In this study we examined diabetes- and
hypertension-induced changes in cardiac structure and function in an animal model of
type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with
omapatrilat, a
vasopeptidase inhibitor, which causes simultaneous inhibition of
angiotensin converting enzyme and
neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high
sodium intake, compared to treatment with
enalapril, a selective inhibitor of
angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-
sodium (NaCl 0.8%) or high-
sodium (NaCl 6%) diet and
enalapril,
omapatrilat or vehicle for 12 weeks. The GK rats developed
hypertension,
cardiac hypertrophy and overexpression of cardiac
natriuretic peptides and profibrotic
connective tissue growth factor compared to nondiabetic Wistar rats. The high
dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction.
Enalapril and
omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-
sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high
dietary sodium. Compared to
enalapril,
omapatrilat reduced the echocardiographically measured left ventricular mass during normal-
sodium diet and improved the diastolic function during high-
sodium diet in GK rats. Furthermore,
omapatrilat reduced relative cardiac weight more effectively than
enalapril during high
sodium intake. Our results suggest that both the
renin-
angiotensin and the
neutral endopeptidase system are involved in the pathogenesis of
diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective
angiotensin converting enzyme inhibition alone.