title: Role of soluble guanylate cyclase activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats.
abstract: Our objective was to evaluate the role of soluble guanylate cyclase (sGC) activation in the gastroprotective effect of the HO-1/CO pathway against alendronate-induced gastric damage in rats. Rats were pretreated, once daily for 4 days, with saline, hemin (HO-1 inducer), or dimanganese decacarbonyl (DMDC, CO donor). Another group received zinc protoporphyrin IX (ZnPP IX, HO-1 antagonist) 1 h before hemin treatment or sGC inhibitor (ODQ) 30 min before hemin and DMDC treatment. After 30 min, gastric damage was induced by alendronate (30 mg/kg) by gavage. On the last day of treatment, 4 h after alendronate administration, the animals were killed. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1β), myeloperoxidase (MPO), or bilirubin. Another group was used to measure gastric mucus. HO-1 expression was determined after saline or alendronate administration by immunohistochemistry. Alendronate induced gastric damage, produced neutrophil accumulation, increased MDA levels and MPO activity, and reduced GSH and mucus in the gastric tissue. Alendronate also increased HO-1 immunoreactivity and the level of bilirubin in gastric mucosa. Pretreatment with hemin or DMDC reduced neutrophil infiltration and TNF-α, IL-1β, and MDA formation, and increased the levels of GSH and mucus in the gastric tissue. ODQ completely abolished the gastroprotective effect of hemin and DMDC and increased alendronate gastric damage. Our results suggest that the HO-1/CO pathway plays a protective role against alendronate-induced gastric damage through mechanisms that can be dependent on sGC activation.
authors.affiliation: Biotechnology and Biodiversity Center Research (BIOTEC), Federal University of Piauí, Campus of Parnaíba, Av. São Sebastião, 2819, CEP: 64202-020, Parnaíba-PI, Brazil.
authors.forename: Natália R D
authors.initials: NR
authors.lastname: Costa
authors.forename: Renan O
authors.initials: RO
authors.lastname: Silva
authors.forename: Lucas A D
authors.initials: LA
authors.lastname: Nicolau
authors.forename: Larisse T
authors.initials: LT
authors.lastname: Lucetti
authors.forename: Ana Paula M
authors.initials: AP
authors.lastname: Santana
authors.forename: Karoline S
authors.initials: KS
authors.lastname: Aragão
authors.forename: Pedro M G
authors.initials: PM
authors.lastname: Soares
authors.forename: Ronaldo A
authors.initials: RA
authors.lastname: Ribeiro
authors.forename: Marcellus H L P
authors.initials: MH
authors.lastname: Souza
authors.forename: André L R
authors.initials: AL
authors.lastname: Barbosa
authors.forename: Jand-Venes R
authors.initials: JV
authors.lastname: Medeiros
mesh_terms: D019386:Alendronate / Q000009:adverse effects*; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D019386:Alendronate