We have shown earlier that cardiomyocyte apoptosis continues at a high level late after
myocardial infarction and contributes to adverse cardiac remodeling. Here we studied whether this process can be inhibited by the
vasopeptidase inhibitor omapatrilat, a
drug which causes simultaneous inhibition of both
angiotensin converting enzyme and
neutral endopeptidase. Our hypothesis was that
omapatrilat-treated rats would have less cardiomyocyte apoptosis, and less adverse cardiac remodeling compared to rats treated with selective inhibitors of
angiotensin converting enzyme,
neutral endopeptidase or placebo.
Myocardial infarction was produced by
ligation of the left anterior descending coronary artery. Rats were randomized to receive
omapatrilat,
captopril,
neutral endopeptidase inhibitor
SQ-28603 or vehicle. Rats treated with
omapatrilat and
captopril had reduced cardiac BNP
mRNA levels and less myocardial
fibrosis by comparison with the vehicle-treated rats. However,
omapatrilat was more effective than
captopril in attenuating
hypertrophy as measured by relative cardiac weight (3.0+/-0.2 vs. 3.8+/-0.2 mg/g, P<0.01) or by echocardiographically determined left ventricular mass (0.61+/-0.05 vs. 0.83+/-0.06 g, P<0.01). Myocardial apoptosis was elevated both in the
infarction border zone (0.129+/-0.017%) and in the remote area (0.035+/-0.005%) still 4 weeks after
myocardial infarction.
Angiotensin converting enzyme inhibition proved to be important in the prevention of apoptosis since both
omapatrilat and
captopril reduced the number of apoptotic myocytes whereas selective
neutral endopeptidase inhibitor
SQ-28603 had no effect. In conclusion, myocardial apoptosis, remaining increased 4 weeks after
myocardial infarction, was reduced by
angiotensin converting enzyme inhibition. Vasopeptidase inhibition was more effective than selective
angiotensin converting enzyme inhibition in preventing adverse cardiac remodeling after
myocardial infarction.