title: The Protective Role of Carbon Monoxide (CO) Produced by Heme Oxygenases and Derived from the CO-Releasing Molecule CORM-2 in the Pathogenesis of Stress-Induced Gastric Lesions: Evidence for Non-Involvement of Nitric Oxide (NO).
abstract: Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1-10 mg/kg oral gavage (i.g.)), RuCl₃ (1 mg/kg i.g.), zinc protoporphyrin IX (ZnPP) (10 mg/kg intraperitoneally (i.p.)), hemin (1-10 mg/kg i.g.) and CORM-2 (1 mg/kg i.g.) combined with N(G)-nitro-l-arginine (l-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.), indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.), and celecoxib (10 mg/kg i.g.) affects gastric lesions following 3.5 h of water immersion and restraint stress (WRS). Gastric blood flow (GBF), the number of gastric lesions and gastric CO and nitric oxide (NO) contents, blood carboxyhemoglobin (COHb) level and the gastric expression of HO-1, HO-2, hypoxia inducible factor 1α (HIF-1α), tumor necrosis factor α (TNF-α), cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) were determined. CORM-2 (1 mg/kg i.g.) and hemin (10 mg/kg i.g.) significantly decreased WRS lesions while increasing GBF, however, RuCl₃ was ineffective. The impact of CORM-2 was reversed by ZnPP, ODQ, indomethacin, SC-560 and celecoxib, but not by l-NNA. CORM-2 decreased NO and increased HO-1 expression and CO and COHb content, downregulated HIF-1α, as well as WRS-elevated COX-2 and iNOS mRNAs. Gastroprotection by CORM-2 and HO depends upon CO's hyperemic and anti-inflammatory properties, but is independent of NO.
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. k.jasnos@interia.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Magierowska
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. m.magierowski@uj.edu.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Magierowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. marcin.surmiak@uj.edu.pl.|Division of Molecular Biology and Clinical Genetics, Department of Medicine, Jagiellonian University Medical College, 31-006 Cracow, Poland. marcin.surmiak@uj.edu.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Surmiak
authors.affiliation: Department of Forensic Toxicology, Institute of Forensic Research, 31-033 Cracow, Poland. juliusz.adamski@gmail.com.
authors.forename: Juliusz
authors.initials: J
authors.lastname: Adamski
authors.affiliation: Department of Ergonomics and Exercise Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-531 Cracow, Poland. agnieszka.mazur@uj.edu.pl.
authors.forename: Agnieszka Irena
authors.initials: AI
authors.lastname: Mazur-Bialy
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. mppajdo@cyf-kr.edu.pl.
authors.forename: Robert
authors.initials: R
authors.lastname: Pajdo
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. agazs@poczta.fm.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Sliwowski
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. skwiecien@cm-uj.krakow.pl.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecien
authors.affiliation: Department of Physiology, Jagiellonian University Medical College, 31-531 Cracow, Poland. mpbrzozo@cyf-kr.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000097:blood / Q000378:metabolism*; D000068579:Celecoxib / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009942:Organometallic Compounds; D011524:Protoporphyrins; D011720:Pyrazoles; D012333:RNA, Messenger; C115461:SC 560; C447082:tricarbonyldichlororuthenium (II) dimer; C017803:zinc protoporphyrin; D019335:Nitroarginine; D009569:Nitric Oxide; D006427:Hemin; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D006419:Heme Oxygenase (Decyclizing); D051546:Cyclooxygenase 2; D000068579:Celecoxib; D007213:Indomethacin
keywords: carbon monoxide; cyclooxygenases; gastric blood flow; gastroprotection; heme oxygenase-1; hypoxia inducible factor 1α; nitric oxide; soluble guanylyl cyclase; stress