Effects of SA7060, a Novel Dual Inhibitor of Neutral Endopeptidase and Angiotensin-Converting Enzyme, on Deoxycorticosterone Acetate-Salt-Induced Hypertension in Rats.

Abstract

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.

Transmembrane proteases in cell growth and invasion: new contributors to angiogenesis?

“…In mice, rat and hamster models, inhibitors of ACE (omapatrilat, fasidotril, Z13752A, SA7060) block both angiotensin II release and bradykinin inactivation thus decreasing the mean blood pressure and augmenting cardiac output (Burrell et al, 2000;Kuro et al, 2000;Laurent et al, 2000;Antczak et al, 2001b).…”

The endocrine system in chronic nitric oxide deficiency

“…Omapatrilat is a mercaptoacyl derivative of a dipeptide surrogate that simultaneously inhibits both ACE and NEP in vitro (25) and in vivo (26). Inhibition of NEP protects vasodilator peptides (natriuretic peptides, bradykinin, and adrenomedullin) from degradation and reduces BP in low renin states (27)(28)(29). ACE inhibition attenuates the formation of AII and lowers BP in low, normal, and high renin experimental models of hypertension in rats (27) and in spontaneously hypertensive rats (30).…”

Aldosterone: good guy or bad guy in cerebrovascular disease?

“…The media to lumen ratio in coronary and mesenteric arteries is increased in rats made hypertensive by the administration of aldosterone or deoxycorticosterone (DOC) and salt [31,32]. Aortic hypertrophy has also been seen in DOC-salt hypertensive rats [33,34]. These effects can be inhibited by endothelin antagonism, ACE inhibition and neutral endopeptidase and proteosome inhibition [31][32][33][34].…”

“…Aortic hypertrophy has also been seen in DOC-salt hypertensive rats [33,34]. These effects can be inhibited by endothelin antagonism, ACE inhibition and neutral endopeptidase and proteosome inhibition [31][32][33][34]. It is important to remember that although these rats have high circulating mineralocorticoids, they also have malignant hypertension, making it difficult to separate the effects of MR activation and blood pressure per se.…”