Effects of SA7060, a novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, on deoxycorticosterone acetate-salt-induced hypertension in rats

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-concerting enzyme (ACE), SA7060, 0-2-[3-[(S)-2-(butolycarbo nyl)-2-hydroxyethyl]-3-isobutylureidol]-3-(2-naphtyl) propionic acid, preve nts deoxycorticosterone acetate (DOCA)-salt-induced hypertension and relate d organ damage, such as cardiovascular hypertrophy, renal dysfunction and r enal 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, candoxa tril, enalapril or vehicle, once daily by gavage, The 4-weeks treatment wit h DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly supp ressed the development of hypertension induced by DOCA and salt, although t he effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and in creases in urinary excretion of protein and blood urea nitrogen were observ ed. This functional damage was improved most efficiently by the treatment w ith SA7060, There were significant increases in urinary excretions of atria l natriuretic peptide and cyclic GRIP in SA7060- or candoxatril-treated ani mals. Histopathological examination of the kidney in DOCA-salt rats reveale d tubular, glomerular and vascular lesions, all of which were improved in a nimals given SA7060 or candoxatril. When the vascular hypertrophy of the ao rta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compare d with the sham rats. The development of vascular hypertrophy was suppresse d by the treatment with SA7060, candoxatril or enalapril, Our findings indi cate that SA7060 efficiently prevents DOCA-salt-induced hypertension and re lated tissue injury mainly by inhibiting NEP. Thus, SA7060 may be useful fo r treatment of both renin-dependent and renin-independent hypertensive subj ects, although further studies examining efficiency in a renin-dependent hy pertensive model are needed.