title: Insights in the mechanisms underlying the anti-ulcer activity of nicorandil.
abstract: This study was conducted to investigate possible mechanisms underlying the gastroprotective effect of nicorandil on experimentally-induced gastric lesions in rats. The rats were randomly assigned to vehicle (saline or tween 80), nicorandil (2 mg/kg), glibenclamide (2 mg/kg), nicorandil plus glibenclamide- and cimetidine (50 mg/kg)-pretreated groups, in addition to the non-stressed control group, to demonstrate whether the KATP channel opening activity contributed to nicorandil's gastroprotection. Gastric lesions were induced by water immersion-restraint stress (WIRS) and ulcer indices were determined. Gastric juice parameters (pH, free and total acid output, and pepsin and mucin concentrations) were determined for each group. Another group of rats was divided into control, saline-pretreated and nicorandil (2 mg/kg)-pretreated subgroups. The rats were subjected to 5 h of WIRS and the stomachs were used for determination of gastric mucosal levels of lipid peroxides, histamine, prostaglandin E2 (PGE2) and total nitrites. Nicorandil displayed significant protection against gastric lesions formation. Glibenclamide, when administered concomitantly with nicorandil, abolished its protective effects. Nicorandil significantly reduced gastric acid secretion and pepsin concentration, but upon co-administration with glibenclamide, these effects were blocked. Additionally, nicorandil significantly reduced gastric mucosal lipid peroxides and total nitrites back to near normal levels and significantly increased gastric mucosal PGE2, but did not alter significantly histamine levels. The results confirm a gastroprotective effect for nicorandil, the mechanism of which comprises KATP channel opening, free radical scavenging, PGE2 elevation, decrease of proteolytic activity and acid output and prevention of the detrimental increase of nitric oxide during WIRS, probably, by inhibiting iNOS activity.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, Egypt.
authors.forename: H A F
authors.initials: HA
authors.lastname: Ismail
authors.forename: M M A
authors.initials: MM
authors.lastname: Khalifa
authors.forename: M K
authors.initials: MK
authors.lastname: Hassan
authors.forename: O M
authors.initials: OM
authors.lastname: Ashour
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents; D015232:Dinoprostone / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D005750:Gastric Juice / Q000737:chemistry; D005753:Gastric Mucosa / Q000473:pathology; D006632:Histamine / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007101:Immersion; D054086:KATP Channels; D008026:Ligation; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D009077:Mucins / Q000032:analysis; D020108:Nicorandil / Q000494:pharmacology*; D009573:Nitrites / Q000378:metabolism; D010434:Pepsin A / Q000032:analysis; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists; D011708:Pylorus / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013276:Stomach Ulcer / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013315:Stress, Psychological / Q000150:complications
chemical_list: D000897:Anti-Ulcer Agents; D054086:KATP Channels; D008054:Lipid Peroxides; D009077:Mucins; D009573:Nitrites; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D020108:Nicorandil; D006632:Histamine; D010434:Pepsin A; D015232:Dinoprostone