Nitric oxide, afferent sensory nerves, and antioxidative enzymes in the mechanism of protection mediated by tricarbonyldichlororuthenium(II) dimer and sodium hydrosulfide against aspirin-induced gastric damage

Abstract

Background Aspirin exerts side effects within the gastrointestinal tract. Hydrogen sulfide (H 2 S) and carbon monoxide (CO) have been implicated in gastroprotection but the mechanism of beneficial action of these gaseous mediators against aspirin-induced damage has not been fully studied. We determined the involvement of afferent sensory neurons, calcitonin-gene-related peptide (CGRP), lipid peroxidation, and nitric oxide (NO) biosynthesis in gastroprotection of H 2 S-releasing NaHS and CO-releasing tricarbonyldichlororuthenium(II) dimer (CORM-2) against aspirin-induced injury. Methods Wistar rats with or without capsaicin-induced denervation of sensory neurons were pretreated with vehicle, CORM-2 (5 mg/kg intragastrically), or NaHS (5 mg/kg intragastrically) with or without capsazepine (5 mg/kg intragastrically) or N G -nitro-L-arginine (L-NNA, 20 mg/kg intraperitoneally). The areas of aspirin-induced lesions and gastric blood flow (GBF) were assessed by planimetry and laser flowmetry respectively. Gastric mucosal messenger RNA and/or protein expression of CGRP, heme oxygenase 1, inducible nitric oxide synthase, cyclooxygenase 2, interleukin-1b, glutathione peroxidase 1 (GPx-1), and superoxide dismutase was determined by real-time PCR or Western blot. Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) content was determined by colorimetric assay. Results Aspirin caused gastric lesions, decreased GBF, and raised MDA content, but pretreatment with NaHS and CORM-2 reduced these effects. Capsaicin-induced denervation or co-treatment with capsazepine reversed the gastroprotective and vasodilatory effects of NaHS but not those of CORM-2. L-NNA reversed NaHS-induced gastroprotection and partly reduced CORM-2-induced gastroprotection. NaHS and CORM-2 decreased MDA and 4-HNE content, restoring GPx-1 protein expression. Conclusions We conclude that H 2 S-but not CO-mediated gastroprotection against aspirin-induced injury involves afferent sensory nerves and partly NO activity. NaHS and CORM-2 prevented aspirin-induced gastric mucosal lipid peroxidation via restoration of microcirculation and antioxidative GPx-1 protein expression.

Carbon monoxide released from its pharmacological donor, tricarbonyldichlororuthenium (II) dimer, accelerates the healing of pre‐existing gastric ulcers

“…Indeed, co‐treatment of CORM‐2 with l ‐NNA, a non‐selective NOS inhibitor, reduced the rate of ulcer healing and increase in GBF evoked by this CO donor. This observation is in line with previously published evidence showing that the inhibition of NOS reduced the gastroprotective effect of CORM‐2 against aspirin‐induced injury (Magierowski et al ., ). Moreover, the peripheral antinociceptive effect of the HO/CO pathway and possibly its contribution to gastroprotection could be mediated by the activation of K ATP channels (Pereira de Ávila et al ., ).…”

“…Our results correspond with previous studies, which revealed that IL‐1β, TNF‐α mRNA and HIF‐1α mRNA and protein expressions were down‐regulated in gastric mucosa pretreated with CORM‐2 and compromised by stress, the administration of alendronate or aspirin (Magierowski et al ., ; Magierowski et al ., ,b). Additionally, CORM‐2 protected the gastric mucosa against aspirin‐induced lesions, downregulating the protein expression of iNOS (Magierowski et al ., ). This indicates that CO releasing CORM‐2 activity in ulcer healing involves similar factors and mechanisms to those observed in CO‐mediated gastroprotection.…”

“…Pretreatment with CORM‐2 dose‐dependently reduced the formation of gastric lesions induced by stress, and this protective effect was accompanied by an increase in GBF (Magierowska et al ., ). Furthermore, CORM‐2 was effective in protecting the gastric mucosa against damage induced by ulcerogenes such as ethanol, alendronate and aspirin (Magierowska et al ., ; Magierowski et al ., ,b; ). Interestingly, haemin dose‐dependently reduced stress‐ or ethanol‐induced gastric damage formation, while ZnPP exerted opposite effects (Magierowska et al ., ; ).…”

“…), the K ATP s inhibitor (Silva et al, 2014). The doses of ODQ, L-NNA, indomethacin and glibenclamide were selected based on previously published data (Silva et al, 2014;Magierowska et al, 2015;Magierowski et al, 2016a;2017a). CORM-2, ZnPP, ODQ or haemin were dissolved in DMSO and saline (1:10) (Magierowski et al, 2016a), while other chemicals and drugs were dissolved in saline.…”

Guided bone regeneration with asymmetric collagen-chitosan membranes containing aspirin-loaded chitosan nanoparticles

“…19 However, systemic drugs, repeatedly used over a long period of time, have potential side effects and may lead to the development of bacterial resistance and local inadequate drug concentrations in the periodontal tissue and gingival crevicular fluid. 24 The long-term use of aspirin may cause side effects in the gastrointestinal tract including hemorrhagic micro-bleeding and gastric erosion; 25,26 and low-dose and topical applications of aspirin to treat disease would be very promising. An aspirin-loaded chitosan nanoparticle has been prepared and used to demonstrate that aspirin can be slowly and controllably released from the composite particles in vitro.…”