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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Investigation into the Potential Anti-Inflammatory Effects of Endothelin Antagonists in a Murine Model of Experimental Monosodium Urate Peritonitis

Stephen J. Getting, Clara Di Filippo, Connie W. Lam, Francesco Rossi and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 90-97; DOI: https://doi.org/10.1124/jpet.104.065573
Stephen J. Getting
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Clara Di Filippo
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Connie W. Lam
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Francesco Rossi
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Michele D'Amico
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Abstract

Endothelin (ET)-1 has been detected in many inflammatory pathologies, including rheumatoid arthritic patients, asthma, and ischemic-reperfusion injury. In this study, we have investigated the effect of a panel of different ET-1 antagonists displaying different selectivities for the receptors in a murine model of experimental inflammatory peritonitis. Systemic treatment of mice with the ETA antagonist C33H44N6O5, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-l-leucyl]-1-methyl-d-tryptophyl]-3-(2-pyridinyl)-d-alanine (FR139317) inhibited neutrophil accumulation. However, a greater degree of inhibition was observed with the ETB antagonist C34H51N5O7, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-d-Trp(1-methoxycarbonyl)-d-Nle-OH (BQ-788) and the ET(A and B) antagonist C52H65N7O10, N-acetyl-α-[10,11-dihydro-5H-dibenzo-[a,d]cycloheptadien-5-yl]-d-Gly-Leu-Asp-lle-lle-Trp (PD145065); all these effects occurred without altering peripheral blood cell counts. Release of the CXC chemokine KC was significantly reduced by the FR139317 and PD145065 but not by BQ-788. Evaluation of the therapeutic potential of these antagonists showed that PD145065 inhibited neutrophil migration and KC release, whereas the others caused a nonsignificant reduction in these parameters. Parameters of endothelial cell activation showed that urate-stimulated interleukin-1β release was inhibited by BQ-788 and PD145065 but not by FR139317, whereas ET-1 was only inhibited by the mixed antagonist. A different scenario was observed with respect to release of the CXC chemokine KC with FR139317 and PD145065 being effective, whereas with a marker of polymorphonuclear activation the ETA and mixed antagonist inhibited adhesion molecule expression. These data show that ET-1 antagonists elicit different mechanisms of actions in the way they display their antimigratory effects in a murine model of monosodium urate crystal peritonitis.

Footnotes

  • This work was supported by the Arthritis Research Campaign UK (Grant G0571). S.J.G. is also a recipient of the Visiting Fellowship of the Second University of Naples.

  • DOI: 10.1124/jpet.104.065573.

  • ABBREVIATIONS: MSU, monosodium urate; PMN, polymorphonuclear; ET, endothelin; FR139317, C33H44N6O5, N-[N-[-N(hexahydro-1H-azepin-1-yl)carbonyl]-l-leucyl]-1-methyl-d-tryptophyl]-3-(2-pyridinyl)-d-alanine); BQ-788, C34H51N5O7, N-cis-2,6-dimethylpiperidinocarbonyl-b-tBu-Ala-d-Trp(1-methoxycarbonyl)-d-Nle-OH; PD145065, C52H65N7O10, N-acetyl-α-[10,11-dihydro-5H-dibenzo[a,d]cycloheptadien-5-yl]-d-Gly-Leu-Asp-lle-lle-Trp; MØ, macrophage; ELISA, enzyme-linked immunosorbent assay; PBS, phosphate-buffered saline; IL, interleukin; EIA, enzyme immunoassay; PAF, platelet-activating factor; LUI135252, darusentan; IRL-1038, H-Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp-OH; SB209670, (+)-(1s,2R,3S)-3-()-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indene-2-carboxylic acid.

    • Received January 16, 2004.
    • Accepted March 2, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Investigation into the Potential Anti-Inflammatory Effects of Endothelin Antagonists in a Murine Model of Experimental Monosodium Urate Peritonitis

Stephen J. Getting, Clara Di Filippo, Connie W. Lam, Francesco Rossi and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 90-97; DOI: https://doi.org/10.1124/jpet.104.065573

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Investigation into the Potential Anti-Inflammatory Effects of Endothelin Antagonists in a Murine Model of Experimental Monosodium Urate Peritonitis

Stephen J. Getting, Clara Di Filippo, Connie W. Lam, Francesco Rossi and Michele D'Amico
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 90-97; DOI: https://doi.org/10.1124/jpet.104.065573
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