Inhibition of Insulin Degrading Enzyme by Racecadotril in the Brain of Wistar Rats

J.-P. Lee; K.-C. Cheng; H.-H. Chung; H.-T. Wu; C.-T. Chen; J.-T. Cheng

doi:10.1055/s-0031-1277183

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2011; 43(7): 489-493
DOI: 10.1055/s-0031-1277183

Original Basic

Inhibition of Insulin Degrading Enzyme by Racecadotril in the Brain of Wistar Rats

J.-P. Lee¹ , K.-C. Cheng² , H.-H. Chung³ , H.-T. Wu³ , C.-T. Chen⁴ , J.-T. Cheng³ ^, ⁴ ^, ⁵

¹Department of Neurosurgery, Da Chien General Hospital, Miaoli City, Taiwan
²Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima City, Japan
³Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
⁴Department of Medical Research and Department of Pediatrics, Chi-Mei Medical Center, Yong Kang, Tainan City, Taiwan
⁵Institute of Medical Science, College of Health Science, Chang Jung Christian University, Guei-Ren, Tainan City, Taiwan

Abstract

Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i. c. v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K_ATP channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i. c. v. pretreatment with insulin antibody or glibenclamide. Also, i. c. v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K_ATP channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain.

Key words

blood glucose - cerebral insulin - K_ATP channels - rececadotril - thiorphan

Full Text

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Correspondence

J.-T. Cheng

Department of Medical

Research

Chi-Mei Medical Center

Yong Kang

73101 Tainan City

Taiwan

Phone: +886/6/331 85 16

Fax: +886/6/331 75 32

Email: m980103@mail.chimei.org.tw