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

• Published in: Nitric oxide 2015-02, Vol.45, p.35-42
• Main Authors: Santana, Ana Paula M, Tavares, Bruno M, Lucetti, Larisse T, Gouveia, Jr, Florêncio S, Ribeiro, Ronaldo A, Soares, Pedro M G, Sousa, Eduardo H S, Lopes, Luiz G F, Medeiros, Jand-Venes R, Souza, Marcellus H L P
• Format: Article
• Language: English
• Subjects: 2,2'-Dipyridyl - analogs & derivatives; Animals; Cytokines - analysis; Cytokines - metabolism; Ethanol - adverse effects; Gastric Mucosa - drug effects; Gastric Mucosa - metabolism; Guanylate Cyclase - metabolism; Inflammation - chemically induced; KATP Channels - metabolism; Mice; Naproxen - adverse effects; Nitrates - analysis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; Nitrites - analysis; Organometallic Compounds; Peroxidase - analysis; Peroxidase - metabolism; Protective Agents - chemistry; Protective Agents - pharmacology; Receptors, Cytoplasmic and Nuclear - metabolism; Soluble Guanylyl Cyclase
• ISSN: 1089-8611
• DOI: 10.1016/j.niox.2015.02.002

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.