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EXPERIMENTAL STUDY

Comparison of the effects of an angiotensin-converting enzyme inhibitor and a vasopeptidase inhibitor after myocardial infarction in the rat

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^*,*

^* Division of Cardiology, University Health Network, Toronto General Hospital, Toronto, Ontario Canada
Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
Department of Medicine, Montreal Heart Institute, Montreal, Quebec, Canada

Manuscript received May 21, 2001; revised manuscript received February 13, 2002, accepted February 26, 2002.

^* Reprint requests and correspondence: Dr. Jean L. Rouleau, Toronto General Hospital, Division of Cardiology, 13EN-212-200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
jean.rouleau{at}uhn.on.ca

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-ß₁; neither effected the anti-inflammatory cytokine interleukin-10, and only captopril reduced the proinflammatory cytokine tumor necrosis factor-alpha (TNF-). Expression of TNF- 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.

Abbreviations and Acronyms   ACEI   angiotensin-converting enzyme inhibitor   Ang II   angiotensin II   ANP   atrial natriuretic peptide   AW   atrial weight   BK   bradykinin   BW   body weight   ET-1   endothelin-1   IgG   immunoglobulin-G   IL   interleukin   LV   left ventricle/ventricular   LVEDP   left ventricular end-diastolic pressure   LVSP   left ventricular systolic pressure   LVW   left ventricular weight   MI   myocardial infarction   mRNA   messenger ribonucleic acid   NEP   neutral endopeptidase inhibitor   RT-PCR   reverse transcriptase-polymerase chain reaction   RV   right ventricle/ventricular   RVSP   right ventricular systolic pressure   RVW   right ventricular weight   TGF-ß   transforming growth factor-beta   TNF-   tumor necrosis factor-alpha   VPI   vasopeptidase inhibitor   +dP/dt   maximum rate of pressure rise

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