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Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice

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Abstract

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ETA and ETB receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ETB receptor antagonism, but rather by endothelin ETA receptor antagonism. Furthermore, endothelin ETA, but not ETB, receptor antagonism inhibited antigen-induced PGE2 production, whereas either selective or combined blockade of endothelin ETA and/or ETB receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.

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Acknowledgments

We thank Ieda R.S. Schivo, Giuliana B. Francisco, and Sérgio R. Rosa for technical assistance. We also thank Actelion Pharmaceuticals Ltd (Allschwil, Switzerland) for the generous gift of bosentan. This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Pesquisa, and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior, Brazil. WAVJ and TMC contributed equally to this work.

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  1. Waldiceu A. Verri Jr

    Present address: Departamento de Ciências Patológicas, Centro de Ciências Biologicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid Pr 445, KM 380, Cx. Postal 6001, 86051-990, Londrina, Parana, Brazil

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Waldiceu A. Verri Jr, Thiago M. Cunha, Danilo A. Magro, Ana T. G. Guerrero, Silvio M. Vieira, Guilherme R. Souza, Sérgio H. Ferreira & Fernando Q. Cunha

  2. Department of Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil

    Vanessa Carregaro

  3. Departamento de Farmacologia Aplicada, FarManguinhos, Fiocruz, Rio de Janeiro, Brazil

    Maria das Graças M. O. Henriques

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  1. Waldiceu A. Verri Jr
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Correspondence to Waldiceu A. Verri Jr or Fernando Q. Cunha.

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Verri Jr, W.A., Cunha, T.M., Magro, D.A. et al. Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice. Naunyn-Schmied Arch Pharmacol 379, 271–279 (2009). https://doi.org/10.1007/s00210-008-0360-1

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