Urocortin prevents indomethacin-induced small intestinal lesions in rats through activation of CRF2 receptors.
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.
Kubo
Yoshikazu
Y
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
Kumano
Aiko
A
Kamei
Kohei
K
Amagase
Kikuko
K
Abe
Naoko
N
Takeuchi
Koji
K
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
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
Brain Res. 2001 Mar 2;893(1-2):29-35
11222989
J Pharmacol Exp Ther. 1997 Feb;280(2):754-60
9023288
J Clin Endocrinol Metab. 2004 Nov;89(11):5352-61
15531481
J Pharmacol Exp Ther. 2002 May;301(2):611-7
11961064
J Immunol. 2006 Sep 1;177(5):3355-61
16920976
Br J Pharmacol. 2002 May;136(2):237-47
12010772
Exp Parasitol. 1974 Oct;36(2):307-15
4416737
Science. 1981 Sep 18;213(4514):1394-7
6267699
Eur J Surg Suppl. 2002;(587):16-22
16144197
Peptides. 2004 Oct;25(10):1733-44
15476940
Peptides. 2007 Jul;28(7):1453-60
17586086
Am J Physiol. 1992 Jan;262(1 Pt 1):G137-43
1733259
Proc Natl Acad Sci U S A. 2005 May 24;102(21):7647-52
15883387
Digestion. 2002;66(1):30-41
12379813
J Physiol. 2004 Apr 1;556(Pt 1):221-34
14755002
Nature. 1995 Nov 16;378(6554):287-92
7477349
Am J Physiol Gastrointest Liver Physiol. 2001 Mar;280(3):G406-19
11171623
Gastroenterology. 2002 Aug;123(2):505-15
12145804
Pharmacol Rev. 2003 Mar;55(1):21-6
12615952
J Clin Invest. 2007 Jan;117(1):33-40
17200704
J Clin Invest. 1989 Jul;84(1):36-42
2661590
Br J Pharmacol. 1993 Nov;110(3):1189-95
7507778
Br J Pharmacol. 1995 Oct;116(4):2286-90
8564261
Am J Physiol Gastrointest Liver Physiol. 2002 Nov;283(5):G1082-9
12381521
FASEB J. 2006 Sep;20(11):1877-9
16855006
Dig Dis Sci. 2006 Jul;51(7):1250-9
16944022
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7570-5
11416224
Am J Physiol. 1987 Oct;253(4 Pt 1):G582-6
2821826
Annu Rev Pharmacol Toxicol. 2004;44:525-57
14744257
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10575-9
7479843
Biochem Biophys Res Commun. 2005 Oct 28;336(3):731-6
16061206
Dig Dis Sci. 1986 Oct;31(10):1114-22
3463496
Inflammation. 1993 Dec;17(6):641-62
7906675
J Clin Endocrinol Metab. 2003 Jan;88(1):478-83
12519893
Am J Physiol. 1999 Apr;276(4):G867-74
10198329
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2843-8
11226328
Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G173-7
11208537
Am J Physiol. 1999 Apr;276(4):G1027-36
10198347
Eur J Pharmacol. 2003 Feb 28;463(1-3):235-72
12600714
Pharmacol Res. 1999 Dec;40(6):517-24
10660951
J Pharmacol Exp Ther. 2002 Mar;300(3):754-61
11861778
Regul Pept. 1990 Apr 24;28(2):137-51
2343161
Am J Physiol Gastrointest Liver Physiol. 2002 Jan;282(1):G34-40
11751155
Am J Physiol Regul Integr Comp Physiol. 2001 Nov;281(5):R1401-10
11641109
J Pharmacol Exp Ther. 1999 Aug;290(2):629-34
10411571
Gastroenterology. 1981 Jan;80(1):94-8
6778761
Regul Pept. 1985 Jul;11(3):193-9
3877318
Endocrinology. 2005 Nov;146(11):5003-11
16081642
Gastroenterology. 2000 Dec;119(6):1569-79
11113078