Prevention of Diabetic Neuropathy with ACE Inhibitors

我们研究的目的是确定用依那普（一种血管紧张素转换酶（ACE）抑制剂）或AVE7688（一种血管肽酶抑制剂，能抑制ACE和中性内肽酶活性）治疗链脲佐菌素诱导的糖尿病大鼠（1型糖尿病动物模型）或Zucker糖尿病脂肪大鼠（2型糖尿病动物模型）是否能预防和/或逆转糖尿病神经病变（DN）的发生/进展。用ACE抑制剂治疗糖尿病患者是治疗肾脏和心血管疾病的一种常见形式。然而，对于ACE抑制剂治疗DN的潜在益处还缺乏了解。ACE抑制剂已被证明具有抗氧化和神经保护特性，这为使用这些药物治疗DN提供了基本原理。我们的工作假设是血管功能障碍在DN的发生/进展中起着重要作用。先前我们证明了在坐骨神经的神经外小动脉中，乙酰胆碱介导的内皮依赖性血管舒张是由一氧化氮（NO）和内皮源性超极化因子（EDHF）介导的，其生物学特性尚不清楚。我们还证明血管张力受降钙素基因相关肽（CGRP）调节，神经外小动脉受含有CGRP的感觉神经支配。我们已经证明，糖尿病会改变这些血管舒张剂的活性，导致流向神经的血流量减少。根据初步研究，我们假设c型利钠肽（CNP）在神经外动脉中具有EDHF的功能。CNP是一种血管扩张剂，由中性内肽酶代谢，糖尿病会降低CNP的活性/表达。我们认为依那普利或av7688治疗1型和2型糖尿病大鼠可通过以下途径减轻DN的发生/进展：1)防止血管组织氧化应激从而保护NO的活性；2)防止CNP的丧失并保护其生物活性；3)保护感觉神经及CGRP的可用性和功能。我们还将使用培养的微血管内皮细胞来检测高血糖对CNP表达的影响。如果成功，这些研究可以为设计临床研究提供理论基础，以进一步测试ACE抑制剂治疗人类DN的疗效。

The goal of our studies is to determine whether treatment of streptozotocin-induced diabetic rats, an animal model for Type I diabetes, or Zucker Diabetic Fatty (ZDF) rats, an animal model for Type II diabetes, with Enalapril, an angiotensin converting enzyme (ACE) inhibitor, or AVE7688, a vasopeptidase inhibitor, which inhibits both ACE and neutral endopeptidase activities, prevents and/or reverses the development/progression of diabetic neuropathy (DN). Treatment of diabetes patients with ACE inhibitors is a common form of treatment for renal and cardiovascular disease. However, there is a lack of knowledge about the potential benefits of ACE inhibitor treatment for DN. ACE inhibitors have been shown to have antioxidant and neuroprotective properties this provides a rationale for using these drugs in the treatment of DN. Our working hypothesis is that vascular dysfunction contributes significantly to the development/progression of DN. Previously we demonstrated that in epineurial arterioles of the sciatic nerve acetylcholine-mediated endothelium-dependent vascular relaxation is mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), whose biological identity is unknown. We also demonstrated that vascular tone is regulated by calcitonin gene-related peptide (CGRP) and that epineurial arterioles are innervated by sensory nerves containing CGRP. We have shown that diabetes alters the activity of each of these vasodilators causing decreased blood flow to the nerve. Based on preliminary studies we hypothesize the C-type natriuretic peptide (CNP) functions as EDHF in epineurial arterioles. CNP, a vasodilator, is metabolized by neutral endopeptidase and CNP activity/expression is decreased by diabetes. We propose that treating Type 1 and Type 2 diabetic rats with Enalapril or AVE 7688 will attenuate the development/progression of DN by: 1) preventing oxidative stress in vascular tissue thereby protecting the activity of NO, 2) preventing the loss of CNP and protecting its bioactivity, and 3) protecting sensory nerves and the availability and function of CGRP. We will also use cultured microvessel endothelial cells to examine the effect of hyperglycemia on CNP expression. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of ACE inhibitor treatment in human DN.