title: Time-dependent changes in inhibitory action of lipopolysaccharide on intestinal motility in rat.
abstract: Endotoxin causes gastrointestinal motility disorder. Aim of this study is to clarify inhibitory mechanisms of lipopolysaccharide (LPS) on smooth muscle contraction in rat ileum. Ileal tissues were isolated from control rat or from LPS-induced peritonitis model rat. Treatment with LPS inhibited carbachol (CCh)-mediated contraction in a time-dependent manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes were also upregulated, but iNOS expression was preceded by a rising of COX-2. All subtypes of prostaglandin E2 (PGE2) receptors (EP1-EP4) were expressed in ileum, and PGE2 and selective EP2 or EP4 agonist inhibited CCh-mediated contraction. Selective iNOS inhibitor did not reverse LPS-induced inhibition of contraction by CCh at 1 and 2 hr, but reduced the inhibitory action at 4 hr after the LPS treatment. COX-2 inhibitor reversed the inhibitory action by LPS in all exposure time. Finally, in ileal tissues isolated from peritonitis model rat, iNOS expression was upregulated only at 4 hr after LPS administration, resulting in enhanced inhibitory action of LPS against CCh-induced contraction. In conclusion, LPS induces COX-2 to produce PGE2, which initially activates EP2 and/or EP4 on smooth muscle cells to inhibit the contractility in early phase of LPS exposure. Moreover, in late phase of LPS treatment, iNOS is expressed to produce NO, which in turn inhibited the contraction by CCh. The inhibitory cascade is similar in the ileum isolated from peritonitis model rat, indicating time-dependent changes of inhibitory action by LPS on intestinal motility in peritonitis.
authors.affiliation: Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shoma
authors.initials: S
authors.lastname: Mikawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ohta
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kaji
authors.forename: Md Shafiqul
authors.initials: MS
authors.lastname: Islam
authors.forename: Takahisa
authors.initials: T
authors.lastname: Murata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ozaki
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hori
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D015971:Gene Expression Regulation, Enzymologic; D007082:Ileum / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced* / Q000473:pathology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C561931:CAY 10580; D008070:Lipopolysaccharides; D011760:Pyrrolidinones; D012333:RNA, Messenger; C016767:sulprostone; D002217:Carbachol; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone