Skip to main content
SpringerLink
Log in

Effect of ACE inhibitors on endothelial dysfunction: Unanswered questions and implications for further investigation and therapy

  • Coronary Artery Disease: Editorial
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

Experimental studies have suggested that angiotensin-converting enzyme (ACE) inhibitors may have an important role in blocking the progression of and/or reversing endothelial dysfunction. The extrapolation of these experimental studies to the clinical situation has, however, been disappointing. Studies of forearm-mediated endothelial vasodilatation in patients with hypertension with captopril, enalapril, and cilazapril have been negative. The finding of the Trial in Reversing Endothelial Dysfunction (TREND) that the administration of quinapril to normotensive patients with coronary artery disease in part restores endothelial-mediated coronary vasodilation, as assessed by intracoronary administration of acetylcholine, has important implications for future therapy and raises several important questions. The differences in the TREND and previous studies of ACE inhibitors on endothelial dysfunction may be due to mechanistic differences in endothelial dysfunction in patients with coronary artery disease and hypertension. Although in general there has been a good correlation between endothelial dysfunction as assessed by forearm flow and coronary endothelial dysfunction as assessed by acetylcholine, these vascular beds may be affected differently by therapeutic interventions, especially with an ACE inhibitor, which may affect sheart stress and angiotensin II formation in different vascular beds differently. Third, one needs to question whether the effect of quinapril on coronary endothelial dysfunction is a class effect or unique to quinapril. It will be necessary to test the effectiveness of other ACE inhibitors on coronary endothelial dysfunction in humans before concluding that the beneficial effects of quinapril are due to a class effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Becker RH, Wimer G, Linz W. Preservation of endothelial function by ramipril in rabbits on a long-term atherogenic diet. J Cardiovasc Pharmacol 1991;18:S110-S115.

    Google Scholar 

  2. Clozel M, Kuhn H, Hefti F, Baumgartner HR. Endothelial dysfunction and subendothelial monocyte macrophages in hypertension: Effect of angiotensin converting enzyme inhibition. Hypertension 1991;18:132–141.

    Google Scholar 

  3. Webb RC, Finto KM, Fisher M, Lee L, Pitt B. Ramipril reverses impaired endothelium dependent relaxation in arteries from rats fed an atherogenic diet. FASEB 1992;6: A1458.

    Google Scholar 

  4. Bossaller C, Auch-Schwelk W, Weber F, Gotze S, Grafe M, Graf K, Fleck E. Endothelium-dependent relaxation are augmented in rats chronically treated with the angiotensin-converting enzyme inhibitor enalapril. J Cardiovasc Pharmacol 1992;20:S91-S95.

    Google Scholar 

  5. Dohi Y, Criscione L, Pfeiffer K, Luscher TF. Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: Studies in perfused mesenteric resistance arteries. J Cardiovasc Pharmacol 1994;24:372–379.

    Google Scholar 

  6. Mombouli JV, Nephtali M, Vanhoutte PM. Effects of the converting enzyme inhibitor cilazaprilat on endothelium-dependent responses. Hypertension 1991;18:II22-II29.

    Google Scholar 

  7. Vane JR, Anggard EE, Botting RM. Regulatory functions of the endothelium. N Engl J Med 1990;323:27–36.

    Google Scholar 

  8. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–526.

    Google Scholar 

  9. Griffin SA, Brown WC, MacPherson F, et al. Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension 1991;17:626–635.

    Google Scholar 

  10. Vanhoutte PM. Endothelium and control of vascular function. State-of-the-art lecture. Hypertension 1989;13:658–667.

    Google Scholar 

  11. Keidar S, Brook JG, Aviram M. Angiotensin II enhanced lipid peroxidation of low-density lipoprotein. Am Physiol Soc. 1993;8:245–248.

    Google Scholar 

  12. Harrison DG, Ohara Y. Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: Implications for impaired vasomotion. Am J Cardiol 1995;75:75B-81.

    Google Scholar 

  13. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141–1148.

    Google Scholar 

  14. Keidar S, Kaplan M, Aviram M. Angiotensin II-modified LDL is taken up by macrophages via the scavenger receptor, leading to cellular cholesterol accumulation. Arterioscler Thromb Vasc Biol 1996;16:97–105.

    Google Scholar 

  15. Farber HW, Center DM, Rounds S, Danilov SM. 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.

    Google Scholar 

  16. Dohi Y, Hahn AWA, Boulanger CM, Buhler FR, Luscher TF. Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries. Hypertension 1987;19:131–137.

    Google Scholar 

  17. Luscher TF, Raij L, Vanhoutte PM. Endothelium-dependent vascular responses in normotensive and hypertensive Dahl rats. Hypertension 1987;9:157–163.

    Google Scholar 

  18. deCavanagh EMV, Inserra F, Ferder L, Romano L, Ercole L, Fraga CG. Superoxide dismutase and glutathione peroxidase activities are increased by enalapril and captopril in mouse liver. FEBS Lett 1995;361:22–24.

    Google Scholar 

  19. Creager MA, Roddy MA. Effect of captopril and enalapril on endothelial function in hypertensive patients. Hypertension 1994;24:499–505.

    Google Scholar 

  20. Kiowski W, Linder L, Nuesch R, Martina B. Effects of cilazapril on vascular structure and function in essential hypertension. Hypertension 1996;27:371–376.

    Google Scholar 

  21. Hirooka Y, Imaizumi T, Masaki H, Aando S, Harada S, Momohera M, Takeshita A. Captopril improves impaired endothelium-dependent vasodilation in hypertensive patients. Hypertension 1992;20:175–180.

    Google Scholar 

  22. Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND Study (Trial on Reversing Endothelial Dysfunction). Circulation 1996, in press.

  23. Virdis A, Ghiadoni L, Lucarinin A, DiLegge V, Taddei S, Salvetti A. Presence of cardiovascular structural changes in essential hypertensive patients with coronary microvascular disease and effects of long-term treatment. Am J Hypertens 1995;9:361–369.

    Google Scholar 

  24. Dahlof B, Herlitz H, Aurell M, Hansson L. Reversal of cardiovascular structural changes when treating essentially hypertension. The importance of the renin-angiotensinaldosterone system. Am J Hypertens 1992;5:900–911.

    Google Scholar 

  25. Agabiti-rosei E, Muiesan ML, Rizzoni D, et al. Regression of cardiovascular structural changes after long-term antihypertensive treatment with the calcium antagonist nitrendipine. J Cardiovasc Pharmacol 1991;18:S5–9.

    Google Scholar 

  26. Cockcroft JR, Chowienczyk PJ, Benjamin N, Ritter JM. Preserved endothelium-dependent vasodilation in essential hypertension. N Engl J Med 1994;330:1029–1035.

    Google Scholar 

  27. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerosis coronary arteries. N Engl J Med 1986;315:1046–51.

    Google Scholar 

  28. Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt B. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 1989;79:287–91.

    Google Scholar 

  29. Zieber AM, Drexler H, Saurbier B, Just H. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension: Endothelium-mediated coronary blood flow modulation in humans. J Clin Invest 1993;92:652–62.

    Google Scholar 

  30. Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the humancoronary and peripheral circulation. J Am Coll Cardiol 1995;26:1235–1241.

    Google Scholar 

  31. Tang T, Connelly BA, Joycer WL. Heterogeneity of endothelial cell function for angiotensin conversion in serialarranged arterioles. J Vasc Res 1995;32:129–137.

    Google Scholar 

  32. Johnston CI, Fabris B, Yamada H, Mendelsohn FAO, Cubela R, Sivell D, Jackson B. Comparative studies of tissue inhibition by angiotensin converting enzyme inhibitors. J Hypertens 1989;7:11S-16.

    Google Scholar 

  33. Cleland JG, Henderson E, McLenachan J, Findlay JN, Dargie HJ. Effect of captopril, an angiotensin-converting enzyme inhibitor in patients with angina pectoris and heart failure. J Am Coll Cardiol 1991;17:733–739.

    Google Scholar 

  34. Harrison DG: Endothelial dysfunction in atherosclerosis. Basic Res Cardiol 1994;89:87–102.

    Google Scholar 

  35. Harrison DG, Ohara Y: Physiologic consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: Implications for impaired vasomotion. Am J Cardiol 1995;75:75B-81.

    Google Scholar 

  36. Treasure CB, Klein JL, Weintraub WS, 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.

    Google Scholar 

  37. Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): Reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995; 26:1133–1139.

    Google Scholar 

  38. Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin therapy pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation 1995;92:2419–2425.

    Google Scholar 

  39. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S) Lancet 1994;344:1383–1389.

    Google Scholar 

  40. Texter M, Lees RS, Pitt B, Dinsmore RE, Uprichard ACG. The quinapril ischemic event trial (QUIET) design and methods: Evaluation of chronic ACE inhibitor therapy after coronary artery intervention. Cardiovasc Drugs Ther 1993; 7:273–282.

    Google Scholar 

  41. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, Pitt B. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056–2069.

    Google Scholar 

  42. Pfeffer MA. ACE inhibition in acute myocardial infarction. N Engl J Med 1995;332:118–120.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Michigan School of Medicine, Ann Arbor, MI, USA

    Bertram Pitt

Authors
  1. Bertram Pitt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pitt, B. Effect of ACE inhibitors on endothelial dysfunction: Unanswered questions and implications for further investigation and therapy. Cardiovasc Drug Ther 10, 469–473 (1996). https://doi.org/10.1007/BF00051113

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00051113

Key Words

Search

Navigation