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PD123319, angiotensin II type II receptor antagonist, inhibits oxidative stress and inflammation in 2, 4-dinitrobenzene sulfonic acid-induced colitis in rat and ameliorates colonic contractility

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Abstract

Angiotensin II, the main effector of renin angiotensin system, plays an important role in the inflammatory process and most of its effects are mediated through the AT1 receptor activation. However, the knowledge about the AT2 receptor involvement in this process is still evolving. We previously found that in an experimental model of colitis, AT2 receptor activation can contribute to the impairment of the muscle contractility in vitro in the course of inflammation. Here, we investigated the potential alleviating effects of the in vivo treatment of PD123319 (1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate), AT2 receptor antagonist, in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat model of colitis. The effects of i.p PD123319 (0.3, 3 and 10 mg/kg) administration to rats subjected to intra-rectal DNBS instillation were investigated. The study revealed that the colon injury and the inflammatory signs were ameliorated by PD123319 when visualized by the histopathological examination. The colon shortening, myeloperoxidase activity, and colonic expression of IL-1β, IL-6 and iNOS were downregulated in a dose-dependent manner in DNBS-induced colitis rats treated with PD123319 and the anti-oxidant defense machinery was also improved. The mechanism of these beneficial effects was found in the ability of PD123319 to inhibit NF-κB activation induced by DNBS. The colonic contractility in inflamed tissues was also improved by PD123319 treatment. In conclusion, our data have demonstrated previously that undescribed proinflammatory effects for the AT2 receptors in DNBS-induced colitis in rats in which they are mediated likely by NF-κB activation and reactive oxygen species generation. Moreover, when the inflammatory process is mitigated by the AT2 receptor antagonist treatment, the smooth muscle is able to recover its functionality.

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Funding

This work was supported by a grant (FFR 2012/2013) from the University of Palermo, Italy.

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Authors and Affiliations

  1. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Viale delle Scienze, 90128, Palermo, Italy

    Maria Grazia Zizzo & Rosa Serio

  2. ATeN (Advanced Technologies Network) Center, Viale delle Scienze, 90128, Palermo, Italy

    Maria Grazia Zizzo & Annalisa Bellanca

  3. University of Palermo, Palermo, Italy

    Gaetano Caldara

  4. Institute of Biomedicine and Molecular Immunology “Alberto Monroy” (IBIM), Consiglio Nazionale delle Ricerche (CNR), 90146, Palermo, Italy

    Domenico Nuzzo & Marta Di Carlo

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  1. Maria Grazia Zizzo
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Correspondence to Maria Grazia Zizzo.

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Zizzo, M.G., Caldara, G., Bellanca, A. et al. PD123319, angiotensin II type II receptor antagonist, inhibits oxidative stress and inflammation in 2, 4-dinitrobenzene sulfonic acid-induced colitis in rat and ameliorates colonic contractility. Inflammopharmacol 28, 187–199 (2020). https://doi.org/10.1007/s10787-019-00619-z

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