We evaluated whether a novel dual inhibitor of
neutral endopeptidase (NEP) and
angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl)
propionic acid, prevents
deoxycorticosterone acetate (
DOCA)-
salt-induced
hypertension and related organ damage, such as cardiovascular
hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with
candoxatril and
enalapril, which are a selective NEP and
ACE inhibitor, respectively. During
DOCA-
salt treatment for 4 weeks, the rats were given SA7060,
candoxatril,
enalapril or vehicle, once daily by gavage. The 4-weeks treatment with
DOCA and
salt produced progressive increases in systolic blood pressure. Daily administration of SA7060,
candoxatril or
enalapril significantly suppressed the development of
hypertension induced by
DOCA and
salt, although the effect of
enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated
DOCA-
salt rats, decreases in
creatinine clearance and increases in urinary excretion of
protein and blood
urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of
atrial natriuretic peptide and
cyclic GMP in SA7060- or
candoxatril-treated animals. Histopathological examination of the kidney in
DOCA-
salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or
candoxatril. When the vascular
hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated
DOCA-
salt rats compared with the
sham rats. The development of vascular
hypertrophy was suppressed by the treatment with SA7060,
candoxatril or
enalapril. Our findings indicate that SA7060 efficiently prevents
DOCA-
salt-induced
hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both
renin-dependent and
renin-independent hypertensive subjects, although further studies examining efficiency in a
renin-dependent hypertensive model are needed.