The nitric oxide donor cis-[Ru(bpy) 2 (SO 3 )NO](PF 6 ) increases gastric mucosa protection in mice – Involvement of the soluble guanylate cyclase/KATP pathway Ana Paula M. Santana a , Bruno M. Tavares a , Larisse T. Lucetti a , Florêncio S. Gouveia Jr. b , Ronaldo A. Ribeiro a , Pedro M.G. Soares c , Eduardo H.S. Sousa b , Luiz G.F. Lopes b , Jand-Venes R. Medeiros d , Marcellus H.L.P. Souza a, * a Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, CE, Brazil b Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, CE, Brazil c Department of Morphology, Federal University of Ceará, Fortaleza, CE, Brazil d Department of Biotechnology and Biodiversity Center Research, Federal University of Piauí, Parnaíba, PI, Brazil ARTICLE INFO Article history: Available online Keywords: Gastric defense NSAIDs Ethanol Nitric oxide donor Soluble guanylate cyclase ATP-sensitive K + channels A B ST R AC T 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 sac- rificed 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 adher- ence 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 pre- vented 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. © 2015 Published by Elsevier Inc. 1. Introduction The gastric mucosa is exposed to various noxious substances and resists damage from hydrochloric acid, hot and cold foodstuffs with different osmolarities, anti-inflammatory drugs (NSAIDs) and ethanol [1]. In the gastrointestinal tract, the use of NSAIDs and ethanol de- creases gastroprotective mechanisms, such as mucus secretion and blood flow [2] resulting in mucosal injury and gastrointestinal bleeding [3,4], by different mechanisms. Naproxen increases the levels of inflammatory mediators and induces neutrophil migra- tion to the gastric mucosa, which are the more important mechanisms to the NSAID-induced gastric injury [5]. On the other hand in ethanol-induced gastric damage, the most important effects are an increase in reactive oxygen species generation and a de- crease in endogenous anti-oxidant defense mechanisms [6,7]. Nitric oxide (NO) is a very important mediator of gastric mucosal defense [8]. Many effects of NO on the gastrointestinal tract seem to depend on the activation of the NO/cGMP/KATP pathway [4,9]. The chemical properties of this molecule enable the synthesis of a wide variety of NO-donors, each with a different rates of NO release [1,8]. In recent years, new metal complexes have been investigated re- garding their ability to work as NO donors, including nitrosyl ruthenium complexes [10–14]. * Corresponding author. Department of Physiology and Pharmacology, Federal University of Ceará, Street Cel. Nunes de Melo, 1315, Rodolfo Teófilo, Fortaleza, CE CEP 60.430-270, Brazil. Fax: +55 85 33668588. E-mail address: souzamar@ufc.br (M.H.L.P. Souza). http://dx.doi.org/10.1016/j.niox.2015.02.002 1089-8603/© 2015 Published by Elsevier Inc. Nitric Oxide ■■ (2015) ■■–■■ ARTICLE IN PRESS Please cite this article in press as: Ana Paula M. Santana, et al., The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric mucosa protection in mice – Involvement of the soluble guanylate cyclase/KATP pathway, Nitric Oxide (2015), doi: 10.1016/j.niox.2015.02.002 Contents lists available at ScienceDirect Nitric Oxide journal homepage: www.elsevier.com/locate/yniox Q2 Q1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75