Trapani A J, Beil M E, Bruseo C W, De Lombaert S, Jeng A Y
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Research, Summit, New Jersey 07901, USA.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S40-3. doi: 10.1097/00005344-200036051-00015.
The purpose of this study was to examine the pharmacologic properties of CGS 35066, a novel aminophosphonate inhibitor of endothelin-converting enzyme-1 (ECE-1). CGS 35066 inhibited the activity of human ECE-1 and rat kidney neutral endopeptidase 24.11 (NEP) in vitro with IC50 values of 22 +/- 0.9 nM and 2.3 +/- 0.03 microM, respectively. The in vivo effects of CGS 35066 were characterized in conscious, catheterized rats. At 30 and 120 min after treatment with vehicle, big endothelin-1 (big ET-1, 0.3 nmol/kg i.v.) produced increases in mean arterial pressure (MAP) of 982 +/- 31 and 992 +/- 43 mmHg x min (area under the curve), respectively. Doses of 0.3, 1.0, 3.0 and 10.0 mg/kg i.v., of CGS 35066 blocked these pressor responses by 61 +/- 7, 78 +/- 4, 93 +/- 4 and 98 +/- 2% at 30 min (p < 0.05 compared with vehicle controls, all doses), and by 29 +/- 7, 63 +/- 5, 63 +/- 5 and 84 +/- 10% at 120 min (p < 0.05, all doses). In contrast, the pressor effect (58 +/- 6 mmHg) of angiotensin-I (300 ng/kg i.v.) was unaffected by the ECE-1 inhibitor (10 mg/kg i.v.) indicating the absence of activity against angiotensin-converting enzyme. In rats infused with atrial natriuretic peptide (ANP), CGS 35066, at 1 mg/kg, had no effect on plasma irANP; however, irANP levels were doubled at a dose of 30 mg/kg. These results demonstrate that CGS 35066 is the most potent and selective ECE inhibitor identified to date.
本研究旨在检测新型氨基膦酸酯类内皮素转化酶-1（ECE-1）抑制剂CGS 35066的药理学特性。CGS 35066在体外可抑制人ECE-1和大鼠肾脏中性内肽酶24.11（NEP）的活性，其IC50值分别为22±0.9 nM和2.3±0.03 μM。在清醒的、已插管的大鼠中对CGS 35066的体内效应进行了表征。在用赋形剂处理30分钟和120分钟后，大内皮素-1（大ET-1，0.3 nmol/kg静脉注射）使平均动脉压（MAP）分别升高982±31和992±43 mmHg·min（曲线下面积）。静脉注射剂量为0.3、1.0,、3.0和10.0 mg/kg的CGS 35066在30分钟时分别使这些升压反应阻断61±7%、78±4%、93±4%和98±2%（与赋形剂对照组相比，所有剂量p<0.05），在120分钟时分别阻断29±７%、63±5%、63±5%和84±10%（所有剂量p<0.05）。相比之下，血管紧张素-I（300 ng/kg静脉注射）的升压效应（58±6 mmHg）不受ECE-1抑制剂（10 mg/kg静脉注射）的影响，表明其对血管紧张素转换酶无活性。在输注心房利钠肽（ANP）的大鼠中，1 mg/kg的CGS 35066对血浆免疫反应性ANP（irANP）无影响；然而，30 mg/kg剂量时irANP水平加倍。这些结果表明，CGS 35066是迄今为止已鉴定出的最有效和最具选择性的ECE抑制剂。
