“Cardioprotection” by ACE-inhibitors in acute myocardial ischemia and infarction?

  • Karin Przyklenk
  • R. A. Kloner


Coronary artery occlusion results in the acute activation of the renin-angiotensin system and production of angiotensin II, a potent vasoconstrictor and positive inotropic agent. This has raised the possibility that angiotensin converting enzyme (ACE) inhibitors might be “cardioprotective” (that is, might attenuate myocardial injury, dysfunction and necrosis) in the setting of acute ischemia and infarction. Captopril, enalapril and ramipril have, in fact, been reported to acutely limit myocardial injury and necrosis in models of permanent coronary artery occlusion. The mechanisms responsible for this cardioprotection are complex, but include favorable alterations in myocardial oxygen supply/demand, and, in some instances, inhibition of bradykinin metabolism and/or increased prostaglandin synthesis. Other studies, however, have failed to document a reduction in infarct size with ACE inhibitor treatment. Results obtained in models of coronary occlusion/reperfusion have also been mixed. In models of brief transient ischemia not associated with necrosis, captopril and zofenopril have consistently been found to attenuate postischemic contractile dysfunction of the viable but “stunned” myocardium during the early hours following relief of ischemia. In contrast, there is no consensus on the effects of enalapril on the stunned myocardium: both positive and negative results have been obtained. Similar disparity has been reported in models of more prolonged ischemia/reperfusion resulting in subendocardial necrosis: some studies have reported myocardial salvage, while others have provided disturbing evidence of apparent exacerbation of myocardial necrosis with captopril and enalapril therapy. Thus, after a decade of investigative effort, the question of whether ACE inhibitors are “cardioprotective” in the setting of acute myocardial ischemia and infarction remains unresolved. Nonetheless, clinical protocols are in progress to assess the effects of early ACE inhibitor treatment in patients with acute myocardial infarction.

Key words

Coronary artery occlusion coronary artery reperfusion myocardial infarct size creatine kinase myocardial contractile function 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bagchi D, Prasad R, Das DK (1989) Direct scavenging of free radicals by captopril, an angiotensin converting enzyme inhibitor. Biochem Biophys Res Comm 158: 52–57PubMedCrossRefGoogle Scholar
  2. 2.
    Bittar N, Zheng HN, Nwosu EA (1991) Captopril is more effective than dipyridamole or labetolol in attenuating myocardial stunning in the dog. Proceedings of the Second International Symposium on ACE Inhibition, London UK, p P–179 (abstract)Google Scholar
  3. 3.
    Bolli R (1992) Attenuation of reperfusion injury by ACE inhibitiors? Basic Res Cardiol: in pressGoogle Scholar
  4. 4.
    Bolli R, Patel BS, Jeroudi MO, Lai EK, McCoy PB (1988) Demonstration of free radical generation in “stunned” myocardium of intact dogs with the use of the spin trap alpha phenyl N-Tert-Butyl Nitrone. J Clin Invest 82: 476–485PubMedCrossRefGoogle Scholar
  5. 5.
    Braunwald E, Kloner RA (1982) The stunned myocardium: prolonged postischemic ventricular dysfunction. Circulation 66: 1146–1149PubMedCrossRefGoogle Scholar
  6. 6.
    Brown EJ Jr, Swinford RD, Shatkin BJ, Honig SC, Cohn PF (1988) Massive reperfusion injury: paradoxical effect of combined angiotensin-converting enzyme inhibition plus myocardial reperfusion. J Am Coll Cardiol 11: 50A (abstract)Google Scholar
  7. 7.
    Cushman DW, Ondetti MA (1980) Inhibitors of angiotensin-converting enzyme. Prog Med Chem 17: 41–104PubMedCrossRefGoogle Scholar
  8. 8.
    Daniell HB, Carson RR, Ballard KD, Thomas GR, Privitera PJ (1984) Effects of captopril on limiting infarct size in conscious dogs. J Cardiovasc Pharmacol 6: 1043–1047PubMedGoogle Scholar
  9. 9.
    de Graeff PA, de Langen CDJ, van Gilst WH, Bel K, Scholtens E, Kingma JH, Wesseling H (1988) Protective effects of captopril against ischemia/reperfusion-induced arrhythmias in vitro and vivo. Am J Med 84 (Suppl 3A): 67–74Google Scholar
  10. 10.
    de Graeff PA, van Gilst WH, de Langen CDJ, Kingma JH, Wesseling H (1987) Concentration-dependent protection by Captopril against myocardial damage during ischemia and reperfusion in a closed chest pig model. J Cardiovasc Pharmacol 9 (Suppl 2): S37–S42Google Scholar
  11. 11.
    de Lorgeril M, Ovize M, Delaye J, Renaud S (1992) Importance of the flow perfusion deficit in the response to Captopril in experimental myocardial infarction. J Cardiovasc Pharmacol 19: 324–329PubMedCrossRefGoogle Scholar
  12. 12.
    di Pasquale P, Barone G, Paterna S, Cannizaro S, Giubilato A (1990) Efficacy of Captopril before thrombolysis in acute myocardial infarction: preliminary findings. Drugs Exp Clin Res 15: 581–589Google Scholar
  13. 13.
    Dzau VJ (1988) Tissue renin-angiotensin system: physiologic and pharmacologic implications. Circulation 77 (Suppl I): II–13CrossRefGoogle Scholar
  14. 14.
    Ertl G (1988) Converting enzyme inhibitors and ischemic heart disease. Eur Heart J 9: 716–727PubMedGoogle Scholar
  15. 15.
    Ertl G, Alexander RW, Kloner RA (1983) Interactions between coronary occlusion and the renin-angiotensin system in the dog. Basic Res Cardiol 78: 518–533PubMedCrossRefGoogle Scholar
  16. 16.
    Ertl G, Kloner RA, Alexander RW, Braunwald E (1982) Limitation of experimental infarct size by an angiotensin-converting enzyme inhibitor. Circulation 65: 40–48PubMedCrossRefGoogle Scholar
  17. 17.
    Gavras H (1990) Angiotensin converting enzyme inhibition and its impact on cardiovascular disease. Circulation 81: 381–388PubMedCrossRefGoogle Scholar
  18. 18.
    Gavras H, Gavras I (1991) Cardioprotective potential of angiotensin converting enzyme inhibitors. J Hypertension 9: 385–392CrossRefGoogle Scholar
  19. 19.
    Gay RG (1990) Early and late effects of Captopril treatment after large myocardial infarction in rats. J Am Coll Cardiol 16: 967–977PubMedCrossRefGoogle Scholar
  20. 20.
    Hartman JC, Wall TM, Hullinger TG (1992) Role of bradykinin in reduction of myocardial infarct size by ramiprilat. J Mol Cell Cardiol 24 ( Suppl III ): S.ll (abstract)Google Scholar
  21. 21.
    Hock CE, Ribeiro GT, Lefer AM (1985) Preservation of ischemic myocardium by a new converting enzyme inhibitor, enalaprilic acid, in acute myocardial infarction. Am Heart J 109: 222–228PubMedCrossRefGoogle Scholar
  22. 22.
    Johnston CI, Clappison BH, Anderson WP, Yasuzjima M (1982) Effect of angiotensin-converting enzyme inhibition on circulating and local kinin levels. Am J Cardiol 49: 1401–1404PubMedCrossRefGoogle Scholar
  23. 23.
    Kingma JH, van Gilst WH, de Graeff PA, Louwerenburg HW, Six AJ, Wesseling H (1989) Captopril during thrombolysis in acute myocardial infarction: feasibility, tolerance and beneficial neurohumoral effects. In: MacGregor GA, Sever PS (eds) Current Advances in ACE Inhibition; Churchill Livingstone, Edinburgh, pp 291–295Google Scholar
  24. 24.
    Kingma JH, van Gilst WH, Peels CH, Jaarsma W, Verheught FW (1990) Converting enzyme inhibition during thrombolytic therapy in acute myocardial infarction. Circulation 82 (Suppl III): III–666 (abstract)Google Scholar
  25. 25.
    Kloner RA, Przyklenk K (1992) Cardioprotection with angiotensin converting enzyme inhibitors: redefined for the 1990’s. Clin Cardiol: in pressGoogle Scholar
  26. 26.
    Kukreja RC, Kontos HA, Hess ML (1990) Captopril and enalaprilat do not scavenge the superoxide anion. Am J Cardiol 65: 241–271CrossRefGoogle Scholar
  27. 27.
    Lefer AM, Peck RC (1984) Cardioprotective effects of enalapril in acute myocardial ischemia. Pharmacology 29: 61–69PubMedCrossRefGoogle Scholar
  28. 28.
    Liang CS, Gavras H, Black J, Sherman LG, Hood WB (1982) Renin-angiotensin system inhibition in acute myocardial infarction in dogs: effects on systemic hemodynamics, myocardial blood flow, segmental myocardial function and infarct size. Circulation 66: 1249–1255PubMedCrossRefGoogle Scholar
  29. 29.
    Linder C, Heusch G (1990) ACE inhibitor for the treatment of myocardial ischemia? Cardiovasc Drugs Therapy 4: 1375–1384CrossRefGoogle Scholar
  30. 30.
    Lindpaintner K, Ganten D (1991) Tissue renin-angiotensin systems and their modulation: the heart as a paradigm for new aspects of converting enzyme inhibition. Cardiology 79 (Suppl 1): 32–44PubMedCrossRefGoogle Scholar
  31. 31.
    Martorana PA, Kettenbach B, Breipohl G, Linz W, Scholkens BA (1990). Reduction of infarct size by local angiotensin-converting enzyme inhibition is abolished by a bradykinin antagonist. Eur J Pharmacol 182: 395–396PubMedCrossRefGoogle Scholar
  32. 32.
    Martorana PA, Linz W, Scholkens BA (1991) Does bradykinin play a role in the cardiac antiischemic effect of the ACE inhibitor? Basic Res Cardiol 86: 293–296PubMedCrossRefGoogle Scholar
  33. 33.
    McAlpine HM, Cobbe SM (1988) Neuroendocrine changes in acute myocardial infarction. Am J Med 84 (Suppl 3A): 61–74PubMedCrossRefGoogle Scholar
  34. 34.
    Mehta PM, Alker KJ, Kloner RA (1988) Functional infarct expansion, left ventricular dilation and isovolumic relaxation time after coronary occlusion: a two-dimensional echocardiography study. J Am Coll Cardiol 11: 630–636PubMedCrossRefGoogle Scholar
  35. 35.
    Mehta PM, Przyklenk K, Kloner RA (1990) Cardioprotective effects of Captopril in myocardial ischemia, ischemia/reperfusion and infarction. Eur Heart J 11 (Suppl B): 94–99PubMedGoogle Scholar
  36. 36.
    Murphy VS, Waldron TL, Goldberg ME (1978) Inhibition of angiotensin-converting enzyme by SQ 14,225 in anesthetized dogs: hemodynamics and renal vascular effects. Proc Soc Exp Biol Med 157: 121–129Google Scholar
  37. 37.
    Nabel EG, Topol EJ, Galeana A, Ellis SG, Bates ER, Werns SW, Walton JA, Muller DW, Schwaiger M, Pitt B (1991) A randomized placebo-controlled trial of combined early intravenous Captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction. J Am Coll Cardiol 17: 467–473PubMedCrossRefGoogle Scholar
  38. 38.
    Nöda K, Sagaguri M, Ideishi M, Ikeda M, Arakawa K (1990) Cardioprotection by ACE inhibitor in ischemic heart is independent of the local angiotensin II formation. J Hypertension 8 (Suppl 3): 106Google Scholar
  39. 39.
    Paul M, Bachman J, Ganten D (1992) The tissue renin-angiotensin systems in cardiovascular disease. Trends Cardiovasc Med 2: 94–99PubMedCrossRefGoogle Scholar
  40. 40.
    Pfeffer JM, Pfeffer MA, Braunwald E (1985) Influence of chronic Captopril therapy in the infarcted left ventricle in the rat. Circ Res 57: 84–95PubMedGoogle Scholar
  41. 41.
    Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E (1988) Effect of Captopril on progressive ventricular dilation after anterior myocardial infarction. N Engl J Med 319: 80–86PubMedCrossRefGoogle Scholar
  42. 42.
    Pfeffer MA, Pfeffer JM, Steinberg C, Finn P (1985) Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with Captopril. Circulation 72: 406–412PubMedCrossRefGoogle Scholar
  43. 43.
    Przyklenk K, Kloner RA (1987) Acute effects of hydralazine and enalapril on contractile function of postischemic stunned myocardium. Am J Cardiol 60: 934–936PubMedCrossRefGoogle Scholar
  44. 44.
    Przyklenk K, Kloner RA (1987) Effect of oxygen-derived free radical scavengers on infarct size following six hours of permanent coronary artery occlusion: salvage or delay of myocyte necrosis? Basic Res Cardiol 82: 146–158PubMedCrossRefGoogle Scholar
  45. 45.
    Przyklenk K, Kloner RA (1989) Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischemic/reperfusion injury. Br J Clin Pharmacol 28: 167S–175SPubMedGoogle Scholar
  46. 46.
    Przyklenk K, Kloner RA (1991) Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action. Am Heart J 121: 1319–1330PubMedCrossRefGoogle Scholar
  47. 47.
    Przyklenk K, Whittaker P, Kloner RA (1989) Zofenopril, a newly developed sulfhydryl-containing converting enzyme inhibitor, enhances contractile function of stunned myocardium. In: MacGregor GA, Severs PS (eds) Current Advances in ACE Inhibition; Churchill Livingstone, Edinburgh, pp 279–282Google Scholar
  48. 48.
    Reddy BR, Wynne J, Kloner RA, Przyklenk K (1991) Pretreatment with the iron chelator deferoxamine fails to provide sustained protection against myocardial ischemia-reperfusion injury. Cardiovasc Res 25: 711–718PubMedCrossRefGoogle Scholar
  49. 49.
    Scholkens BA, Linz W (1990) Cardioprotective effects of ACE inhibitors: experimental proof and clinical perspectives. Clin Physiol Biochem 8 (Suppl 1): 33–43PubMedGoogle Scholar
  50. 50.
    Schwartz SL, Williams GH (1982) Angiotensin-converting enzyme inhibition and prostaglandins. Am J Cardiol 49: 1405–1409CrossRefGoogle Scholar
  51. 51.
    Schwartz SL, Williams GH, Hollenberg NK, Levine TB, Dluhy RC, Moore TJ (1980) Captopril-induced changes in prostaglandin production. J Clin Invest 65: 1257–1264CrossRefGoogle Scholar
  52. 52.
    Sharpe N, Smith H, Murphy J, Greaves S, Hart H, Gamble G (1991) Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition. Lancet 337: 872–876PubMedCrossRefGoogle Scholar
  53. 53.
    Sigurdsson A, Held P, Andersson G, Swedberg K (1991) Enalaprit in acute myocardial infarction: tolerability and effects on the renin-angiotensin system. Int J Cardiol 33: 114–124CrossRefGoogle Scholar
  54. 54.
    Simpson PJ, Mickelson J, Fantone JC, Gallagher KP, Lucchesi BR (1987) Sustained myocardial protection by iloprost with prolonged infusion in a canine model of temporary regional ischemia. Fed Proc 46: 1144 (abstract)Google Scholar
  55. 55.
    Sweet CS, Ludden CT, Stabilito II, Emmert SE, Hey JF (1988) Beneficial effects of milrinone and enalapril on long-term survival of rats with healed myocardial infarction. Eur J Pharmacol 147: 29–38PubMedCrossRefGoogle Scholar
  56. 56.
    Tio RA, de Langen CDJ, de Graeff PA, van Gilst WH, Bel KJ, Wolters GTP, Mook PH, van Wijngaarden J, Wesseling H (1990) The effects of oral pretreatment with zofenopril, an angiotensin-converting enzyme inhibitor, on early reperfusion and subsequent elec-trophysiologic stability in the pig. Cardiovasc Drugs Therapy 4: 695–704Google Scholar
  57. 57.
    Tobe TJM, de Langen CDJ, Weersink EGL, van Wijngaarden J, Bel KJ, de Graeff PA, van Gilst WH, Wesseling H (1992) The angiotensin converting enzyme inhibitor Perindopril improves survival after experimental myocardial infarction in pigs. J Cardiovasc Pharmacol 19: 732–740Google Scholar
  58. 58.
    van Gilst, de Graeff PA, Wesseling H, de Langen CDJ (1986) Reduction of reperfusion arrhythmias in the ischemic isolated rat heart by angiotensin converting enzyme inhibitors: a comparison of Captopril, enalapril, and HOE 498. J Cardiovasc Pharmacol 8: 722–728Google Scholar
  59. 59.
    van Gilst WH, Kingma JH for the CATS Investigators Group (1991) Early intervention with angiotensin-converting enzyme inhibitors during thrombolytic therapy in acute myocardial infarction: rationale and design of Captopril and thrombolysis study. Am J Cardiol 68: 111D–115D.Google Scholar
  60. 60.
    van Wijngaarden J, Tobe TJM, Weersink EGL, Bel KJ, de Graeff PA, de Langen CDJ, van Gilst WH, Wesseling H (1992) Effects of early angiotensin-converting enzyme inhibition in a pig model of myocardial ischemia and reperfusion. J Cardiovasc Pharmacol 19: 408–416Google Scholar
  61. 61.
    Weglicki WB, Mak IT, Simic MG (1990) Mechanisms of cardiovascular drugs as antioxidants. J Mol Cell Cardiol 22: 1199–1208PubMedCrossRefGoogle Scholar
  62. 62.
    Westlin W, Mullane K (1988) Does Captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 77 (Suppl I): 130–139Google Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt 1993

Authors and Affiliations

  • Karin Przyklenk
    • 1
    • 2
  • R. A. Kloner
    • 1
    • 2
  1. 1.Heart Institute/ResearchHospital of the Good SamaritanLos AngelesUSA
  2. 2.University of Southern CaliforniaLos AngelesUSA

Personalised recommendations