Olmesartan ameliorates peripheral nerve dysfunction in Zucker diabetic fatty rats

Abstract

Angiotensin (ANG) II type 1 receptor (AT1R) blockers have neuroprotective effects against neuronal lesions. The present study examines whether the AT1R blocker olmesartan improves peripheral nerve dysfunction in rats with type 2 diabetes. Fourteen-week-old male type 2 diabetic Zucker diabetic fatty (ZDF) rats were orally administered with olmesartan (6 mg/kg per day; n = 7) or not treated (n = 7) and then followed up for nine weeks. Age-matched and sex-matched nondiabetic lean rats served as controls (n = 7). Olmesartan for 9 weeks did not influence blood glucose and A1c levels that were higher in untreated ZDF (U-ZDF) rats than in control rats. In U-ZDF rats, myelinated fiber density and myelin areas of myelinated fibers in peroneal nerves significantly increased and decreased, respectively, and the intraepidermal nerve fiber density (IENFD) of footpad skin tended to decrease. The U-ZDF rats developed mechanical hyperalgesia, thermal hypoalgesia and slower sensory and motor nerve conduction in the sciatic-tibial nerves. Olmesartan increased myelin areas and IENFD and ameliorated sensory nerve conduction deficits. These beneficial effects of olmesartan were associated with ANG II and insulin receptor upregulation in sensory neurons as well as deactivation of Erk1/2 in sciatic nerves. Olmesartan appears to improve the structure and function of small and large nerves and upregulate ANG II and insulin receptors in sensory neurons of rats with type 2 diabetes.