Treatment of Streptozotocin-Induced Diabetic Rats With AVE7688, a Vasopeptidase Inhibitor

Effect on Vascular and Neural Disease

  1. Eric P. Davidson12,
  2. Travis L. Kleinschmidt2,
  3. Christine L. Oltman12,
  4. Donald D. Lund12 and
  5. Mark A. Yorek12
  1. 1Department of Veterans Affairs Iowa City Health Care System, Iowa City, Iowa
  2. 2Department of Internal Medicine, University of Iowa, Iowa City, Iowa
  1. Address correspondence and reprint requests to Mark A. Yorek, Room 204, Building 40, Department of Veterans Affairs Iowa City Health Care System, Iowa City, IA 52246. E-mail: mark-yorek{at}uiowa.edu

Abstract

In epineurial arterioles, acetylcholine-mediated vascular relaxation is mediated by nitric oxide and endothelium-derived hyperpolarizing factor (EDHF), and both mechanisms are impaired by diabetes. The mediator responsible for the effect of EDHF is unknown. In epineurial arterioles, C-type natriuretic peptide (CNP) has properties consistent with EDHF-like activity. Epineurial arterioles express CNP, and exogenous CNP causes a concentration-dependent vascular relaxation. In streptozotocin-induced diabetic rats, CNP-mediated vascular relaxation in epineurial arterioles is decreased. Since CNP may be a regulator of vascular function, a vasopeptidase inhibitor may be an effective treatment for diabetes-induced vascular and neural disease. Vasopeptidase inhibitors inhibit ACE activity and neutral endopeptidase, which degrades natriuretic peptides. Streptozotocin-induced diabetic rats were treated with AVE7688 (450 mg/kg in the diet), a vasopeptidase inhibitor, for 8–10 weeks after 4 weeks of untreated diabetes. Treatment of diabetic rats corrected the diabetes-induced decrease in endoneurial blood flow, significantly improved motor and sensory nerve conduction velocity, prevented the development of hypoalgesia in the hind paw, and reduced superoxide and nitrotyrosine levels in epineurial arterioles. The diabetes-induced decrease in acetylcholine-mediated vascular relaxation by epineurial arterioles was significantly improved with treatment. These studies suggest that vasopeptidase inhibitors may be an effective approach for the treatment of diabetic vascular and neural dysfunction.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted November 5, 2006.
    • Received August 23, 2006.
| Table of Contents