In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor

The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibito ry potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N- and C-domains) was investigated with t he use of 3 substrates: angiotensin I, which is equally cleaved by the 2 AC E domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C -domain in high salt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In v itro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting a ngiotensin I hydrolysis. Omapatrilat inhibited similarly both N- and C-doma in hydrolysis, whereas fosinoprilat was slightly more specific for the N-do main, The in vivo selective inhibitory potency of single oral doses of 10 m g omapatrilat and 20 mg fosinopril were investigated in a double-blind, pla cebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to b e more specific for the N-domain than the C-domain in vivo, since plasma an d urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separatel y in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors.