Urocortin Prevents Indomethacin-induced Small Intestinal Lesions in Rats Through Activation of CRF2 Receptors

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2009 Aug 27

PMID 19707872

Citations 6

Authors

Yoshikazu Kubo

Aiko Kumano

Kohei Kamei

Kikuko Amagase

Naoko Abe

Koji Takeuchi

Affiliations

Soon will be listed here.

Abstract

Purpose: The role of corticotropin-releasing factor (CRF) in the pathogenesis of indomethacin-induced small intestinal lesions was examined in rats.

Methods: Animals were given indomethacin (10 mg/kg) subcutaneously and killed 24 h later. Urocortin I [a nonselective CRF receptor (CRFR) agonist], astressin (a nonselective CRFR antagonist), NBI-27914 (a CRFR1 antagonist), or astressin-2B (a CRFR2 antagonist) was given intravenously 10 min before the administration of indomethacin.

Results: Indomethacin caused hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility, mucosal invasion of enterobacteria, up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of mucosal myeloperoxidase (MPO) activity. Pretreatment of the animals with astressin, a non-selective CRFR antagonist, aggravated the lesions in a dose-dependent manner. Likewise, astressin-2B also exacerbated the intestinal ulcerogenic response induced by indomethacin, while NBI-27914 did not. Urocortin I prevented indomethacin-induced intestinal lesions, together with the suppression of bacterial invasion and an increase in mucosal MPO activity and iNOS expression; these effects were significantly reversed by co-administration of astressin-2B but not NBI-27914. Urocortin I suppressed the hypermotility response to indomethacin, and this effect was also abrogated by astressin-2B but not NBI-27914.

Conclusions: These results suggest that urocortin 1 prevents indomethacin-induced small intestinal lesions, and that this action is mediated by the activation of CRFR2 and is functionally associated with the suppression of the intestinal hypermotility response caused by indomethacin. It is assumed that endogenous CRF contributes to the maintenance of the mucosal defensive ability of the small intestine against indomethacin through the activation of CRFR2.

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