Author + information
- Received May 21, 2001
- Revision received February 13, 2002
- Accepted February 26, 2002
- Published online May 15, 2002.
- Nathalie Lapointe, MSc*,
- Charles Blais Jr, PhD†,
- Albert Adam, PhD†,
- Thomas Parker, MD, FACC*,
- Martin G Sirois, PhD‡,
- Hugues Gosselin, DT‡,
- Robert Clément, BSc‡ and
- Jean L Rouleau, MD, FACC*,* ()
- ↵*Reprint requests and correspondence:
Dr. Jean L. Rouleau, Toronto General Hospital, Division of Cardiology, 13EN-212-200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
Objectives The goal of this study was to compare the effects of the vasopeptidase inhibitor omapatrilat and the angiotensin-converting enzyme inhibitor (ACEI) captopril in the postmyocardial infarction (MI) rat model.
Background The cardioprotective effects of ACEIs after MI are thought to be partially due to an increase in bradykinin (BK). Vasopeptidase inhibitors inhibit both ACE and neutral endopeptidase (NEP), further reduce BK metabolism and increase natriuretic peptides, which may result in better cardioprotective effects than with ACEIs after MI.
Methods Myocardial infarction was induced in 514 Wistar male rats by ligation of the anterior coronary artery. Rats surviving 4 h after MI (n = 282) were assigned to omapatrilat (40 or 80 mg/kg/day), captopril (160 mg/kg/day) or no treatment. After 56 days, neurohumoral, hemodynamic, ventricular remodeling, morphometry, immunohistochemistry and cardiac cytokine expression were measured.
Results Omapatrilat and captopril resulted in similarly improved survival, cardiac hemodynamics and reduced cardiac fibrosis and hypertrophy after MI. The pattern of left ventricular (LV) remodeling differed, omapatrilat causing less attenuation of the rightward shift of the LV pressure-volume relation at lower filling pressures than captopril. Both interventions reduced messenger ribonucleic acid expression of the profibrotic cytokine transforming growth factor-β1; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Expression of TNF-α was in cardiomyocytes. Both medications reduced circulating endothelin-1, angiotensin II and catecholamines, but only omapatrilat increased atrial natriuretic peptides.
Conclusions This study indicates that both omapatrilat and captopril markedly improve post-MI survival, cardiac function and cardiac remodeling in the rat. It would appear that the addition of NEP inhibition to those of ACEIs does not result in significant further benefit after MI.
☆ Supported by a joint grant of the Canadian Medical Research Council, Ottawa, Ontario, Canada and Bristol-Myers Squibb, Montreal, Quebec, Canada.
- Received May 21, 2001.
- Revision received February 13, 2002.
- Accepted February 26, 2002.
- American College of Cardiology Foundation