title: Urocortin prevents indomethacin-induced small intestinal lesions in rats through activation of CRF2 receptors.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kubo
authors.forename: Aiko
authors.initials: A
authors.lastname: Kumano
authors.forename: Kohei
authors.initials: K
authors.lastname: Kamei
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Naoko
authors.initials: N
authors.lastname: Abe
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage; D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin; D007275:Injections, Intravenous; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010437:Peptic Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000633:toxicity; D009195:Peroxidase / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D054832:Urocortins / Q000008:administration & dosage*; D000099052:CRF Receptor, Type 1
chemical_list: C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D000814:Aniline Compounds; C101531:CRF receptor type 2; D005765:Gastrointestinal Agents; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011743:Pyrimidines; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C528574:astressin-2B; C104416:astressin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007213:Indomethacin
references.citation: Brain Res. 2001 Mar 2;893(1-2):29-35
references.pmid: 11222989
references.citation: J Pharmacol Exp Ther. 1997 Feb;280(2):754-60
references.pmid: 9023288
references.citation: J Clin Endocrinol Metab. 2004 Nov;89(11):5352-61
references.pmid: 15531481
references.citation: J Pharmacol Exp Ther. 2002 May;301(2):611-7
references.pmid: 11961064
references.citation: J Immunol. 2006 Sep 1;177(5):3355-61
references.pmid: 16920976
references.citation: Br J Pharmacol. 2002 May;136(2):237-47
references.pmid: 12010772
references.citation: Exp Parasitol. 1974 Oct;36(2):307-15
references.pmid: 4416737
references.citation: Science. 1981 Sep 18;213(4514):1394-7
references.pmid: 6267699
references.citation: Eur J Surg Suppl. 2002;(587):16-22
references.pmid: 16144197
references.citation: Peptides. 2004 Oct;25(10):1733-44
references.pmid: 15476940
references.citation: Peptides. 2007 Jul;28(7):1453-60
references.pmid: 17586086
references.citation: Am J Physiol. 1992 Jan;262(1 Pt 1):G137-43
references.pmid: 1733259
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7647-52
references.pmid: 15883387
references.citation: Digestion. 2002;66(1):30-41
references.pmid: 12379813
references.citation: J Physiol. 2004 Apr 1;556(Pt 1):221-34
references.pmid: 14755002
references.citation: Nature. 1995 Nov 16;378(6554):287-92
references.pmid: 7477349
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Mar;280(3):G406-19
references.pmid: 11171623
references.citation: Gastroenterology. 2002 Aug;123(2):505-15
references.pmid: 12145804
references.citation: Pharmacol Rev. 2003 Mar;55(1):21-6
references.pmid: 12615952
references.citation: J Clin Invest. 2007 Jan;117(1):33-40
references.pmid: 17200704
references.citation: J Clin Invest. 1989 Jul;84(1):36-42
references.pmid: 2661590
references.citation: Br J Pharmacol. 1993 Nov;110(3):1189-95
references.pmid: 7507778
references.citation: Br J Pharmacol. 1995 Oct;116(4):2286-90
references.pmid: 8564261
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Nov;283(5):G1082-9
references.pmid: 12381521
references.citation: FASEB J. 2006 Sep;20(11):1877-9
references.pmid: 16855006
references.citation: Dig Dis Sci. 2006 Jul;51(7):1250-9
references.pmid: 16944022
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7570-5
references.pmid: 11416224
references.citation: Am J Physiol. 1987 Oct;253(4 Pt 1):G582-6
references.pmid: 2821826
references.citation: Annu Rev Pharmacol Toxicol. 2004;44:525-57
references.pmid: 14744257
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10575-9
references.pmid: 7479843
references.citation: Biochem Biophys Res Commun. 2005 Oct 28;336(3):731-6
references.pmid: 16061206
references.citation: Dig Dis Sci. 1986 Oct;31(10):1114-22
references.pmid: 3463496
references.citation: Inflammation. 1993 Dec;17(6):641-62
references.pmid: 7906675
references.citation: J Clin Endocrinol Metab. 2003 Jan;88(1):478-83
references.pmid: 12519893
references.citation: Am J Physiol. 1999 Apr;276(4):G867-74
references.pmid: 10198329
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2843-8
references.pmid: 11226328
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G173-7
references.pmid: 11208537
references.citation: Am J Physiol. 1999 Apr;276(4):G1027-36
references.pmid: 10198347
references.citation: Eur J Pharmacol. 2003 Feb 28;463(1-3):235-72
references.pmid: 12600714
references.citation: Pharmacol Res. 1999 Dec;40(6):517-24
references.pmid: 10660951
references.citation: J Pharmacol Exp Ther. 2002 Mar;300(3):754-61
references.pmid: 11861778
references.citation: Regul Pept. 1990 Apr 24;28(2):137-51
references.pmid: 2343161
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G34-40
references.pmid: 11751155
references.citation: Am J Physiol Regul Integr Comp Physiol. 2001 Nov;281(5):R1401-10
references.pmid: 11641109
references.citation: J Pharmacol Exp Ther. 1999 Aug;290(2):629-34
references.pmid: 10411571
references.citation: Gastroenterology. 1981 Jan;80(1):94-8
references.pmid: 6778761
references.citation: Regul Pept. 1985 Jul;11(3):193-9
references.pmid: 3877318
references.citation: Endocrinology. 2005 Nov;146(11):5003-11
references.pmid: 16081642
references.citation: Gastroenterology. 2000 Dec;119(6):1569-79
references.pmid: 11113078