Skip to main content
Log in

Potential antithrombotic and fibrinolytic properties of the angiotensin converting enzyme inhibitors

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Summary

As a class of therapeutic agents, the ACE inhibitors have proven to have long-term mortality benefit when used after myocardial infarction and among patients with symptomatic congestive heart failure. Clinical trial data also indicate that the use of ACE inhibitors is associated with reduced rates of recurrent coronary thrombosis, an observation that raises the possibility that the renin-angiotensin system may be directly involved in the thrombotic process and that the ACE inhibitors may have valuable fibrinolytic and/ or antithrombotic effects. Recent in vitro and in vivo studies of angiotensin II and its interactions with the fibrinolytic system, particularly with the primary inhibitor of intravascular fibrinolysis, plasminogen activator inhibitor type 1 (PAI-1), provide substantial support for this hypothesis. In addition, a series of cross-sectional studies have described a genetic linkage between a common ACE gene polymorphism (DD) and the prevalence of clinical cardiovascular events, an intriguing finding as this polymorphism may account for much of the population variability in plasma ACE levels. Taken together, the totality of available clinical and experimental findings support the possibility of a direct linkage between the ACE system and vascular thrombosis that merits further prospective evaluation.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Cushman D, Ondetti M. History of the design of captopril and related inhibitors of angiotensin converting enzyme.Hypertension 1991;17:589–592.

    PubMed  Google Scholar 

  2. Williams GH. Converting-enzyme inhibitors in the treatment of hypertension.N Engl J Med 1988;319:1517.

    PubMed  Google Scholar 

  3. Braunwald E. ACE inhibitors: A cornerstone of the treatment of heart failure.N Engl J Med 1991;325:351–353.

    PubMed  Google Scholar 

  4. Pfeffer M. Angiotensin-converting enzyme inhibition in congestive heart failure: Benefit and perspective.Am Heart J 1993;126:789–793.

    PubMed  Google Scholar 

  5. 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;87:1969–1973.

    PubMed  Google Scholar 

  6. Pfeffer MA, Braunwald E, Moye LA, et al, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med 1992;327:669–677.

    PubMed  Google Scholar 

  7. SOLVD Investigators. Effect of Enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med 1991;325:293–301.

    Google Scholar 

  8. SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction.N Engl J Med 1992;327:685–691.

    Google Scholar 

  9. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: Experimental observations and clinical implications.Circulation 1990;81:1161–1172.

    PubMed  Google Scholar 

  10. CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure.N Engl J Med 1987;316:1429.

    Google Scholar 

  11. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease II, short-term reductions in blood pressure: Overview of randomized drug trials in their epidemiological context.Lancet 1990;335:827–838.

    PubMed  Google Scholar 

  12. Brunner HR, Laragh JH, Baer L, et al. Essential hypertension: Renin and aldosterone, heart attack and stroke.N Engl J Med 1991;324:1098–1104.

    PubMed  Google Scholar 

  13. Alderman MH, Madhaven S, Ooi WL, Cohen H, Sealey JE, Laragh JH. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension.N Engl J Med 1991;324:1098–1104.

    PubMed  Google Scholar 

  14. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions.Lancet 1992;340:1173–1178.

    PubMed  Google Scholar 

  15. Meade TW, Cooper JA, Peart WS. Plasma renin activity and ischemic heart disease.N Engl J Med 1993;329:616–619.

    PubMed  Google Scholar 

  16. Sogaard P, Gotzsche C-O, Ravkilde J, et al. Effects of captopril on ischemia and dysfunction of the left ventricle after myocardial infarction.Circulation 1993;87:1093.

    PubMed  Google Scholar 

  17. Chobanian AV, Haudenschild CC, Nickerson C, Hope S. Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.Hypertension 1992;20:473.

    PubMed  Google Scholar 

  18. Berk BC, Vekshtein V, Gordon HM, Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells.Hypertension 1989;13:305–314.

    PubMed  Google Scholar 

  19. Katz AM. Angiotensin-II: Hemodynamic regulator or growth factor?J Mol Cell Cardiol 1990;22:739–747.

    PubMed  Google Scholar 

  20. Daeman MJ, Lombardi DM, Bosman FT, Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall.Circ Res 1991;68:4450.

    Google Scholar 

  21. Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, Saruta T. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscles.J Hypertens 1991;9:17–22.

    PubMed  Google Scholar 

  22. Powell JS, Clozel JP, Muller RK, et al. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury.Science 1989;245:186.

    PubMed  Google Scholar 

  23. Bonithon-Kopp C, Ducimetiere P, Touboul PJ, Feve JM, Billaud E, Courbon D, Heraud V. Plasma angiotensinconverting enzyme activity and carotid wall thickening.Circulation 1994;89:952–954.

    PubMed  Google Scholar 

  24. MERCATOR Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: A multicenter, randomized, double-blind placebo-controlled trial.Circulation 1992;86:100.

    Google Scholar 

  25. Kiowski W, Zuber M, Elsasser S, Erne P, Pfisterer M, Burkart F. Coronary vasodilatation and improved myocardial lactate metabolism after angiotensin converting enzyme inhibition with enalapril in patients with congestive heart failure.Am Heart J 1991;122:1382–1388.

    PubMed  Google Scholar 

  26. Sprengers ED, Kluft C. Plasminogen activator inhibitors.Blood 1987;69:381–387.

    PubMed  Google Scholar 

  27. Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction.Lancet 1993;341:1165–1168.

    PubMed  Google Scholar 

  28. Ridker PM, Hennekens CH, Stampfer MJ, Manson JE, Vaughan DE. Prospective study of endogenous tissue plasminogen activator and risk of stroke.Lancet 1994;343:940–43.

    PubMed  Google Scholar 

  29. Ridker PM, Vaughan DE, Stampfer MJ, et al. Baseline fibrinolytic state and the risk of future venous thrombosis. A prospective study of endogenous tissue-type plasminogen activator and plasminogen activator inhibitor.Circulation 1992;85:1822–27.

    PubMed  Google Scholar 

  30. Hamsten A, Wimon B, DeFaire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction.N Engl J Med 1985;313:1557–1563.

    PubMed  Google Scholar 

  31. Hamsten A, Walldius G, Szamosi A, Blomback M, deFaire U, Dahlen G, Wiman B. Plasminogen activator inhibitor in plasma: Risk factor for recurrent myocardial infarction.Lancet 1987;2:3–9.

    PubMed  Google Scholar 

  32. Oseroff A, Krishnamurti C, Hassett A, Tang D, Alving B. Plasminogen activator and plasminogen activator inhibitor activities in men with coronary artery disease.J Lab Clin Med 1989;113:88–93.

    PubMed  Google Scholar 

  33. Aznar J, Estelles A, Tormo G, Sapena P, Tormo V, Blanch S, Espana F. Plasminogen activator inhibitor activity and other fibrinolytic variables in patients with coronary artery disease.Br Heart J 1988;59L:535–541.

    Google Scholar 

  34. Paramo JA, Colucci M, Collen D. Plasminogen activator inhibitor in the blood of patients with coronary artery disease.Br Med J 1985;291:573–574.

    Google Scholar 

  35. Levi M, Biemond BJ, vanZonneveld A-J, ten Catae JW, Pannekoek H. Inhibition of plasminogen activator inhibitor-1 activity results in premotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis.Circulation 1992;85:305–312.

    PubMed  Google Scholar 

  36. Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator ihibitor.J Clin Invest 1989;83:1747–1752.

    PubMed  Google Scholar 

  37. Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D. Brief report: Complete deficiency of plasminogen-activator inhibitor type 1 due to a frame shift mutation.N Engl J Med 1992;327:1729–33.

    PubMed  Google Scholar 

  38. Eriksson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene.Nature 1990;346:74–76.

    PubMed  Google Scholar 

  39. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study.Lancet 1993;342;1076–1079.

    PubMed  Google Scholar 

  40. Gavras I, Gavras H. The use of ACE-inhibitors in hypertension. In: Kostis JB, DeFelice EA, eds.Angiotensin Converting Enzyme Inhibitors. New York: Alan R. Liss, 1987:93–122.

    Google Scholar 

  41. Vaughan DE, Shen C, Lazos SA. Angiotensin II induces plasminogen activator inhibitor (PAI-1) in vitro (abstract).Circulation 1992;86 (Suppl I):I557.

    Google Scholar 

  42. Olson JA Jr, Shiverick KT, Ogilvie S, Buhi WC, Raizade MK. Angiotensin II induces secretion of plasminogen activator inhibitor-1 and a tissue metalloprotease inhibitor-related protein from rat brain astrocytes.Neurobiology 1991;88:1928–1932.

    Google Scholar 

  43. Gader AMA, Clarkson AR, Cash JD. The plasminogen activator and coagulation factor VIII responses to adrenaline, noradrenaline, and salbutamol in man.Thromb Res 1973;2:9–16.

    Google Scholar 

  44. Kjaelgaard A, Kjaelgaard M. In vitro stimulation of plasminogen activator release from vein walls by adrenaline.J Clin Pathol 1986;39:1241–1244.

    PubMed  Google Scholar 

  45. Chandler WL, Veith RC, Fellingham GW, et al. Fibrinolytic response during exercise and epinephrine infusion in the same subjects.J Am Coll Cardiol 1992;19:1412–1420.

    PubMed  Google Scholar 

  46. Larsson PT, Wiman B, Olsson G, Angelin B, Hjemdahl P. Influence of metoprolol treatment on sympatho-adrenal activation of fibrinolysis.Thromb Haemost 1990;63:482–487.

    PubMed  Google Scholar 

  47. Wright RA, Flapan AD, Alberti KGMM, Ludlan C, Fox KAA. Effects of captopril therapy on endogenous fibrinoysis in men with recent, uncomplicated myocardial infarction.J Am Coll Cardiol 1994;24:67–73.

    PubMed  Google Scholar 

  48. Swartz SL, Moore TJ. Effect of Angiotensin II on collagen induced platelet aggregation in normotensive subjects.Thromb Haemost 1990;63:87–90.

    PubMed  Google Scholar 

  49. 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.

    PubMed  Google Scholar 

  50. Tiret L, Kee F, Poirier O, et al. Deletion polymorphism in angiotensin-converting enzyme gene associated with parental history of myocardial infarction.Lancet 1993;341; 991–992.

    PubMed  Google Scholar 

  51. Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin-1 converting enzyme gene accounting for half the variance of serum enzyme levels.J Clin Invest 1990;86:1342–1346.

    Google Scholar 

  52. Marian AJ, Yu Q-T, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death.Lancet 1993;342:1085–1086.

    PubMed  Google Scholar 

  53. Raynolds MV, Bristow MR, Bush EW, et al. Angiotensinconverting enzyme DD genotype in patients with ischaemic or idiopathic dilated cardiomyopathy.Lancet 1993;342:1073–1076.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Dr. Ridker is the recipient of a Clinician Scientist Award from the American Heart Association. Dr. Vaughan is the recipient of a Clinical Investigator Award from the United States Veterans Administration.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ridker, P.M., Vaughan, D.E. Potential antithrombotic and fibrinolytic properties of the angiotensin converting enzyme inhibitors. J Thromb Thrombol 1, 251–257 (1995). https://doi.org/10.1007/BF01060734

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01060734

Key words

Navigation