Department of Internal Medicine, University of Iowa, Iowa City, IA, 52246, United States.
Eur J Pharmacol. 2012 Feb 29;677(1-3):180-7. doi: 10.1016/j.ejphar.2011.12.003. Epub 2011 Dec 14.
Treating high fat fed/low dose streptozotocin-diabetic rats; model of type 2 diabetes, with ilepatril (vasopeptidase inhibitor, blocks neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE)) improved vascular and neural functions. Next, studies were performed to determine the individual effect of inhibition of NEP and ACE on diabetes-induced vascular and neural dysfunctions. High fat fed rats (8 weeks) were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks, were treated for 12 weeks with ilepatril, enalapril (ACE inhibitor) or candoxatril (NEP inhibitor) followed by analysis of vascular and neural functions. Glucose clearance was impaired in diabetic rats and was not improved with treatment although treatment with ilepatril or candoxatril partially improved insulin stimulated glucose uptake by isolated soleus muscle. Diabetes caused slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber (IENF) profiles and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide (CGRP) in epineurial arterioles of the sciatic nerve. Inhibition of NEP improved nerve conduction velocity and inhibition of NEP or ACE improved thermal sensitivity and protected IENF density. Ilepatril and candoxatril treatments of diabetic rats were efficacious in improving vascular responsiveness to acetylcholine in epineurial arterioles; whereas all three treatments improved vascular response to CGRP. These studies suggest that inhibition of NEP and ACE activity is an effective approach for treatment of type 2 diabetes neural and vascular complications.
治疗高脂肪喂养/低剂量链脲佐菌素糖尿病大鼠；2 型糖尿病模型，用 ilepatril（血管肽酶抑制剂，阻断中性内肽酶（NEP）和血管紧张素转换酶（ACE））改善血管和神经功能。接下来，进行了研究以确定抑制 NEP 和 ACE 对糖尿病引起的血管和神经功能障碍的单独作用。用 30mg/kg 链脲佐菌素（ip）处理高脂肪喂养的大鼠（8 周），并在另外 4 周后，用 ilepatril、依那普利（ACE 抑制剂）或坎地沙坦（NEP 抑制剂）治疗 12 周，然后分析血管和神经功能。糖尿病大鼠的葡萄糖清除率受损，尽管用 ilepatril 或坎地沙坦治疗可部分改善分离的比目鱼肌中胰岛素刺激的葡萄糖摄取，但治疗并未改善。糖尿病导致运动和感觉神经传导速度减慢，热痛觉减退，表皮内神经纤维（IENF）形态减少，以及坐骨神经epineurial 动脉中乙酰胆碱和降钙素基因相关肽（CGRP）引起的血管舒张受损。抑制 NEP 可改善神经传导速度，抑制 NEP 或 ACE 可改善热敏感性并保护 IENF 密度。ilepatril 和坎地沙坦治疗糖尿病大鼠可有效改善 epineurial 动脉中乙酰胆碱的血管反应性；而所有三种治疗方法均改善了 CGRP 的血管反应性。这些研究表明，抑制 NEP 和 ACE 活性是治疗 2 型糖尿病神经和血管并发症的有效方法。
