Skip to main content
SpringerLink
Log in

Comparative effects of a vasopeptidase inhibitor vs. an angiotensin convertin enzyme inhibitor on cardiomyocyte apoptosis in rats with heart failure

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Apoptosis is involved in ventricular remodeling after myocardial infarction (MI). We investigated the effects of the vasopeptidase inhibitor (VPI) omapatrilat on cardiomyocyte apoptosis and compared it to the angiotensin converting enzyme inhibitor (ACEI) captopril in the rat post-MI model and in cultured neonatal rat cardiomyocytes. Wistar males rats surviving 4 h post-MI were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, hemodynamic measurements were performed (n = 96) and rats were sacrificed. One group had assessment of cardiac remodeling and detection of DNA fragments by in situ end labelling method (ISEL), while the other had morphologic measurements and DNA laddering assessed. In addition, cultured neonatal rat cardiomyocytes (n = 6) were treated for 72 h with vehicle, captopril or omapatrilat in the presence or absence of the apoptosis inducing agent H2O2. Omapatrilat and captopril resulted in similar improvements of hemodynamic measurements, ventricular weight and dilatation, cardiac fibrosis and myocardial cell cross-section in large MI rats. Omapatrilat increased scar thickness more than did captopril. All sham-operated groups had little evidence of apoptosis. In the large MI group, there was a significant increase in ISEL-positive cells in the control (0.095 ± 0.016%) and captopril (0.124 ± 0.024%) groups in comparison with control sham-operated (0.006 ± 0.006%), but this increase was limited to the peri-MI area. Omapatrilat (0.012 ± 0.012% for both doses) prevented the increase in apoptosis in the peri-MI area. Also, omapatrilat but not captopril reduced DNA laddering in large MI. Moreover, in cultured neonatal rat cardiomyocytes, omapatrilat but not captopril reduced apoptosis as assessed by DNA laddering. The VPI omapatrilat, with its combination of NEP and ACE inhibition, suppresses cardiomyocyte apoptosis post-MI and in neonatal cultured rat cardiomyocytes more than the ACEI captopril, but this does not result in significant hemodynamic or morphologic differences between omapatrilat and captopril.

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

Similar content being viewed by others

Reference

  1. Pfeffer J, Pfeffer M, Braunwald E: Hemodynamic benefits and prolonged survival with long-term captopril therapy in rats with myocardial infarction and heart failure. Circulation 75: I149-I155, 1987

    Google Scholar 

  2. Olivetti G, Capasso J, Meggs L, Sonnenblick E, Anversa P: Cellular basis of chronic ventricular remodeling after myocardial infarction in rats. Circ Res 68: 856-869, 1991

    Google Scholar 

  3. Hasegawa K, Iwai-Kanai E, Sasayama S: Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. J Cell Physiol 186: 11-18, 2001

    Google Scholar 

  4. Colucci W: Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 80: 15L-25L, 1997

    Google Scholar 

  5. Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara J, Quaini E, Di LC, Beltrami C, Krajewski S, Reed J, Anversa P: Apoptosis in the failing human heart. N Engl J Med 336: 1131-1141, 1997

    Google Scholar 

  6. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki L: Apoptosis in human acute myocardial infarction. Circulation 95: 320-323, 1997

    Google Scholar 

  7. Olivetti G, Quaini F, Sala R, Lagrasta C, Corradi D, Bonacina E, Gambert S, Cigola E, Anversa P: Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 28: 2005-2016, 1996

    Google Scholar 

  8. Narula J, Haider N, Virmani R, Di ST, Kolodgie F, Hajjar R, Schmidt U, Semigran M, Dec G, Khaw B: Apoptosis in myocytes in end-stage heart failure (see comments). N Engl J Med 335: 1182-1189, 1996

    Google Scholar 

  9. Sam F, Sawyer D, Chang D, Eberli F, Ngoy S, Jain M, Amin J, Apstein C, Colucci W: Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart. Am J Physiol Heart Circ Physiol 279: H422-H428, 2000

    Google Scholar 

  10. Pfeffer M, Braunwald E, Moye L, Basta L, Brown E, Cuddy T, Davis B, Geltman E, Goldman S, Flaker G 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. The SAVE Investigators. N Engl J Med 327: 669-677, 1992

    Google Scholar 

  11. McDonald K, Mock J, D'Aloia A, Parrish T, Hauer K, Francis G, Stillman A, Cohn J: Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis. Circulation 91: 2043-2048, 1995

    Google Scholar 

  12. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens B: Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev 47: 25-49, 1995

    Google Scholar 

  13. Blais C, Marceau F, Rouleau J, Adam A: The kallikrein-kininogen-kinin system: Lessons from the quantification of endogenous kinins. Peptides 21: 1903-1940, 2000

    Google Scholar 

  14. Goussev A, Sharov V, Shimoyama H, Tanimura M, Lesch M, Goldstein S, Sabbah H: Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol 275: H626-H631, 1998

    Google Scholar 

  15. Holm A, Andersen C, Haunso S, Hansen P: ACE-inhibition promotes apoptosis after balloon injury of rat carotid arteries. Cardiovasc Res 45: 777-782, 2000

    Google Scholar 

  16. Li Z, Bing O, Long X, Robinson K, Lakatta E: Increased cardiomyocyte apoptosis during the transition to heart failure in the spontaneously hypertensive rat. Am J Physiol 272: H2313-H2319, 1997

    Google Scholar 

  17. Buemi M, Allegra A, Marino D, Marino M, Medici M, De PG, Ruello A, Corica F, Frisina N: Does captopril have a direct pro-apoptotic effect? Nephron 81: 99-101, 1999

    Google Scholar 

  18. Yoshida H, Zhang J, Chao L, Chao J: Kallikrein gene delivery attenuates myocardial infarction and apoptosis after myocardial ischemia and reperfusion. Hypertension 35: 25-31, 2000

    Google Scholar 

  19. Corti R, Burnett J, Rouleau J, Ruschitzka F, Luscher T: Vasopeptidase inhibitors: A new therapeutic concept in cardiovascular disease? (In Process Citation). Circulation 104: 1856-1862, 2001

    Google Scholar 

  20. Rouleau J, Pfeffer M, Stewart D, Isaac D, Sestier F, Kerut E, Porter C, Proulx G, Qian C, Block A: Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial (see comments). Lancet 356: 615-620, 2000

    Google Scholar 

  21. Nicotera P, Brune B, Bagetta G: Nitric oxide: Inducer or suppressor of apoptosis? Trends Pharmacol Sci 18: 189-190, 1997

    Google Scholar 

  22. Dimmeler S, Zeiher A: Nitric oxide and apoptosis: Another paradigm for the double-edged role of nitric oxide. Nitric Oxide 1: 275-281, 1997

    Google Scholar 

  23. Suenobu N, Shichiri M, Iwashina M, Marumo F, Hirata Y: Natriuretic peptides and nitric oxide induce endothelial apoptosis via a cGMP-dependent mechanism. Arterioscler Thromb Vasc Biol 19: 140-146, 1999

    Google Scholar 

  24. Pfeffer M, Pfeffer J, Fishbein M, Fletcher P, Spadaro J, Kloner R, Braunwald E: Myocardial infarct size and ventricular function in rats. Circ Res 44: 503-512, 1979

    Google Scholar 

  25. Nguyen Q, Cernacek P, Calderoni A, Stewart D, Picard P, Sirois P, White M, Rouleau J: Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat. Circulation 98: 2323-2330, 1998

    Google Scholar 

  26. Levy M, Cernacek P: Renal natriuretic effects of atrial natriuretic peptide in dogs with alloxan-induced acute pulmonary edema. Clin Invest Med 19: 435-443, 1996

    Google Scholar 

  27. Milano C, Dolber P, Rockman H et al.: Myocardial expression of a constitutively active alpha 1b-adrenergic receptor in trangenic mice induces cardiac hypertrophy. Proc Natl Acad Sci U S A 91: 10109-10113, 1994

    Google Scholar 

  28. Hu J, Van Eldik LJ: S100 beta induces apoptotic cell death in cultured astrocytes via a nitric oxide-dependent pathway. Biochim Biophys Acta 1313: 239-245, 1996

    Google Scholar 

  29. Parker T, Packer S, Schneider M: Peptide growth factors can provoke ‘fetal’ contractile protein gene expression in rat cardiac myocytes. J Clin Invest 85: 507-514, 1990

    Google Scholar 

  30. Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki L, Tikkanen I: Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 280: H2726-H2731, 2001

    Google Scholar 

  31. Abbate A, Biondi-Zoccai GG, Bussani R, Dobrina A, Camilot D, Feroce F, Rossiello R, Baldi F, Biasucci LM, Baldi A. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. J Am Coll Cardiol 41: 753-760, 2003

    Google Scholar 

  32. Tea B, Dam T, Moreau P, Hamet P, de B D: Apoptosis during regression of cardiac hypertrophy in spontaneously hypertensive rats. Temporal regulation and spatial heterogeneity. Hypertension 34: 229-235, 1999

    Google Scholar 

  33. Bäcklund T, Palojoki E, Eriksson A, Grönholm T, Vuolteenaho O, Saraste A, Nieminen S, Voipio-Pulkki L, Laine M, Tikkanen I: Dual NEP/ACE inhibition is superior to selective ACE inhibition in preventing myocardial hypertrophy after experimental myocardial infarction in rat. Eur Heart J 22: 141, 2001

    Google Scholar 

  34. Wu C, Bishopric N, Pratt R: Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 272: 14860-14866, 1997

    Google Scholar 

  35. Dumoulin M, Adam A, Rouleau J, Lamontagne D: Comparison of a vasopeptidase inhibitor with neutral endopeptidase and angiotensin-converting enzyme inhibitors on bradykinin metabolism in the rat coronary bed. J Cardiovasc Pharmacol 37: 359-366, 2001

    Google Scholar 

  36. Raut R, Rouleau J, Blais CJ, Gosselin H, Molinaro G, Sirois M, Lepage Y, Crine P, Adam A: Bradykinin metabolism in the postinfarcted rat heart: Role of ACE and neutral endopeptidase 24.11. Am J Physiol 276: H1769-H1779, 1999

    Google Scholar 

  37. Leesar M, Stoddard M, Manchikalapudi S, Bolli R: Bradykinin-induced preconditioning in patients undergoing coronary angioplasty. J Am Coll Cardiol 34: 639-650, 1999

    Google Scholar 

  38. Nakamura M, Wang N, Zhao Z, Wilcox J, Thourani V, Guyton R, Vinten-Johansen J: Preconditioning decreases Bax expression, PMN accumulation and apoptosis in reperfused rat heart. Cardiovasc Res 45: 661-670, 2000

    Google Scholar 

  39. Piot C, Padmanaban D, Ursell P, Sievers R, Wolfe C: Ischemic preconditioning decreases apoptosis in rat hearts in vivo. Circulation 96: 1598-1604, 1997

    Google Scholar 

  40. Kishi K, Muromoto N, Nakaya Y, Miyata I, Hagi A, Hayashi H, Ebina Y: Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway (published erratum appears in Diabetes 1998 Jul; 47(7): 1170). Diabetes 47: 550-558, 1998

    Google Scholar 

  41. Linz W, Wiemer G, Scholkens B: Beneficial effects of bradykinin on myocardial energy metabolism and infarct size. Am J Cardiol 80: 118A-123A, 1997

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, University Health Network/Mount Sinai Hospital, Toronto General Hospital, Toronto, ON, Canada

    Nathalie Lapointe, James N. Tsoporis, Thomas G. Parker, Dominique Rouleau, Graham Slaughter & Jean L. Rouleau

  2. Faculty of Pharmacy, University of Montreal, Montreal, Québec, Canada

    Charles Blais & Albert Adam

  3. Faculty of Medicine, Montreal Heart Institute, Montréal, Québec, Canada

    Robert Clément

  4. Institut de Recherche Clinique, Montréal, Québec, Canada

    Christian F. Deschepper

Authors
  1. Nathalie Lapointe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James N. Tsoporis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas G. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles Blais
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Albert Adam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dominique Rouleau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Graham Slaughter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert Clément
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christian F. Deschepper
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean L. Rouleau
    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

Lapointe, N., Tsoporis, J.N., Parker, T.G. et al. Comparative effects of a vasopeptidase inhibitor vs. an angiotensin convertin enzyme inhibitor on cardiomyocyte apoptosis in rats with heart failure. Mol Cell Biochem 254, 235–245 (2003). https://doi.org/10.1023/A:1027328403952

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1027328403952

Search

Navigation