Abstract

BackgroundAspirin exerts side effects within the gastrointestinal tract. Hydrogen sulfide (H2S) 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 H2S-releasing NaHS and CO-releasing tricarbonyldichlororuthenium(II) dimer (CORM-2) against aspirin-induced injury.MethodsWistar 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 NG-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-1β, 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.ResultsAspirin 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.ConclusionsWe conclude that H2S- 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.

Highlights

  • Aspirin is the most popular representative among the nonsteroidal anti-inflammatory drugs (NSAIDs), which, exerts side effects within the gastrointestinal tract, including hemorrhagic microbleedings and gastric erosions [1,2,3,4]

  • We conclude that H2S- but not carbon monoxide (CO)-mediated gastroprotection against aspirin-induced injury involves afferent sensory nerves and partly nitric oxide (NO) activity

  • We aimed to investigate the involvement of afferent sensory neurons, calcitonin-gene-related peptide (CGRP), and vanilloid receptor 1 in gastroprotection of H2S released from NaHS and CO released from tricarbonyldichlororuthenium(II) dimer (CORM-2) and the accompanying changes in gastric blood flow (GBF) with regard to experimental gastric lesions induced by aspirin

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Summary

Introduction

Aspirin is the most popular representative among the nonsteroidal anti-inflammatory drugs (NSAIDs), which, exerts side effects within the gastrointestinal tract, including hemorrhagic microbleedings and gastric erosions [1,2,3,4]. The gaseous mediators hydrogen sulfide (H2S), carbon monoxide (CO), and nitric oxide (NO) were reported to afford gastroprotection against injury induced by noxious agents but the mechanism of this beneficial action of these molecules has not been fully elucidated [5,6,7,8,9,10]. The H2S-releasing derivatives of NSAIDs, such as ATB-346, exert an anti-inflammatory effect similar to that of the parent drugs (naproxen in the case of ATB346) but cause pronouncedly fewer side effects as compared with the native form of the drug This indicates the usefulness of this new class of H2S derivatives of NSAIDs and the potential safety and possible translation to clinical settings [14]. We determined the involvement of afferent sensory neurons, calcitonin-gene-related peptide (CGRP), lipid peroxidation, and nitric oxide (NO) biosynthesis in gastroprotection of H2S-releasing NaHS and CO-releasing tricarbonyldichlororuthenium(II) dimer (CORM-2) against aspirin-induced injury

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