EFFECTS OF OMAPATRILAT IN LOW, NORMAL, AND HIGH RENIN EXPERIMENTAL-HYPERTENSION

Combined inhibition of neutral endopeptidase (NEP) and angiotensin con verting enzyme (ACE) produces cardiovascular effects greater than thos e elicited by selective inhibition of either enzyme alone. Dual metall oprotease inhibitors are single molecules that inhibit both NEP and AC E and produce cardiovascular effects in animal models similar to those elicited by the combination of NEP and ACE inhibitors. The purpose of this study was to determined the duration of antihypertensive activit y of the dual metalloprotease inhibitor omapatrilat in rodent models o f hypertension. Omapatrilat inhibited NEP (K-i = 9 nmol/L) and ACE (K- i = 6 nmol/L) activities in vitro and inhibited the presser response t o angiotensin I in rats after intravenous administration with a potenc y and duration of action similar to those of the long acting ACE inhib itor fosinoprilat. After single dose administration, omapatrilat lower ed mean arterial blood pressure (aortic catheter) in sodium depleted s pontaneously hypertensive rats (high renin model) from 148 +/- 5 to 10 6 +/- 3 mm Hg (baseline to 24 h), in deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167 +/- 4 to 141 +/- 5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162 +/- 4 to 138 +/- 3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral admi nistration, omapatrilat (100 mu mol/kg/day) persistently lowered systo lic blood pressure (tail cuff) in spontaneously hypertensive rats duri ng 11 days of treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic catheter) was lower (P < .05) in the group receiving omapatrilat (133 +/- 5 mm Hg) than in the group receiving vehicle (14 9 +/- 2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral anti hypertensive effects in low, normal, and high renin models of hyperten sion. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent. (C) 1998 American Journal of Hypertension, Lt d.