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.