Possible involvement of hyperinsulinemia and adrenergic activation in the pathogenesis of indomethacin-induced antral ulcers in nonfasted hamsters and refed rats

K Kuratani, M Yamazaki, H Kodama and I Yamaguchi

Tsukuba Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Ibaraki, Japan.

Subcutaneous doses of indomethacin (IND) produced mainly antral ulcers in refed rats, almost exclusively corpus erosions in fasted rats, but no antral or corpus mucosal insult in nonfasted rats. In contrast, IND- treatment in nonfasted hamsters caused antral ulcers but minimal corpus erosions. Mild and severe hyperinsulinemia were observed in refed rats and nonfasted hamsters, respectively. The hyperinsulinemia and antral ulcers in the animals were significantly attenuated by a pretreatment (80 mg/kg, i.v., in rats, 60 mg/kg, i.p., in hamsters) of streptozotocin. Furthermore, the antral ulcers were dose-dependently attenuated by prazosin, an adrenergic alpha-1 antagonist, and yohimbine, an adrenergic alpha-2 antagonist, but not by propranolol, an adrenergic beta antagonist. The large doses of atropine (3.2-10 mg/kg, p.o.) also attenuated the ulcers. The histamine H2 receptor antagonist, famotidine (1-10 mg/kg, p.o.), significantly attenuated the antral ulcers in nonfasted hamsters, but not in refed rats. The latter two drugs exhibited greater inhibition of the corpus erosions in fasted rats compared with the antral ulcers in refed rats and nonfasted hamsters. The corpus erosions were more extensive after streptozotocin treatment (80 mg/kg, i.v.) and were aggravated significantly by yohimbine, whereas they were hardly affected by prazosin or propranolol. It is thus concluded that hyperinsulinemia and adrenergic activation are commonly involved in the etiology of the IND-induced antral ulcers in refed rats and nonfasted hamsters. Vagal activity, which plays a crucial role in the etiology of the corpus erosions in fasted rats, may play a part in the antral ulcer formation in nonfasted hamsters, but not in refed rats.

Volume 263, Issue 3, pp. 951-955, 12/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics