Influence of adrenalectomy on protective effects of urocortin I, a corticotropin-releasing factor (CRF)-related peptide, against indomethacin-induced enteropathy in rats

Abstract

The influence of adrenalectomy on indomethacin-induced enteropathy in rats was examined and the possible involvement of adrenal glucocorticoids in protective effects of urocortin I, a CRF agonist, was investigated. Male SD rats were administered indomethacin (10 mg/kg) s.c., killed 24 h later, and small intestines were examined for hemorrhagic lesions. Urocortin I (20 μg/kg) was given i.v. 10 min before indomethacin. Bilateral adrenalectomy was performed a week before the experiment. Indomethacin caused hemorrhagic lesions in small intestines, accompanied by intestinal hypermotility, enterobacterial invasion and iNOS expression. Adrenalectomy markedly increased ulcerogenic and motility responses caused by indomethacin, with further enhanced bacterial invasion and iNOS expression. This worsening effect was reproduced by pretreatment with mifepristone. Urocortin I prevented indomethacin-induced enteropathy; this effect was abrogated by astressin 2B, a CRF2 receptor antagonist, but was not affected by either adrenalectomy or mifepristone pretreatment. These results suggest that adrenalectomy aggravates indomethacin-induced enteropathy, and intestinal hypermotility response may be the key element in the mechanism underlying this aggravation, while endogenous glucocorticoids play a role in intestinal mucosal defense against these lesions but do not account for protective effects of urocortin I, which are mediated by peripheral CRF2 receptors.