Effects of gastroprokinetic agents on gastroparesis in streptozotocin-induced diabetic rats.
The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. A slight decrease in gastric emptying was observed in the diabetic rats from 2 to 52 weeks after the diabetes induction. We also investigated the influence of gastroprokinetic agents on STZ-induced diabetic gastroparesis and subdiaphragmatic vagotomy-induced gastroparesis in rats. The selective 5-HT3 receptor antagonists ramosetron (YM060), YM114 (KAE-393), granisetron and ondansetron, and the substituted benzamides (5-HT4 receptor agonist/5-HT3 receptor antagonists) cisapride mosapride and SC-53116 dose-dependently enhanced gastric emptying in normal rats. These compounds also reversed the impairment of diabetic gastroparesis rats at 7 days after the STZ injection, but higher doses were required. The solid gastric emptying in subdiaphragmatic vagotomized rats was also delayed. Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.
Yamano
M
M
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba, Ibaraki, Japan.
Kamato
T
T
Nagakura
Y
Y
Miyata
K
K
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D020117:Cisapride; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005746:Gastric Emptying / Q000187:drug effects*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D018589:Gastroparesis / Q000503:physiopathology*; D017829:Granisetron / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014628:Vagotomy
D001549:Benzamides; D001562:Benzimidazoles; D001786:Blood Glucose; D020117:Cisapride; D017829:Granisetron; D009025:Morpholines; D017294:Ondansetron; D010880:Piperidines; D011758:Pyrroles; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C074211:SC 53116; C071315:ramosetron; C062720:mosapride