Effect of Inhibition of Angiotensin-Converting Enzyme and/or Neutral Endopeptidase on Neuropathy in High-Fat-Fed C57Bl/6J Mice

Lawrence Coppey,Bao Lu,Mark A Yorek,Craig Gerard

doi:10.1155/2012/326806

Abstract

We have demonstrated that treating diet-induced obese (DIO) mice with the vasopeptidase inhibitor ilepatril improved neural function. Vasopeptidase inhibitors block angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity. We propose that increased activity of ACE and NEP contributes to pathophysiology of DIO. To address this issue C57Bl/6J mice or mice deficient in NEP were fed a high-fat diet and treated with ilepatril, enalapril, ACE inhibitor, or candoxatril, NEP inhibitor, using both prevention and intervention protocols. Endpoints included glucose utilization and neural function determination. In the prevention study glucose tolerance was impaired in DIO C57Bl/6J mice and improved with ilepatril or enalapril. Sensory nerve conduction velocity, thermal nociception, and intraepidermal nerve fiber density were impaired in DIO C57Bl/6J mice and improved with ilepatril or candoxatril. In the intervention study only enalapril improved glucose tolerance. Sensory nerve conduction velocity and intraepidermal nerve fiber density were improved by all three treatments, whereas thermal nociception was improved by ilepatril or candoxatril. In NEP-deficient mice DIO impaired glucose utilization and this was improved with enalapril. Nerve function was not impaired by DIO in NEP-deficient mice. These studies suggest that ACE and NEP play a role in pathophysiology associated with DIO.

Highlights

We reported that deletion of neutral endopeptidase (NEP) provides protection from obesity- and diabetesinduced neural complications [1]
We have demonstrated that treating diet-induced obese (DIO) mice with the vasopeptidase inhibitor ilepatril improved neural function
In order to further elucidate the effects of vasopeptidase inhibitors in peripheral nerve dysfunction associated with obesity we examined the effect of diet-induced obesity on nerve conduction velocity and thermal response latency in the hindpaw of C57Bl/6J mice and mice deficient in NEP treated with ilepatril, enalapril, angiotensin-converting enzyme (ACE) inhibitor, or candoxatril, NEP inhibitor [1, 2]

Summary

Introduction

We reported that deletion of neutral endopeptidase (NEP) provides protection from obesity- and diabetesinduced neural complications [1]. We have shown that treating obese and streptozotocin-diabetic mice with the vasopeptidase inhibitor ilepatril prevented neural complications including slowing of nerve conduction velocity, thermal hypoalgesia, and decreased intraepidermal nerve fiber density [2]. Vasopeptidase inhibitors are drugs that simultaneously inhibit NEP and angiotensin-converting enzyme (ACE) activity [3]. Inhibition of ACE and NEP activity would be expected to improve vascular and neural function. In this regard we have demonstrated that treating type 1 and type 2 diabetic rats as well as a genetic rat model of obesity with ilepatril improves vascular and neural dysfunction [14,15,16]

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Discussion

Conclusion