title: The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric mucosa protection in mice--involvement of the soluble guanylate cyclase/K(ATP) pathway.
abstract: Here, we have evaluated the protective effect of the NO donor cis-[Ru(bpy)2(SO3)NO](PF6) (FOR0810) in experimental models of gastric damage induced by naproxen or ethanol in mice, and the involvement of soluble guanylate cyclase (sGC) and ATP-sensitive K(+) channels (KATP) in these events. Swiss mice were pre-treated with saline, ODQ (a soluble guanylate cyclase inhibitor; 10 mg kg(-1)) or glibenclamide (a KATP channels blocker; 10 mg kg(-1)). After either 30 min or 1 h, FOR0810 (3 mg kg(-1)) was administered. At the end of 30 min, the animals received naproxen (300 mg kg(-1)) by gavage. After 6 h, the animals were sacrificed and gastric damage, myeloperoxidase (MPO) activity, and TNF-α and IL-1β gastric concentrations were evaluated. In addition, the effects of FOR0810 on naproxen-induced mesenteric leukocyte adherence were determined by intravital microscopy. Other groups, were pre-treated with saline, ODQ or glibenclamide. After either 30 min or 1 h, FOR0810 was administered. At the end of 30 min, the animals received 50% ethanol by gavage. After 1 h, the animals were sacrificed, and gastric damage, gastric reduced glutathione (GSH) concentration and malondialdehyde (MDA) levels were determined. In naproxen-induced gastric damage, FOR0810 prevented gastric injury, decreased gastric MPO activity and leukocyte adherence, associated with a decrease in TNFα and IL-1β gastric concentrations. FOR0810 also prevented ethanol-induced gastric damage by increase in GSH levels and decrease in MDA levels. ODQ and glibenclamide completely reversed FOR0810's ability to prevent gastric damage by either naproxen or ethanol. We infer that FOR0810 prevented gastric damage through the activation of both sGC and KATP channels, which triggered a decrease in both free radical and cytokine production via the blocking of neutrophil adhesion and infiltration.
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Ana Paula M
authors: AP
authors: Santana
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Bruno M
authors: BM
authors: Tavares
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Larisse T
authors: LT
authors: Lucetti
authors: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Florêncio S
authors: FS
authors: Gouveia
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Ronaldo A
authors: RA
authors: Ribeiro
authors: Department of Morphology, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Pedro M G
authors: PM
authors: Soares
authors: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Eduardo H S
authors: EH
authors: Sousa
authors: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil.
authors: Luiz G F
authors: LG
authors: Lopes
authors: Department of Biotechnology and Biodiversity Center Research, Federal University of Piauí, Parnaíba, PI, Brazil.
authors: Jand-Venes R
authors: JV
authors: Medeiros
authors: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil. Electronic address: souzamar@ufc.br.
authors: Marcellus H L P
authors: MH
authors: Souza
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives; D000818:Animals; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced; D054086:KATP Channels / Q000378:metabolism*; D051379:Mice; D009288:Naproxen / Q000009:adverse effects; D009566:Nitrates / Q000032:analysis; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology*; D009573:Nitrites / Q000032:analysis; D009942:Organometallic Compounds; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D016207:Cytokines; D054086:KATP Channels; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009942:Organometallic Compounds; D020011:Protective Agents; D018160:Receptors, Cytoplasmic and Nuclear; C103599:bis(bipyridyl)ruthenium(II); D000431:Ethanol; D015082:2,2'-Dipyridyl; D009288:Naproxen; D009195:Peroxidase; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: ATP-sensitive K(+) channels; Ethanol; Gastric defense; NSAIDs; Nitric oxide donor; Soluble guanylate cyclase