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Mechanisms Involved in Protection Afforded by l-Arginine in Ibuprofen-Induced Gastric Damage: Role of Nitric Oxide and Prostaglandins

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Abstract

l-Arginine (l-arg) exhibits multiple biological properties and plays an important role in the regulation of different functions in pathological conditions. Many of these effects could be achieved on this amino acid serving as a substrate for the enzyme nitric oxide synthase (NOS). At the gastrointestinal level, recent reports revealed its protective activities involving a hyperemic response increasing the gastric blood flow. The aim of this study was to characterize the relationship between NOS activity/expression and prostaglandin changes (PGs) in rats gastric mucosa, with l-arg associated resistance to the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (IBP). The protective effect of oral l-arg (100 mg/kg body wt), administerred together with IBP (100 mg/kg body wt, per os), was evident enough 90 min after drug administration, although a significant protection persisted for more than 6 hr. Pretreatment with NG-nitro-l-arginine (l-NNA) (40 mg/kg body wt, intraperitoneally), a competitive inhibitor of constitutive NOS, partly altered the protection afforded by the amino acid. In contrast, no changes could be observed after inducible NOS inhibition [aminoguanidine (AG) 50 mg/Kg body wt, intraperitoneally). l-arg, plus IBP, produced a significant increase of the cyclic GMP (cGMP) response in tissue samples from rat stomach, 90 min and 6 h after drug administration. iNOS activity and mRNA expression were higher in IBP-treated rats, and no differences were observed in inducible responses in the l-arg plus IBP group. No variations in the cNOS activity and expression were found among the different groups of animals assayed. The measurement of mucosal PGE2 content confirmed that biosynthesis of the eicosanoid is maintained by l-arg for over 90 min after IBP, while a total inhibition was observed 6 hr later. The mechanisms of the l-arg protective effect on the damaged induced by IBP could be explained by the different period after drug administration. The early phase is mediated by cyclooxygenase/prostaglandins pathway (COX/PGs) although NO liberated by cNOS and the guanylate cyclase/cGMP pathway could be also relevant. The later phase implicates inhibition of the iNOS/NO response.

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Authors and Affiliations

  1. Department of Pharmacology, University of Seville, Seville, Spain

    Dolores Jiménez, M. José Martin, José Esteban & Antonio Esteras

  2. Faculty of Pharmacy, University of Seville, Seville, Spain

    Dolores Jiménez, M. José Martin, José Esteban & Antonio Esteras

  3. Department of Biochemistry and Molecular Biology, University of Seville, Seville, Spain

    David Pozo & Catalina Alarcón

  4. Zambón Group, Barcelona, Spain

    Leo Bruseghini

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  1. Dolores Jiménez
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Jiménez, D., Martin, M.J., Pozo, D. et al. Mechanisms Involved in Protection Afforded by l-Arginine in Ibuprofen-Induced Gastric Damage: Role of Nitric Oxide and Prostaglandins. Dig Dis Sci 47, 44–53 (2002). https://doi.org/10.1023/A:1013203217788

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