Jandeleit-Dahm Karin, Lassila Markus, Davis Belinda J, Candido Riccardo, Johnston Colin I, Allen Terri J, Burrell Louise M, Cooper Mark E
The Baker Heart Research Institute, Vascular Division, Danielle Alberti Memorial Centre for Diabetes Complications, Melbourne, Australia.
J Hypertens. 2005 Nov;23(11):2071-82. doi: 10.1097/01.hjh.0000184747.41565.a1.
To investigate the effects of the combined angiotensin-converting enzyme (ACE)/neutral endopeptidase (NEP) inhibitor omapatrilat on atherosclerosis and renal injury in a model of diabetes-associated accelerated atherosclerosis and renal injury.
The study was performed using diabetic apolipoprotein E-knockout (apo E-KO) mice, a model combining hyperlipidemia and hyperglycemia, which leads to accelerated atherosclerosis and renal injury.
Diabetes was induced by the injection of streptozotocin in 6-week old apo E-KO mice. Diabetic animals received no treatment (n = 12) or treatment with the ACE/NEP inhibitor omapatrilat (30 mg/kg per day, via gavage, n = 12) or quinapril (10 mg/kg per day, in drinking water, n = 12) for 20 weeks. Non-diabetic apo E-KO mice (n = 12) served as controls.
Omapatrilat reduced atherosclerosis and protected the mice from renal structural injury and albuminuria. The protective effects were associated with tissue inhibition of aortic and renal ACE and NEP as well as a significant reduction in blood pressure. Omapatrilat had similar anti-atherosclerotic effects compared with the ACE inhibitor quinapril in association with an almost complete inhibition of aortic ACE activity by both drugs. Omapatrilat conferred superior renoprotection in the diabetic apo E-KO mouse compared with quinapril in the context of greater renal ACE inhibition by omapatrilat than seen with quinapril, additional renal NEP inhibition and a modestly enhanced antihypertensive response.
These studies demonstrate the anti-atherosclerotic and renoprotective effects of omapatrilat in diabetic apo E-KO mice, a model of accelerated atherosclerosis and renal injury. These effects were observed in association with the local inhibition of ACE and NEP at the tissue level in the aorta and kidney. These results suggest that the anti-atherosclerotic effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse is predominantly mediated by its capacity to inhibit local vascular ACE. By contrast, in the kidney, local renal ACE and NEP inhibition and the superior antihypertensive effect of omapatrilat all contribute to the renoprotective effect conferred by omapatrilat treatment in the diabetic apo E-KO mouse.
在糖尿病相关的加速动脉粥样硬化和肾损伤模型中，研究血管紧张素转换酶（ACE）/中性内肽酶（NEP）联合抑制剂奥美沙坦酯对动脉粥样硬化和肾损伤的影响。
本研究使用糖尿病载脂蛋白E基因敲除（apo E-KO）小鼠进行，该模型合并了高脂血症和高血糖症，可导致加速动脉粥样硬化和肾损伤。
给6周龄的apo E-KO小鼠注射链脲佐菌素诱导糖尿病。糖尿病动物不接受治疗（n = 12），或接受ACE/NEP抑制剂奥美沙坦酯治疗（每天30 mg/kg，经口灌胃，n = 12）或喹那普利治疗（每天10 mg/kg，加入饮用水中，n = 12），持续20周。非糖尿病apo E-KO小鼠（n = 12）作为对照。
奥美沙坦酯减轻了动脉粥样硬化，保护小鼠免受肾结构损伤和蛋白尿的影响。这些保护作用与主动脉和肾脏中ACE和NEP的组织抑制以及血压的显著降低有关。与ACE抑制剂喹那普利相比，奥美沙坦酯具有相似的抗动脉粥样硬化作用，两种药物均可几乎完全抑制主动脉ACE活性。在糖尿病apo E-KO小鼠中，与喹那普利相比，奥美沙坦酯具有更好的肾脏保护作用，因为奥美沙坦酯对肾脏ACE的抑制作用比喹那普利更强，还能额外抑制肾脏NEP，并适度增强降压反应。
这些研究证明了奥美沙坦酯在糖尿病apo E-KO小鼠（一种加速动脉粥样硬化和肾损伤模型）中的抗动脉粥样硬化和肾脏保护作用。这些作用与主动脉和肾脏组织水平上ACE和NEP的局部抑制有关。这些结果表明，奥美沙坦酯治疗糖尿病apo E-KO小鼠所产生的抗动脉粥样硬化作用主要是由其抑制局部血管ACE的能力介导的。相比之下，在肾脏中，局部肾脏ACE和NEP的抑制以及奥美沙坦酯更好的降压作用均有助于奥美沙坦酯治疗糖尿病apo E-KO小鼠时产生的肾脏保护作用。
