The American Journal of Medicine
Volume 110, Issue 6 , Pages 471-480 , 15 April 2001

Formulating clinical strategies for angiotensin antagonism: a review of preclinical and clinical studies

  • Raymond Tabibiazar, MD

      Affiliations

    • Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
    • ,
  • Aamer H Jamali, MD

      Affiliations

    • Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
    • ,
  • Stanley G Rockson, MD

      Affiliations

    • Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
    • Corresponding Author InformationRequests for reprints should be addressed to Stanley G. Rockson, MD, Division of Cardiovascular Medicine, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California 94306

Received 28 August 2000 ,Revised 23 January 2001 ,Accepted 23 January 2001.

References 

  1. Gibbons GH, Pfeffer MA. The role of angiotensin in cardiovascular disease: pathophysiologic insights and therapeutic implications. E. Topol, Ed. In: Textbook of Cardiovascular Medicine Updates. Vol 1. NJ: Lippincott Williams & Wilkins Healthcare; 1998:1–12.
  2. Yusuf S, Sleight P, Pogue J, et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153
  3. Drexler H. Hypertension, heart failure, and endothelial function. Am J Cardiol. 1998;82:20S–22S
  4. Mombouli JV, Vanhoutte PM. Endothelial dysfunction (from physiology to therapy). J Mol Cell Cardiol. 1999;31:61–74
  5. Kim HS, Krege JH, Kluckman KD, et al.  Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA. 1995;92:2735–2739
  6. Smithies O, Maeda N. Gene targeting approaches to complex genetic diseases (atherosclerosis and essential hypertension). Proc Natl Acad Sci USA. 1995;92:5266–5272
  7. Ito M, Oliverio MI, Mannon PJ, et al.  Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA. 1995;92:3521–3525
  8. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy and failure. Arch Intern Med. 1993;153:937–942
  9. Danser AH, Schalekamp MA, Bax WA, et al.  Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation. 1995;92:1387–1388
  10. Ueda S, Meredith PA, Morton JJ, et al.  ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans. Circulation. 1998;98:2148–2153
  11. Cambien F, Poirier O, Lecerf L, et al.  Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641–644
  12. Beohar N, Damaraju S, Prather A, et al.  Angiotensin-I converting enzyme genotype DD is a risk factor for coronary artery disease. J Invest Med. 1995;43:275–280
  13. Captopril and Thrombolysis Study Investigators Pinto YM, van Gilst WH, Kingma JH, Schunkert H. Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. J Am Coll Cardiol. 1995;25:1622–1626
  14. Dakik HA, Mahmarian JJ, Verani MS, et al.  Association of angiotensin I-converting enzyme gene polymorphism with myocardial ischemia and patency of infarct-related artery in patients with acute myocardial infarction. J Am Coll Cardiol. 1997;29:1468–1473
  15. Celentano A, Mancini FP, Crivaro M, et al.  Cardiovascular risk factors, angiotensin-converting enzyme gene I/D polymorphism, and left ventricular mass in systemic hypertension. Am J Cardiol. 1999;83:1196–1200
  16. Montgomery HE, Clarkson P, Dollery CM, et al.  Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training. Circulation. 1997;96:741–747
  17. Amant C, Bauters C, Bodart JC, et al.  D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting. Circulation. 1997;96:56–60
  18. Kokkonen JO, Saarinen J, Kovanen PT. Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid. Inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase A-like activity. Circulation. 1997;95:1455–1463
  19. Wright JW, Harding JW. Brain angiotensin receptor subtypes AT1, AT2, and AT4 and their functions. Regulatory Peptides. 1995;59:269–295
  20. Unger T, Chung O, Csikos T, et al.  Angiotensin receptors. J Hypertens. 1996;14(suppl):95–103
  21. Pitt B, Konstam MA. Overview of angiotensin II-receptor antagonists. Am J Cardiol. 1998;82:47S–49S
  22. Bartunek J, Weinberg EO, Tajima M, et al.  Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts. Circulation. 1999;99:22–25
  23. Liu YH, Yang XP, Sharov VG, et al.  Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:1926–1935
  24. Tamura T, Said S, Harris J, et al.  Reverse remodeling of cardiac myocyte hypertrophy in hypertension and failure by targeting of the renin-angiotensin system. Circulation. 2000;102:253–259
  25. Briand SI, Bellemare JM, Bernier SG, Guillemette G. Study on the functionality and molecular properties of the AT4 receptor. Endocrine Res. 1998;24:315–323
  26. Kramar EA, Harding JW, Wright JW. Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes. Regulatory Peptides. 1997;68:131–138
  27. Kim S, Izumi Y, Yano M, et al.  Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery. Circulation. 1998;97:1731–1737
  28. Potter DD, Sobey CG, Tompkins PK, et al.  Evidence that macrophages in atherosclerotic lesions contain angiotensin II. Circulation. 1998;98:800–807
  29. Itoh H, Mukoyama M, Pratt RE, et al.  Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest. 1993;91:2268–2274
  30. Lindpaintner K, Ganten D. The cardiac renin-angiotensin system. An appraisal of present experimental and clinical evidence. Circulation Res. 1991;68:905–921
  31. Harrap SB, Dominiczak AF, Fraser R, et al.  Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults. Circulation. 1996;93:1148–1154
  32. Taniyama Y, Morishita R, Nakagami H, et al.  Potential contribution of a novel antifibrotic factor, hepatocyte growth factor, to prevention of myocardial fibrosis by angiotensin II blockade in cardiomyopathic hamsters. Circulation. 2000;102:246–252
  33. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95:1115–1118
  34. Gainer JV, Morrow JD, Loveland A, et al.  Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998;339:1285–1292
  35. Squire I, Okane K, Anderson N, Reid J. Bradykinin B2 receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men. Hypertension. 2000;36:132–136
  36. Vaughan DE. Endothelial function, fibrinolysis, and angiotensin-converting enzyme inhibition. Clin Cardiol. 1997;20(suppl 2):34–37
  37. Donnelly R. Angiotensin-converting enzyme inhibitors and insulin sensitivity (metabolic effects in hypertension, diabetes, and heart failure). J Cardiovasc Pharmacol. 1992;20(suppl 11):38–44
  38. Tomiyama H, Kushiro T, Abeta H, et al.  Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension. 1994;23:450–455
  39. Ura N, Higashiura K, Shimamoto K. The mechanisms of insulin sensitivity improving effects of angiotensin converting enzyme inhibitor. Immunopharmacology. 1999;44:153–159
  40. Nakagawa H, Daihara M, Tamakawa H, et al.  Effects of quinapril and losartan on insulin sensitivity in genetic hypertensive rats with different metabolic abnormalities. J Cardiovasc Pharmacol. 1999;34:28–33
  41. Berkenboom G, Langer I, Carpentier Y, et al.  Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins (a bradykinin-dependent mechanism). Hypertension. 1997;30:371–376
  42. Wirth KJ, Linz W, Wiemer G, Scholkens BA. Kinins and cardioprotection. Pharmacolog Res. 1997;35:527–530
  43. Wiemer G, Linz W, Hatrik S, et al.  Angiotensin-converting enzyme inhibition alters nitric oxide and superoxide release in normotensive and hypertensive rats. Hypertension. 1997;30:1183–1190
  44. Linz W, Wiemer G, Scholkens BA. Beneficial effects of bradykinin on myocardial energy metabolism and infarct size. Am J Cardiol. 1997;80:118A–123A
  45. Emanueli C, Maestri R, Corradi D, et al.  Dilated and failing cardiomyopathy in bradykinin B(2) receptor knockout mice. Circulation. 1999;100:2359–2365
  46. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circulation Res. 1994;74:1141–1148
  47. Swedberg K, Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure (results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)). Am J Cardiol. 1988;62:60A–66A
  48. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure (a placebo-controlled, randomized, double-blind study). Circulation. 1984;70:271–278
  49. Captopril Multicenter Research Group . A placebo-controlled trial of captopril in refractory chronic congestive heart failure. J Am Coll Cardiol. 1983;2:755–763
  50. SOLVD Investigators . Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302
  51. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685–691. [Published erratum appears in N Engl J Med. 1992;327:1768.]
  52. Cohn JN, Johnson G, Ziesche S, et al.  A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303–310
  53. Acute Infarction Ramipril Efficacy (AIRE) Study Investigators . Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821–828
  54. SAVE Investigators Pfeffer MA, Braunwald E, Moye LA, et al.  Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327:669–677
  55. Warner JG, Metzger DC, Kitzman DW, et al.  Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567–1572
  56. Losartan Hemodynamic Study Group Crozier I, Ikram H, Awan N, et al.  Losartan in heart failure. Hemodynamic effects and tolerability. Circulation. 1995;91:691–697
  57. Gottlieb SS, Dickstein K, Fleck E, et al.  Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation. 1993;88:1602–1609
  58. Havranek EP, Thomas I, Smith WB, et al.  Dose-related beneficial long-term hemodynamic and clinical efficacy of irbesartan in heart failure. J Am Coll Cardiol. 1999;33:1174–1181
  59. Riegger GA, Bouzo H, Petr P, et al.  Improvement in exercise tolerance and symptoms of congestive heart failure during treatment with candesartan cilexetil. Circulation. 1999;100:2224–2230[in process citation]
  60. Parker AB, Azevedo ER, Baird MG, et al.  ARCTIC (assessment of haemodynamic response in patients with congestive heart failure to telmisartan. A multicentre dose-ranging study in Canada). Am Heart J. 1999;138:843–848
  61. Losartan Pilot Exercise Study Investigators Lang RM, Elkayam U, Yellen LG, et al.  Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. J Am Coll Cardiol. 1997;30:983–991
  62. Dickstein K, Chang P, Willenheimer R, et al.  Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol. 1995;26:438–445
  63. Guazzi M, Melzi G, Agostoni P. Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997;80:1572–1576
  64. Mazayev VP, Fomina IG, Kazakov EN, et al.  Valsartan in heart failure patients previously untreated with an ACE inhibitor. Int J Cardiol. 1998;65:239–246
  65. Pitt B, Poole-Wilson PA, Segal R, et al.  Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure (randomized trial—the Losartan Heart Failure Survival Study ELITE II). Lancet. 2000;355:1582–1587
  66. Pepine CJ. Rationale for ACE inhibition as an anti-ischaemic therapy. Eur Heart J. 1998;19(suppl G):34–40
  67. Remme WJ. Bradykinin-mediated cardiovascular protective actions of ACE inhibitors. A new dimension in anti-ischaemic therapy?. Drugs. 1997;54(suppl 5):59–70
  68. Pfeffer M, McMurray J, Leizorovicz A, et al. Valsartan in Acute Myocardial Infarction Trial (VALIANT): rationale and design. Am Heart J. 2000;140:727–750.
  69. Dickstein K, Kjekshus J. Comparison of the effects of losartan and captopril on mortality in patients after acute myocardial infarction (the OPTIMAAL trial design. Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan). Am J Cardiol. 1999;83:477–481
  70. Schlueter W, Keilani T, Batlle DC. Metabolic effects of converting enzyme inhibitors (focus on the reduction of cholesterol and lipoprotein(a) by fosinopril). Am J Cardiol. 1993;72:37H–44H
  71. Lerch M, Teuscher AU, Beissner P, et al.  Effects of angiotensin II-receptor blockade with losartan on insulin sensitivity, lipid profile, and endothelin in normotensive offspring of hypertensive parents. J Cardiovasc Pharmacol. 1998;31:576–580
  72. Mancini GB, Henry GC, Macaya C, et al.  Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) study. Circulation. 1996;94:258–265
  73. Schiffrin E, Park J, Intengan H, Touyz R. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation. 2000;101:1653–1659
  74. Prasad A, Tupas-Habib T, Schenke W, et al.  Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis. Circulation. 2000;101:2349–2354
  75. Anderson TJ, Elstein E, Haber H, Charbonneau F. Comparative study of ACE inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000;35:60–66
  76. Dominguez LJ, Barbagallo M, Kattah W, et al.  Quinapril reduces microalbuminuria in essential hypertensive and in diabetic hypertensive subjects. Am J Hypertens. 1995;8:808–814
  77. Ritz E. Nephropathy in type 2 diabetes. J Intern Med. 1999;245:111–126
  78. Kohzuki M, Yasujima M, Liu PF, et al.  Cardiovascular and renal protective effects of losartan in spontaneously hypertensive rats with diabetes mellitus. Clin Exp Pharmacol Physiol. 1995;1(suppl 7):366–367
  79. Remuzzi A, Perico N, Amuchastegui CS, et al.  Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol. 1993;4:40–49
  80. Yotsumoto T, Naitoh T, Shikada K, Tanaka S. Effects of specific antagonists of angiotensin II receptors and captopril on diabetic nephropathy in mice. Jpn J Pharmacol. 1997;75:59–64
  81. Andersen S, Tarnow L, Rossing P, et al.  Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int. 2000;57:601–606
  82. Mogyorosi A, Sonkodi S. AT1 receptor antagonists (a challenge for ACE inhibitors in diabetic nephropathy). Diabetes Metab Res Rev. 1999;15:55–58
  83. Hebert LA, Falkenhain ME, Nahman NS, et al.  Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy. Am J Nephrol. 1999;19:1–6
  84. Fogari R, Zoppi A, Corradi L, et al.  Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br J Clin Pharmacol. 1998;46:467–471
  85. Higashiura K, Ura N, Takada T, et al.  The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose- fed rats. Am J Hypertens. 2000;13:290–297
  86. Carvalho CR, Thirone AC, Gontijo JA, et al.  Effect of captopril, losartan, and bradykinin on early steps of insulin action. Diabetes. 1997;46:1950–1957
  87. Strawn WB, Chappell MC, Dean RH, et al.  Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation. 2000;101:1586–1593
  88. Sato M, Engelman RM, Otani H, et al.  Myocardial protection by preconditioning of heart with losartan, an angiotensin II type 1-receptor blocker (implication of bradykinin-dependent and bradykinin-independent mechanisms). Circulation. 2000;102(suppl 3):346–351
  89. Goodfield NE, Newby DE, Ludlam CA, Flapan AD. Effects of acute angiotensin II type 1 receptor antagonism and angiotensin converting enzyme inhibition on plasma fibrinolytic parameters in patients with heart failure. Circulation. 1999;99:2983–2985
  90. Cohn JN, Tognoni G. Effect of the angiotensin receptor blocker valsartan on morbidity and mortality in heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2000;102:2672-b.
  91. Stys T, Lawson WE, Smaldone GC, Stys A. Does aspirin attenuate the beneficial effects of angiotensin-converting enzyme inhibition in heart failure?. Arch Intern Med. 2000;160:1409–1413

PII: S0002-9343(01)00641-6

The American Journal of Medicine
Volume 110, Issue 6 , Pages 471-480 , 15 April 2001

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