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)

Int J Mol Sci. 2016 Mar 24;17(4):442. doi: 10.3390/ijms17040442.


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.

Keywords: carbon monoxide; cyclooxygenases; gastric blood flow; gastroprotection; heme oxygenase-1; hypoxia inducible factor 1α; nitric oxide; soluble guanylyl cyclase; stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Monoxide / blood
  • Carbon Monoxide / metabolism*
  • Celecoxib / pharmacology
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / metabolism*
  • Heme Oxygenase (Decyclizing) / antagonists & inhibitors
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Hemin / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Indomethacin / pharmacology
  • Male
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Nitroarginine / pharmacology
  • Organometallic Compounds / chemistry
  • Organometallic Compounds / pharmacology*
  • Protoporphyrins / pharmacology
  • Pyrazoles / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Stress, Physiological*


  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Organometallic Compounds
  • Protoporphyrins
  • Pyrazoles
  • RNA, Messenger
  • SC 560
  • tricarbonyldichlororuthenium (II) dimer
  • zinc protoporphyrin
  • Nitroarginine
  • Nitric Oxide
  • Hemin
  • Carbon Monoxide
  • Nitric Oxide Synthase Type II
  • Heme Oxygenase (Decyclizing)
  • Cyclooxygenase 2
  • Celecoxib
  • Indomethacin