Prevention of Diabetic Neuropathy with ACE Inhibitors

Summary

Principal Investigator: Mark Yorek
Abstract: 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.
Funding Period: 2006-09-15 - 2008-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Treatment of streptozotocin-induced diabetic rats with AVE7688, a vasopeptidase inhibitor: effect on vascular and neural disease
    Eric P Davidson
    Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA 52246, USA
    Diabetes 56:355-62. 2007
  2. ncbi Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats
    Irina G Obrosova
    Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA
    Am J Physiol Endocrinol Metab 293:E1645-55. 2007
  3. ncbi Vascular and neural dysfunction in Zucker diabetic fatty rats: a difficult condition to reverse
    C L Oltman
    Veteran Affairs Medical Center, University of Iowa, Iowa City, IA 52246, USA
    Diabetes Obes Metab 10:64-74. 2008
  4. ncbi Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes
    Christine L Oltman
    Department of Veterans Affairs, Iowa City, Iowa 52246, USA
    Vascul Pharmacol 48:47-53. 2008
  5. ncbi Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin
    Ulla C Kopp
    Department of Internal Medicine, Department of Veterans Affairs Medical Center, Bldg 41, Rm 124, Highway 6W, Iowa City, IA 52246, USA
    Am J Physiol Regul Integr Comp Physiol 294:R858-66. 2008
  6. ncbi The potential role of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy
    Mark A Yorek
    Department of Internal Medicine, University of Iowa and Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA, 52246, USA
    Curr Drug Targets 9:77-84. 2008
  7. pmc Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction
    C L Oltman
    Veteran Affairs Medical Center, Iowa City, IA 52246, USA
    Diabetes Obes Metab 11:223-33. 2009

Detail Information

Publications7

  1. ncbi Treatment of streptozotocin-induced diabetic rats with AVE7688, a vasopeptidase inhibitor: effect on vascular and neural disease
    Eric P Davidson
    Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA 52246, USA
    Diabetes 56:355-62. 2007
    ..These studies suggest that vasopeptidase inhibitors may be an effective approach for the treatment of diabetic vascular and neural dysfunction...
  2. ncbi Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats
    Irina G Obrosova
    Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA
    Am J Physiol Endocrinol Metab 293:E1645-55. 2007
    ..The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models...
  3. ncbi Vascular and neural dysfunction in Zucker diabetic fatty rats: a difficult condition to reverse
    C L Oltman
    Veteran Affairs Medical Center, University of Iowa, Iowa City, IA 52246, USA
    Diabetes Obes Metab 10:64-74. 2008
    ..We had previously demonstrated that vascular and neural dysfunction in Zucker diabetic fatty (ZDF) rats is progressive. In this study, we sought to determine whether monotherapy of ZDF rats can reverse the vascular and nerve defects...
  4. ncbi Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes
    Christine L Oltman
    Department of Veterans Affairs, Iowa City, Iowa 52246, USA
    Vascul Pharmacol 48:47-53. 2008
    ....
  5. ncbi Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin
    Ulla C Kopp
    Department of Internal Medicine, Department of Veterans Affairs Medical Center, Bldg 41, Rm 124, Highway 6W, Iowa City, IA 52246, USA
    Am J Physiol Regul Integr Comp Physiol 294:R858-66. 2008
    ..We conclude that the mechanisms involved in the decreased responsiveness of the renal sensory nerves in STZ rats involve activation of the renin angiotensin system in STZ but not in obese ZDF rats...
  6. ncbi The potential role of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy
    Mark A Yorek
    Department of Internal Medicine, University of Iowa and Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA, 52246, USA
    Curr Drug Targets 9:77-84. 2008
    ..The purpose of this review is to evaluate the use of angiotensin converting enzyme and vasopeptidase inhibitors in the treatment of diabetic neuropathy...
  7. pmc Treatment of Zucker diabetic fatty rats with AVE7688 improves vascular and neural dysfunction
    C L Oltman
    Veteran Affairs Medical Center, Iowa City, IA 52246, USA
    Diabetes Obes Metab 11:223-33. 2009
    ..In this study, we determined the effect of treating Zucker diabetic fatty (ZDF) rats, an animal model of type 2 diabetes, with AVE7688 on vascular and neural function...