title: Inhibition of insulin degrading enzyme by racecadotril in the brain of Wistar rats.
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.
authors.affiliation: Department of Neurosurgery, Da Chien General Hospital, Miaoli City, Taiwan.
authors.forename: J-P
authors.initials: JP
authors.lastname: Lee
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
authors.forename: H-H
authors.initials: HH
authors.lastname: Chung
authors.forename: H-T
authors.initials: HT
authors.lastname: Wu
authors.forename: C-T
authors.initials: CT
authors.lastname: Chen
authors.forename: J-T
authors.initials: JT
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D001786:Blood Glucose / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015244:Thiorphan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014020:Tissue Extracts; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism
chemical_list: D000906:Antibodies; D001786:Blood Glucose; D007328:Insulin; D054086:KATP Channels; D014020:Tissue Extracts; C049331:racecadotril; D015244:Thiorphan; D007339:Insulysin; D005905:Glyburide