Tu1987 Decrease in the Upper Medullary NOS Activity is Involved in Impaired Gastric Accommodation: A Lesson From a Water-Avoidance Stress Model Using Conscious Guinea Pigs

Abstract

Background and Aims: Gastric accommodation is a response associated with relaxation in the proximal stomach following ingestion of a meal, and is regulated by nitrergic neurons. Impaired gastric accommodation is thought to be involved with early satiation in functional dyspepsia (FD), and functional analysis and drug evaluation for gastric accommodation is important for planning clinical therapy. Rikkunshito, a traditional Japanese medicine, is used to treat various gastrointestinal tract disorders in Japan, and has been reported to improve anorexia caused by chemotherapy (Gastroenterology. 2008;134:2004) and impaired gastrointestinal motility caused by selective serotonin reuptake inhibitors through ghrelin secretion. This study examined the effects of rikkunshito on gastric accommodation, and evaluated the effects of rikkunshito and its components on a newly created model of impaired gastric accommodation in conscious guinea pigs.Methods: A polyethylene bag was inserted through the distal part of the gastric body and placed at the proximal stomach of 5-weekold male Hartley guinea pigs. Measurement of gastric accommodation was performed as follows: air (6 mL) was injected into the polyethylene bag at a flow rate of 2 mL/min, and intrabag pressure at baseline was recorded for 1 min. Immediately after oral administration of a liquid meal (4 mL, 1.7 kcal), air (6 mL) was again injected into the bag, and intrabag pressure was recorded 6 times, for 1 min each time at intervals of 5 min. A nitric oxide synthase (NOS) inhibitor, NG-Nitro-L-arginine (L-NNA) (1-10 mg/kg), rikkunshito (2501,000 mg/kg), or components of rikkunshito (L-arginine, isoliquiritigenin, hesperidin, or 3,3',4'5,6,7,8-heptamethoxyflavone (HMF)) (1-20 mg/kg) were administered orally 60 or 30 min before the liquid meal. Results: Liquid meal significantly decreased intrabag pressure 5-20 min after administration when compared with baseline levels. The 1,000 mg/kg rikkunshito, but not 250 or 500 mg/kg, promoted a decrease in intrabag pressure with the liquid meal, indicating the improvement of gastric accommodation. L-NNA dose-dependently inhibited decreases in intrabag pressure with the liquid meal, and 10 mg/kg L-NNA completely prevented any meal-induced accommodation. Rikkunshito dose dependently ameliorated the effects of L-NNA. Isoliquiritigenin, but not hesperidin or HMF, significantly ameliorated the gastric accommodation inhibited by L-NNA. L-arginine tended to ameliorate the inhibited gastric accommodation by L-NNA.Conclusions: Rikkunshito ameliorates impaired gastric accommodation by a NOS inhibitor in conscious guinea pigs, and that action is partly mediated by isoliquiritigenin.