Prevention of Diabetic Neuropathy with ACE Inhibitors

我们研究的目的是确定用依那普利（一种血管紧张素转化酶（ACE）抑制剂）或AVE 7688（一种血管肽酶抑制剂，可抑制ACE和中性内肽酶活性）治疗链脲佐菌素诱导的糖尿病大鼠（一种I型糖尿病动物模型）或Zucker糖尿病肥胖（ZDF）大鼠（一种II型糖尿病动物模型），预防和/或逆转糖尿病性神经病变（DN）的发展/进展。用ACE抑制剂治疗糖尿病患者是肾脏和心血管疾病的常见治疗形式。然而，对于ACE抑制剂治疗DN的潜在益处缺乏了解。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提供了理论基础。我们的工作假设是，血管功能障碍显著有助于DN的发展/进展。以前，我们证明，在坐骨神经的神经外膜小动脉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），其生物学身份是未知的。我们还表明，血管紧张度是由降钙素基因相关肽（CGRP）和神经外膜小动脉的感觉神经含有CGRP的支配。我们已经证明，糖尿病改变了这些血管扩张剂的活性，导致神经血流量减少。基于初步的研究，我们假设C型利钠肽（CNP）的功能EDHF在神经外膜小动脉。CNP是一种血管扩张剂，通过中性内肽酶代谢，CNP活性/表达因糖尿病而降低。我们认为，依那普利或AVE 7688治疗1型和2型糖尿病大鼠将通过以下方式减轻DN的发生/进展：1）防止血管组织中的氧化应激，从而保护NO的活性，2）防止CNP的损失并保护其生物活性，3）保护感觉神经和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查高血糖对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依据，以进一步测试ACE抑制剂治疗人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.