Trippodo N C, Robl J A, Asaad M M, Fox M, Panchal B C, Schaeffer T R
The Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Am J Hypertens. 1998 Mar;11(3 Pt 1):363-72. doi: 10.1016/s0895-7061(97)00404-4.
Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) produces cardiovascular effects greater than those elicited by selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are single molecules that inhibit both NEP and ACE 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 activity of the dual metalloprotease inhibitor omapatrilat in rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE (Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to angiotensin I in rats after intravenous administration with a potency and duration of action similar to those of the long acting ACE inhibitor fosinoprilat. After single dose administration, omapatrilat lowered mean arterial blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive rats (high renin model) from 148+/-5 to 106+/-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 administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic blood pressure (tail cuff) in spontaneously hypertensive rats during 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 (149+/-2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent.
中性内肽酶（NEP）和血管紧张素转换酶（ACE）的联合抑制所产生的心血管效应，比单独选择性抑制这两种酶中的任何一种所引发的效应都要大。双重金属蛋白酶抑制剂是一种能同时抑制NEP和ACE的单分子，在动物模型中所产生的心血管效应，类似于NEP抑制剂和ACE抑制剂联合使用时所引发的效应。本研究的目的是确定双重金属蛋白酶抑制剂奥帕曲拉在高血压啮齿动物模型中的降压活性持续时间。奥帕曲拉在体外可抑制NEP（Ki = 9 nmol/L）和ACE（Ki = 6 nmol/L）的活性，静脉给药后，它对大鼠血管紧张素I升压反应的抑制作用，其效力和作用持续时间与长效ACE抑制剂福辛普利拉相似。单次给药后，奥帕曲拉可使钠耗竭自发性高血压大鼠（高肾素模型）的平均动脉血压（主动脉插管）从148±5降至106±3 mmHg（基线至24小时），使醋酸脱氧皮质酮 - 盐高血压大鼠（低肾素）从167±4降至141±5 mmHg，使自发性高血压大鼠（正常肾素）从162±4降至138±3 mmHg（所有模型中，24小时时与赋形剂相比P < 0.05）。口服给药后，在11天的治疗期间，奥帕曲拉（100 μmol/kg/天）可使自发性高血压大鼠的收缩压（尾套法）持续降低；在第12天给药后24小时，接受奥帕曲拉的组（133±5 mmHg）的平均动脉血压（主动脉插管）低于接受赋形剂的组（149±2 mmHg，P < 0.05）。结果表明，奥帕曲拉是一种有效的NEP和ACE双重金属蛋白酶抑制剂，在低、正常和高肾素高血压模型中具有持久的口服降压作用。奥帕曲拉有潜力成为一种有效的广谱抗高血压药物。
