
O’Rourke MF, Safar ME, Dzau V. The cardiovascular continuum extended: aging effects on the aorta and microvasculature. Vasc Med. 2010;15(6):461–8.
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth. 2004;93:105–13.
Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111:363–8.
Tomasian D, Keaney JF, Vita JA. Antioxidants and the bioactivity of endothelium-derived nitric oxide. Cardiovasc Res. 2000;47(3):426–35.
Lüscher TF, Barton M. Biology of the endothelium. Clin Cardiol. 1997;20:II3–10.
Taddei S, Ghiadoni L, Virdis A, Versari D, Salvetti A. Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies. Curr Pharm Des. 2003;9:2385–402.
Dzau VJ. Theodore Cooper Lecture. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension. 2001;37(4):1047–52.
Griendling KK, Lassègue B, Murphy TJ, Alexander RW. Angiotensin II receptor pharmacology. Adv Pharmacol. 1994;28:269–306.
Kossmann S, Hu H, Steven S, et al. Inflammatory monocytes determine endothelial nitric-oxide synthase uncoupling and nitro-oxidative stress induced by angiotensin II. J Biol Chem. 2014;289:27540–50.
Li DT, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation. Circ Res. 1999;84:1043–9.
Watanabe T, Barker TA, Berk BC. Angiotensin II and the endothelium: diverse signals and effects. Hypertension. 2005;45:163–9.
Tamarat R, Silvestre JS, Durie M, Levy BI. Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Investig. 2002;82:747–56.
Arenas IA, Xu Y, Lopez-Jaramillo P, Davidge ST. Angiotensin II-induced MMP-2 release from endothelial cells is mediated by TNF-alpha. Am J Physiol Cell Physiol. 2004;286:C779–84.
Levy BI, Benessiano J, Henrion D, et al. Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Investig. 1996;98:418–25.
Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin–angiotensin system and fibrinolytic function. Circulation. 1993;87:1969–73.
Kayashima Y, Smithies O, Kakoki M. The kallikrein–kinin system and oxidative stress. Curr Opin Nephrol Hypertens. 2012;21(1):92–6.
Kuhr F, Lowry J, Zhang Y, et al. Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors. Neuropeptides. 2010;44(2):145–54.
Su JB. Kinins and cardiovascular diseases. Curr Pharm Des. 2006;12:3423–35.
Su JB, Hoüel R, Héloire F, et al. Stimulation of bradykinin B(1) receptors induces vasodilation in conductance and resistance coronary vessels in conscious dogs: comparison with B(2) receptor stimulation. Circulation. 2000;101:1848–53.
Su JB. Different cross-talk sites between the renin–angiotensin and the kallikrein–kinin systems. J Renin Angiotensin Aldosterone Syst. 2014;15:319–28.
Taddei S, Bortolotto L. Unraveling the pivotal role of bradykinin in ACE inhibitor activity. Am J Cardiovasc Drugs. 2016;16:309–21.
Baudin B, Berard M, Carrier JL, et al. Vascular origin deter-mines angiotensin I-converting enzyme expression in endothelial cells. Endothelium. 1997;5(1):73–84.
Taddei S, Versari D, Cipriano A, et al. Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpo-larizing factor in essential hypertensive patients. J Am Coll Cardiol. 2006;48(3):508–15.
Bentley JP, Asselbergs FW, Coffey CS, et al. Cardiovascular risk associated with interactions among polymorphisms in genes from the renin–angiotensin, bradykinin, and fibrinolytic systems. PLoS One. 2010;5(9):e12757.
Wiman B, Andersson T, Hallqvist J, et al. Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study. Arterioscler Thromb Vasc Biol. 2000;20(8):2019–23.
Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. 1998;97(22):2222–9.
Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelial dysfunction as a target for prevention of cardiovascular disease. Diabetes Care. 2009;32(Suppl 2):S314–21.
Virdis A, Ghiadoni L, Taddei S. Effects of antihypertensive treatment on endothelial function. Curr Hypertens Rep. 2011;13:276–81.
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin–angiotensin system. J Hypertens. 2007;25(5):951–8.
van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin–angiotensin–aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33(16):2088–97.
Strauss MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: further evidence for the ARB-MI paradox. Circulation. 2017;135(22):2088–90.
Virdis A, Neves MF, Amiri F, Touyz RM, Schiffrin EL. Role of NAD(P)H oxidase on vascular alterations in angiotensin II-infused mice. J Hypertens. 2004;22:535–42.
Ceconi C, Fox KM, Remme WJ, EUROPA Investigators, PERTINENT Investigators and the Statistical Committee, et al. ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73:237–46.
Ceconi C, Francolini G, Olivares A, Comini L, Bachetti T, Ferrari R. Angiotensin-converting enzyme (ACE) inhibitors have different selectivity for bradykinin binding sites of human somatic ACE. Eur J Pharmacol. 2007;577:1–6.
Ceconi C, Francolini G, Bastianon D, et al. Differences in the effect of angiotensin-converting enzyme inhibitors on the rate of endothelial cell apoptosis in vitro and in vivo studies. Cardiovasc Drugs Ther. 2007;21(6):423–9.
Ferrari R, Guardigli G, Ceconi C. Secondary prevention of CAD with ACE inhibitors: a struggle between life and death of the endothelium. Cardiovasc Drug Ther. 2010;24:331–9.
You D, Cochain C, Loinard C, et al. Hypertension impairs postnatal vasculogenesis: role of antihypertensive agents. Hypertension. 2008;51:1537–44.
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–27.
Tropeano AI, Boutouyrie P, Pannier B, et al. Brachial pressure-independent reduction in carotid stiffness after long-term angiotensin-converting enzyme inhibition in diabetic hypertensives. Hypertension. 2006;48(1):80–6.
Williams B, Lacy PS, Thom SM, CAFE Investigators; Anglo-Scandinavian Cardiac Outcomes Trial Investigators; CAFE Steering Committee and Writing Committee, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213–25.
Bruining N, deWinter S, Roelandt J, et al. Coronary calcium significantly affects quantitative analysis of coronary ultrasound: importance for atherosclerosis progression/regression studies. Coron Artery Dis. 2009;20:409–14.
Rodriguez-Granillo GA, Vos J, Bruining N, Investigators of the EUROPA Study, et al. Long-term effect of perindopril on coronary atherosclerosis progression (from the perindopril’s prospective effect on coronary atherosclerosis by angiography and intravascular ultrasound evaluation [PERSPECTIVE] study). Am J Cardiol. 2007;100(2):159–63.
Ferrari R. Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med. 2006;166:659–66.
Poulter NR, Wedel H, Dahlöf B, ASCOT Investigators, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial- Blood Pressure Lowering Arm (ASCOT-BPLA). Lancet. 2005;366:907–13.
Gupta A, Mackay J, Whitehouse A, et al. Long-term mortality after blood pressure-lowering and lipid-lowering treatment in patients with hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Legacy study: 16-year follow-up results of a randomised factorial trial. Lancet. 2018;392(10153):1127–37.
Patel A; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829–40.
Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–8.
Scheen AJ. Etude Clinique du mois. L’étude EUROPA: protection cardio-vasculaire avec le périndopril chez les patients avec coronaropathie stable. Rev Med Liège. 2003;58:713–6.
PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–41.
Scheen AJ. Etude Clinique du mois. Protection secondaire de l’accident vasculaire cérébral par le périndopril: l’étude PROGRESS. Rev Med Liège. 2001;56:792–5.
Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J. 2006;27:2338–45.
Williams B, Mancia G, Spiering W, Authors/Task Force Members, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36(10):1953–2041.
Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122(3):290–300.