title: Involvement of corticotropin-releasing factor and corticotropin-releasing factor 2 receptors in pathogenesis of ischemia/reperfusion-induced enteritis in rats.
abstract: We herein investigated, using a corticotropin-releasing factor (CRF) agonist and antagonists, whether CRF plays a role in the pathogenesis of ischemia/reperfusion-induced small intestinal lesions in rats. Under pentobarbital anesthesia, the superior mesenteric artery was clamped (ischemia) for 75 min, followed by reperfusion with removal of the clamp. After a 24-h reperfusion, the area of hemorrhagic lesions that developed in the small intestine was measured. Urocortin I (CRF receptor 1/2 agonist), astressin (CRF receptor 1/2 antagonist), NBI27914 (CRF receptor 1 antagonist), or astressin 2B (CRF receptor 2 antagonist) was administered i.v. twice: 5 min before ischemia and 6 hours after reperfusion. Ischemia/reperfusion caused hemorrhagic lesions in the small intestine in ampicillin- and aminoguanidine-inhibitable manners, accompanied by enterobacterial invasion and the up-regulation of inducible nitric oxide synthase expression and myeloperoxidase activity. The severity of ischemia/reperfusion-induced lesions was significantly reduced by astressin and astressin 2B, but not by NBI27914, with the suppression of bacterial invasion, myeloperoxidase activity, and inducible nitric oxide synthase expression. In contrast, urocortin I markedly aggravated these lesions, and this response was completely abrogated by the co-administration of astressin 2B, but not NBI27914. The gene expression of CRF, CRF receptor 1, and CRF receptor 2 was observed in the small intestine, and remained unchanged following ischemia/reperfusion. These results suggest that ischemia/reperfusion caused hemorrhagic lesions in the small intestine, the pathogenesis of which involved enterobacteria and inducible nitric oxide synthase/nitric oxide. These lesions were aggravated by urocortin I in an astressin 2B-inhibitable manner, but suppressed by astressin in a CRF receptor 2-dependent manner. Endogenous CRF may be involved in the pathogenesis of ischemia/reperfusion-induced enteritis, possibly via the activation of peripheral CRF receptor 2.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp.|General Incorporated Association, Kyoto Research Center for Gastrointestinal Diseases, Karasuma-Oike, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kumano
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Abe
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kotani
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D004751:Enteritis / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D004755:Enterobacteriaceae / Q000302:isolation & purification; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D015427:Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat