Role of angiotensin-converting enzyme inhibition in reversal of endothelial dysfunction in coronary artery disease

  • G.B.John Mancini
    Requests for reprints should be addressed to G.B. John Mancini, MD, Vancouver Hospital and Health Sciences Centre, Room 3300—Laurel Pavilion, 950 West 10th Avenue, Vancouver, British Columbia, Canada, V5Z 4E3
    Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Cardiovascular Imaging Laboratory, Vancouver Hospital and Health Sciences Centre, Vancouver, British Columbia, Canada
    Search for articles by this author


      Angiotensin-converting enzyme (ACE) inhibitors have shown unexpected benefits in the prevention of ischemic events in patients with hypertension and congestive heart failure. In addition to these clinical observations, there is a growing body of knowledge about the molecular and cellular effects of ACE inhibitors. For example, ACE inhibition prevents stimulation of smooth muscle cell angiotensin II receptors, thereby blocking both contractile and proliferative actions. Angiotensin II blockade also diminishes the production of superoxide anion, which inactivates ambient nitric oxide. ACE inhibition of kininase II inhibits the breakdown of bradykinin, a direct stimulant of nitric oxide release from the intact endothelial cell. Thus, at the cellular level within the vasculature, ACE inhibition shifts the balance of ongoing mechanisms in favor of those promoting vasodilatory, antiaggregatory, antithrombotic, and antiproliferative effects. These effects underlie the potential benefits of ACE inhibition in the therapy of ischemia and atherosclerosis. Some data is available in humans to show that these effects can be sustained for months, thereby maintaining improved endothelial function and, presumably, allowing the initiation of steps that might alter the progression of atherosclerosis. Definitive information is not yet available in humans to show that ACE inhibition clearly alters the progression of atherosclerosis or diminishes coronary events in uncomplicated coronary disease. This promising area of investigation is, however, the subject of multiple clinical trials, which should provide clarification of this important question in coming years.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lonn E.M.
        • Yusuf S.
        • Jha P.
        • et al.
        Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection.
        Circulation. 1994; 90: 2056-2069
        • Rubanyi G.M.
        The role of endothelium in cardiovascular homeostasis and diseases.
        J Cardiovasc Pharmacol. 1993; 22: S1-S14
        • Ludmer P.L.
        • Selwyn A.P.
        • Shook T.L.
        • et al.
        Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.
        N Engl J Med. 1986; 315: 1046-1051
        • Werns S.W.
        • Walton J.A.
        • Hsia H.H.
        • et al.
        Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease.
        Circulation. 1989; 79: 287-291
        • Vita J.A.
        • Treasure C.B.
        • Nabel E.G.
        • et al.
        Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.
        Circulation. 1990; 81: 491-497
        • von Lutterotti N.
        • Caranzaro D.F.
        • Sealey J.E.
        • Laragh J.H.
        Renin is not synthesized by cardiac and extrarenal vascular tissues.
        Circulation. 1994; 89: 458-470
        • Dzau V.J.
        • Re R.
        Tissue angiotensin system in cardiovascular medicine.
        Circulation. 1994; 89: 493-498
        • Dusting G.J.
        • Macdonald P.S.
        Endogenous nitric oxide in cardiovascular disease and transplantation.
        Ann Med. 1995; 27: 395-406
        • Naftilan A.J.
        • Pratt R.E.
        • Dzau V.J.
        Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells.
        J Clin Invest. 1989; 83: 1419-1424
        • Naftilan A.J.
        • Pratt R.E.
        • Eldridge C.S.
        • Lin H.D.
        • Dzau V.J.
        Angiotensin II induces c-fos expression in smooth muscle via transcriptional control.
        Hypertension. 1989; 13: 706-711
        • Griendling K.K.
        • Minieri C.A.
        • Ollerenshaw J.D.
        • Alexander R.W.
        Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.
        Circ Res. 1994; 74: 1141-1148
        • Chobanian A.V.
        • Haudenschild C.C.
        • Nickerson C.
        • Hope S.
        Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.
        Hypertension. 1992; 20: 473-477
        • Aberg G.
        • Ferrer P.
        Effects of captopril on atherosclerosis in Cynomolgus monkeys.
        J Cardiovas Pharmacol. 1990; 15: S65-S72
        • Rolland P.H.
        • Charpiot P.
        • Friggi A.
        • et al.
        Effects of angiotensin-converting enzyme inhibition with perindopril on hemodynamics, arterial structure, and wall rheology in the hindquarters of atherosclerotic mini-pigs.
        Am J Cardiol. 1993; 71: 22E-27E
        • Farber H.W.
        • Center D.M.
        • Rounds S.
        • Danilov S.M.
        Components of the angiotensin system cause release of a neutrophil chemoattractant from cultured bovine and human endothelial cells.
        Eur Heart J. 1990; 11: 100-107
        • Chobanian A.V.
        • Alexander R.W.
        Exacerbation of atherosclerosis by hypertension.
        Arch Intern Med. 1996; 156: 1952-1956
        • Lüscher T.F.
        • Boulanger C.M.
        • Dohi Y.
        • Yang Z.
        Endothelium-derived contracting factors.
        Hypertension. 1992; 19: 117-130
        • James I.M.
        • Dickenson E.J.
        • Burgoyne W.
        • et al.
        Treatment of hypertension with captopril.
        J Human Hypertens. 1988; 2: 21-25
        • Ridker P.M.
        An epidemiologic assessment of thrombotic risk factors for cardiovascular disease.
        Curr Opin Lipidol. 1992; 3: 285-290
        • MacMahon S.
        • Peto R.
        • Cutler R.
        • et al.
        Blood pressure, stroke, and coronary heart disease.
        Lancet. 1990; 335: 765-774
        • Collins R.
        • Peto R.
        • MacMahon S.
        • et al.
        Blood pressure, stroke and coronary heart disease.
        Lancet. 1990; 335: 827-838
        • Lüscher T.F.
        • Noll G.
        Endothelial function as an end-point in interventional trials.
        J Hyperten. 1996; 14: S111-S121
        • Gilligan D.M.
        • Badar D.M.
        • Panza J.A.
        • et al.
        Acute vascular effects of estrogen in postmenopausal women.
        Circulation. 1994; 90: 786-791
        • Gilligan D.M.
        • Badar D.M.
        • Panza J.A.
        • et al.
        Effects of estrogen replacement therapy on peripheral vasomotor function in postmenopausal women.
        Am J Cardiol. 1995; 75: 264-268
        • Hirooka Y.
        • Imaizumi T.
        • Masaki H.
        • et al.
        Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients.
        Hypertension. 1992; 20: 175-180
        • Panza J.A.
        • Quyyumi A.A.
        • Callahan T.S.
        • Epstein S.E.
        Effect of antihypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension.
        J Am Coll Cardiol. 1993; 21: 1145-1151
        • Creager M.A.
        • Roddy M.-A.
        Effect of captopril and enalapril on endothelial function in hypertensive patients.
        Hypertension. 1994; 24: 499-505
        • Kiowski W.
        • Linder L.
        • Nuesch R.
        • Martina B.
        Effects of cilazapril on vascular structure and function in essential hypertension.
        Hypertension. 1996; 27: 371-376
        • Zhuo J.L.
        • Froomes P.
        • Casley D.
        • et al.
        Perindopril chronically inhibits angiotensin-converting enzyme in both the endothelium and adventitia of the internal mammary artery in patients with ischemic heart disease.
        Circulation. 1997; 96: 174-182
        • Rutherford J.D.
        • Pfeffer M.A.
        • Moyé L.A.
        • et al.
        Effects of captopril on ischemic events after myocardial infarction.
        Circulation. 1994; 90: 1731-1738
        • Yusuf S.
        • Pepine C.J.
        • Garces C.
        • et al.
        Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions.
        Lancet. 1992; 340: 1173-1178
        • Flather M.D.
        • Kober L.
        • Pfeffer M.A.
        • et al.
        Meta-analysis of individual patient data from trials of long-term ACE-inhibitor treatment after acute myocardial infarction (SAVE, AIRE, and TRACE Studies).
        Circulation. 1997; 98 (Abstr.): I-706
        • Mancini G.B.J.
        • Henry G.C.
        • Macaya C.
        • et al.
        Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease.
        Circulation. 1996; 94: 258-265
        • Schlaifer J.D.
        • Wargovich T.J.
        • O’Neill B.
        • et al.
        Effects of quinapril on coronary blood flow in coronary artery disease patients with endothelial dysfunction.
        Am J Cardiol. 1997; 80: 1594-1597
        • Schlaifer J.D.
        • Mancini G.B.J.
        • O’Neill B.J.
        • et al.
        Influence of smoking status on angiotensin-converting enzyme inhibition-related improvement in coronary endothelial function.
        Eur Heart J. 1997; 18 (Abstr.): 15
        • Pitt B.
        • Pepine C.
        • O’Neill B.
        • et al.
        Modulation of ACE inhibitor efficacy on coronary endothelial dysfunction by low density lipoprotein cholesterol.
        J Am Coll Cardiol. 1997; 29 (Abstr.): 70A
        • Pepine C.J.
        Ongoing clinical trials of angiotensin-converting enzyme inhibitors for treatment of coronary artery disease in patients with preserved left ventricular function.
        J Am Coll Cardiol. 1996; 27: 1048-1052
        • Pepine C.J.
        Potential role of angiotensin-converting enzyme inhibition in myocardial ischemia and current clinical trials.
        Clin Cardiol. 1997; 20: II-58-II-64
        • Lees R.S.
        • Pitt B.
        • Chan R.C.
        • et al.
        Baseline clinical and angiographic data in the Quinapril Ischemic Event (QUIET) Trial.
        Am J Cardiol. 1996; 78: 1011-1016
        • Cashin-Hemphill L.
        • Dinsmore R.E.
        • Chan R.C.
        • et al.
        Atherosclerosis progression in subjects with and without post-angioplasty restenosis in QUIET.
        J Am Coll Cardiol. 1997; 29 (Abstr.): 418A
        • Cashin-Hemphill L.
        • Dinsmore R.E.
        • Chan R.C.
        • et al.
        LDL cholesterol and angiographic progression in the QUIET Trial.
        J Am Coll Cardiol. 1997; 29 (Abstr.): 85A
        • Treasure C.B.
        • Klein J.L.
        • Weintraub W.S.
        • et al.
        Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease.
        N Engl J Med. 1995; 332: 481-487
        • Anderson T.J.
        • Meredith I.T.
        • Yeung A.C.
        • et al.
        The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion.
        N Engl J Med. 1995; 332: 488-493