Physiology&Behavior,Vol. 47, pp. 197-202. ¢ Pergamon Press plc, 1990. Printed in the U.S.A.

0031-9384/90 $3.00 + .00

Effect of an Endogenous Satiety Substance, 2-Buten-4-Olide, on Gastric Acid Secretion and Experimental Ulceration in Rats IWAO ARAI, CHIKA USUKI-ITO, MAKOTO MURAMATSU, SUSUMU OTOMO, TAKEMASA SHIRAISHI* AND YUTAKA OOMURA¢

Research Center, Taisho Pharmaceutical Co., Ltd. 1-403, Yoshino-cho, Ohmiya, Saitama 330 *Department of Physiology, Tokai University School of Medicine, Bohseidai, Isehara 259-11 "~Department of Central Nervous Function Control System Toyama Medical and Pharmaceutical University, Toyama, 930-01 Institute of Bio-active Substance, Nihon Zoki Co. Hyogo, 673-14 Japan R e c e i v e d 3 O c t o b e r 1989

ARAI, I., C. USUKI-ITO, M. MURAMATSU, S. OTOMO, T. SHIRAISHI AND Y. OOMURA. Effect of an endogenoussatiety substance, 2-buten-4-olide, on gastric acid secretion and experimental ulceration in rats. PHYSIOL BEHAV 47(1) 197-202, 1990.--The involvement of a feeding-related endogenous sugar acid, 2-buten-4-olide (2-B40) on central regulation of gastric acid secretion, and its antiulcer effects on several gastric and duodenal experimental ulcer models were investigated in rats. Spontaneous gastric acid secretion was not affected by 2-B40 at doses below 10 mg/kg. The peripheral secretagogue-stimulated gastric secretions were significantly increased by pretreatment with 2-B40. Gastric acid secretion induced by 2-deoxy-D-glucose (2-DG) was significantly suppressed by pretreatment with 2-B40 at doses between 0.1 and 100 mg/kg. Gastric and duodenal ulcerations induced by cold stress plus indomethacin, restraint and water immersion stress, pylorus ligation or cysteamine were also inhibited by pretreatment with 2-B40. The results suggest that antiulcer effects of 2-B40 are due to suppression of gastric acid secretion via reduction of activity of the vagus nerve and gastric-related hypothalamic neurons. Thus, 2-B40 may be useful for treatment of gastroduodenal ulcer. Endogenous sugar acid 2-Buten-4-olide Feeding control 2-Deoxy-D-glucose

Ulcer

Vagus

IT is well known that various stressful situations cause gastric lesions in men and animals. An important factor related to ulceration induced by stress is the increase in gastric acid secretion (12,35). Stress induces significant functional changes in the stomach via the autonomic nervous system. Gastric acid secretion is strongly influenced by activity of the vagus nerve and gastricrelated hypothalamic neurons (17, 27-29). Stress loading and administration of insulin or 2-deoxy-D-glucose (2-DG) (6, 8, 13, 25, 30) cause vagus-mediated gastric acid secretion. Vagotomy inhibits stress-induced gastric acid secretion (1, 15, 32, 34). Recently, we reported that restraint- and water immersion stressinduced gastric acid secretion is correlated with brain glucose uptake, and suggested that this gastric acid secretion is a consequence of excitation of gastric-type lateral hypothalamic glucose sensitive neurons, as insulin-stimulated gastric acid secretion (3) is. On the other hand, two short chain sugar acids, 3,4-dihydroxybutanoic acid lactone (3,4-DB), and 2,4,5-trihydroxypentanoic acid lactone (3,4,5-TP) have been identified in the serum of fasted

Rat

Gastric acid secretion

Stress

rats (24). Previous evidence suggests that 3,4-DB and 3,4,5-TP act as endogenous satiety and hunger substances, respectively (24). It has also been reported that electrophoretically applied 3,4-DB significantly and specifically suppresses 2-DG-induced gastric acid secretion and the activity of gastric type of glucose sensitive neurons in the lateral hypothalamic area (26). Intravenous 3,4-DB, however, has no effect on the amount of food eaten by rats because of its low penetration of the blood-brain barrier (24). Recently, 2-buten-4-olide (2-B40), a synthetic derivative of 3,4-DB, has been found in the serum of both men and rats (20,21); its penetration of the blood-brain barrier permits suppression of food intake (21). In the present study we investigated the effects of 2-B40 on gastric acid secretion and ulceration, and discuss the possibility of its use as an antiulcer drug. METHOD

Animals Tests were performed on 440 male Wistar rats, weighing

197

198

ARAI ET AL.

180-250 g. Animals were fasted but allowed free access to water for 18 hours before the experiments. Measurement of Gastric Acid Secretion Two experimental methods were used in this study. 1) Basal gastric acid secretion was examined in conscious rats with pylorus ligation. 2) Gastric acid secretion stimulated by secretagogues was examined in stomach perfusate from rats anesthetized with urethane (1.25 g/kg, SC). Gastric acid secretion in pylorus-ligated rats (23). After rats were anesthetized with ether, the abdomen was incised and the pylorus was ligated. Four hours after the pylorus ligation, the animals were killed, the gastric contents were collected, and the volume and acidity were measured. Acidity was determined by titration with 0.01 N NaOH using phenolphthalein as the indicator. Gastric acid secretion in stomach perfusate of anesthetized rats. Measurement of the gastric acid secretion was performed according to the procedure described by Maeda-Hagiwara and Watanabc (16) with slight modification. The trachea was exposed and cannulated. A dual polyethylene gastric cannula was inserted into the gastric lumen after ligation of the pylorus. The inlet and outlet tubes of the dual cannula were connected to a saline reservoir and the stomach was continuously perfused at a rate of 10 ml/min with saline solution (adjusted to pH 7.0 with NaOH) through the gastric cannula using a perfusion pump. The perfusate was titrated in the reservoir with 0.01 N NaOH at pH 7.0 using an automatic titrator (GT-05, Mitsubishi Kasei) with a personal computer (PC-9800, NEC). The acid output during the 5-min period in the perfusate was continuously recorded for 8 hours. Gastric acid secretion was induced by 2-DG, methacholine, gastrin and histamine.

O[ ...... 2-deoxy-D-g&~ose 300rng/kg, s.c.

~oiB N-6

tO :E

Q.

2-deoxy-D-glucose 300 rng/k~ &c. 2-[340 1 rng/kg, i.p.

Effect of an endogenous satiety substance, 2-buten-4-olide, on gastric acid secretion and experimental ulceration in rats.

The involvement of a feeding-related endogenous sugar acid, 2-buten-4-olide (2-B4O) on central regulation of gastric acid secretion, and its antiulcer...
552KB Sizes 0 Downloads 0 Views